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Finding the Intracellular Signaling Pathways Affected by Mood Disorder Treatments
Abstract
Postmortem and brain imaging studies have revealed structural changes and cell loss in cortico-limbic regions of the brain in bipolar disorder and major depression. Consistent with these findings, mood stabilizers such as lithium ion and valproic acid, which are used to treat bipolar disorder, as well as antidepressants and electroconvulsive therapy have recently been shown to activate interconnected intracellular signaling pathways that promote neurogenesis and synaptic plasticity. These insights should assist in understanding the pathophysiology of severe mood disorders as well as aid in the development of more effective treatments.
... The MAPK signalling pathway has been shown to be involved in neuronal differentiation and axon growth [29]. The MAPK pathway has also been implicated in the development of depression [30], as the inhibition of MAPK signalling inducing depressive-like behaviours [31]. Indeed, some pharmacological treatments for depression activate the MAPK signalling pathway [32]. ...
... Interestingly, these effects appeared to be region-specific, as increased progenitor cell population in the rostral hippocampus and intact LTP in the Schaffer collateral pathway were also found in Smad3-null mice [51]. Similarly, increased levels of TGF-β reduced neurogenesis in vitro and in vivo at rates largely similar to that in Smad3-deficient animals [9,30,53,54]. Contrary to these findings, it was shown that knockout of TGF-β receptor activin receptor-like kinase 5 (ALK5) resulted in decreased neurogenesis, whereas upregulation of ALK5 resulted in greater neurogenesis and improved memory functions [55]. This indicates that the components in the canonical pathway, especially Smad3, potentially plays a role in memory and cognitive functions and may regulate neurogenesis differentially in various parts of the brain. ...
TGF-β/Smad signalling has been the subject of extensive research due to its role in the cell cycle and carcinogenesis. Modifications to the TGF-β/Smad signalling pathway have been found to produce disparate effects on neurogenesis. We review the current research on canonical and non-canonical TGF-β/Smad signalling pathways and their functions in neurogenesis. We also examine the observed role of neurogenesis in neuropsychiatric disorders and the relationship between TGF-β/Smad signalling and neurogenesis in response to stressors. Overlapping mechanisms of cell proliferation , neurogenesis, and the development of mood disorders in response to stressors suggest that TGF-β/Smad signalling is an important regulator of stress response and is implicated in the behavioural outcomes of mood disorders.
... __________________ 101 Figure 37 : L'hypothèse des monoamines : les différents acteurs et les données expérimentales (Chopra et al. 2011 Figure 38 : L'axe HPA dans la dépression (Belmaker and Agam 2008). ________________________________________ 110 Figure 39 : Voies intracellulaires modulées par les antidépresseurs (Coyle and Duman 2003). _____________ 112 Figure Moyen Age (Grandmougin et al. 1997). ...
... Le récepteur du BDNF est TrkB (Tyrosine-related kinase B)(Castren and Rantamaki 2010). Son activation induit les voies de signalisation MAPK (mitogenactivated protein kinase) et PI3K (phosphatidylinositol-3 kinase)/Akt(Duman et al. 2000;Coyle and Duman 2003). L'effecteur terminal de ces voies de signalisation est CREB (cAMP response element-binding). ...
La mutation à l’origine de la maladie de Huntington (MH) correspond à une expansion anormale de glutamines sur la protéine huntingtine (HTT). La MH est caractérisée par des symptômes moteurs et cognitifs mais également des troubles psychiatriques tels que l’anxiété et la dépression.Au cours de ma thèse, j’ai montré que la HTT module le statut anxio-dépressif de la souris via ses phosphorylations aux sérines 1181/1201. En effet, l’ablation des phosphorylations sur la HTT endogène améliore significativement le phénotype anxio-dépressif de la souris. Chez la souris, cette modulation dépend d’une augmentation de la maturation et de la survie des nouveaux neurones dans l’hippocampe. En effet, l’irradiation focale de l’hippocampe, dans un contexte où les phosphorylations sont absentes, supprime la neurogenèse et la réduction du statut anxio-dépressif observée en l’absence de phosphorylations. Au niveau moléculaire, la HTT non phosphorylée accroît l’association des moteurs moléculaires et des vésicules de BDNF sur les microtubules, ce qui augmente les dynamiques et la libération du BDNF. Ceci active la voie de signalisation MAPK/CREB dans l’hippocampe, cette voie pouvant ainsi stimuler la neurogenèse.J’ai ensuite étudié le rôle de ces phosphorylations dans un contexte MH et j’ai démontré l’effet anxiolytique/antidépresseur de l’absence de ces phosphorylations.J’ai également montré le rôle de ces phosphorylations de la HTT au cours du développement du cortex embryonnaire.Les résultats obtenus au cours de ma thèse suggèrent que les mécanismes fondamentaux de neurogenèse sont régulés par la HTT et ses phosphorylations. De plus, ils identifient une nouvelle voie de modulation de l’anxiété/dépression faisant intervenir la HTT.
... We observed downregulation of the WNT receptors FZD8 and FZD9 and upregulation of the WNT receptor ligand WNT5A. The -catenin/WNT pathway is regulated by antidepressants and antipsychotics Coyle and Duman, 2003). Opposing regulation of the FZD receptors and Wnt ligand makes it difficult to determine the functional consequences on Wnt signaling in postmortem tissue. ...
... Opposing regulation of the FZD receptors and Wnt ligand makes it difficult to determine the functional consequences on Wnt signaling in postmortem tissue. However, the possible significance of altered Wnt signaling is highlighted by studies demonstrating that a major downstream effector of this pathway, glycogen synthase kinase-3, is inhibited by lithium as well as antidepressant drugs Coyle and Duman, 2003). ...
... Furthermore, in clinical and animal studies, HIIT was found to increase the expression of peroxisome proliferator-activated receptorgamma coactivator-1alpha (PGC-1α), thereby increasing the expression of fibronectin type III domain-containing protein 5 (FNDC5); thus, the further release of BDNF was promoted (Agudelo et al., 2014;Little et al., 2011;Wrann et al., 2013). The released BDNF subsequently reverses neuronal death due to depression via the BDNF-TrkB-PI3k-Akt and BDNF-TrkB-MAPK/ERK signaling pathways and also increasing neurogenesis and synaptic activity, thus treating depressive symptoms (Coyle & Duman, 2003;Fries et al., 2022). ...
Background
The exact causal mechanisms of depression remain unclear due to the complexity of the triggers, which has led to limitations in treating depression using modern drugs. High-intensity interval training (HIIT) is as effective as medication in treating depression without toxic side effects. Typically, HIIT requires less time commitment (i.e., shorter exercise duration) and exhibits pronounced benefits on depressive symptoms than other forms of physical exercise. This review summarizes the risk reduction and clinical effects of HIIT for depression and discusses the underlying mechanisms, providing a theoretical basis for utilizing HIIT in treating depression.
Methods
A database search was conducted in PubMed, Embase, Web of Science, and Scopus from inception up to October 2022. The methodological quality of the included literature was evaluated by the physiotherapy evidence database (PEDro) scale criteria. The review focused on evaluating the changes in depression risk or symptoms of HIIT interventions in healthy individuals, patients with depression, and patients with other disorders co-morbid with depression. Consequently, the mechanisms associated with depression related HIIT were summarized.
Results
A total of 586 participants (52 % female; mean age: 43.58±8.93 years) from 22 studies were included. Implementing HIIT using different exercise types alleviates depressive symptoms in individuals with depression and in individuals with depression who have exhibited comorbidities and reduced depression scale scores in subjects immediately after acute exercise. In addition, the long-interval HIIT and short-interval HIIT in the treatment of patients with cardiovascular or psychiatric disorders may reduce depressive symptoms via complex exercise-related changes on several levels, including by effecting the following measures: releasing monoamines, reducing neuronal death, inducing neurogenesis, modulating the functional homeostasis of the HPA axis, and enhancing the level of inflammation in the body.
Conclusion
HIIT is a relatively safe and effective antidepressant, which may involve multiple neurobiological mechanisms (release of monoamines, reducing neuronal death, inducing neurogenesis, modulating the functional homeostasis of the HPA axis, and enhancing the level of inflammation in the body), thereby reducing the risk or symptoms of depression in participants.
... Understanding how lithium impacts these pathways is a complex task, as these pathways interact with one another in intricate ways. Additionally, the specific effects of lithium can vary depending on factors such as dosage, treatment duration, and an individual's unique biology [83] [84][85] [86]. Lithium's ability to modulate intracellular signaling pathways is a key component of its therapeutic potential, but it's important to note that these pathways are just one piece of the puzzle in understanding how lithium works to stabilize mood and cognition in individuals with bipolar disorder. ...
Lithium is a naturally occurring element in the Earth's crust and is also found in trace amounts within the human body. The exact amount of lithium present in the human body can vary, but it's generally estimated to be around 7 to 30 micrograms (µg) per liter of blood. This small amount is not enough to have a noticeable impact on the body's overall chemistry. Lithium carbonate is a compound that contains the element lithium, along with carbon and oxygen. It is commonly used as a medication to treat bipolar disorder and other mood disorders due to its mood-stabilizing effects. Lithium carbonate helps balance the levels of certain neurotransmitters in the brain, which can help manage the extreme mood swings associated with bipolar disorder. Lithium carbonate is usually prescribed in the form of oral tablets or capsules. The dosage is carefully determined by a healthcare professional based on the individual's specific needs and medical history. Regular blood tests are often conducted to monitor the levels of lithium in the bloodstream, as there is a narrow therapeutic range between an effective dose and a toxic dose. It's important for individuals taking lithium carbonate to be closely monitored by their healthcare provider and to follow the prescribed dosage and guidelines. As with any medication, lithium carbonate can have potential side effects, medication should not be started or stopped without medical supervision due to the potential for side effects and interactions with other medications.
... Currently, over 320 million people are affected by MDD worldwide (1). The neurobiological understanding of mood disorders has shifted its focus some 20 years ago from monoaminergic transmission to neural plasticity and resilience (2,3). Besides classical pharma-and psychotherapy, electroconvulsive therapy (ECT) has been established as effective treatment for MDD putatively via increase of adenosine concentrations (4). ...
Introduction
Sleep deprivation and electroconvulsive therapy (ECT) effectively ameliorate symptoms in major depressive disorder (MDD). In rodents, both are associated with an enhancement of cerebral adenosine levels, which in turn likely influence adenosinergic receptor expression. The aim of the current study was to investigate cerebral A1 adenosine receptor (A1AR) availability in patients with MDD as a potential mediating factor of antidepressant effects of ECT using [¹⁸F]CPFPX and positron emission tomography (PET).
Methods
Regional A1AR availability was determined before and after a series of ECT applications (mean number ± SD 10.4 ± 1.2) in 14 subjects (4 males, mean age 49.5 ± 11.8 years). Clinical outcome, measured by neuropsychological testing, and ECT parameters were correlated with changes in A1AR availability.
Results
ECT had a strong antidepressive effect (p < 0.01) while on average cerebral A1AR availability remained unaltered between pre-and post-ECT conditions (F = 0.65, p = 0.42, mean difference ± SD 3.93% ± 22.7%). There was no correlation between changes in clinical outcome parameters and regional A1AR availability, although individual patients showed striking bidirectional alterations of up to 30–40% in A1AR availability after ECT. Solely, for the mean seizure quality index of the applied ECTs a significant association with changes in A1AR availability was found (rs = −0.6, p = 0.02).
Discussion
In the present study, therapeutically effective ECT treatment did not result in coherent changes of A1AR availability after a series of ECT treatments. These findings do not exclude a potential role for cerebral A1ARs in ECT, but shift attention to rather short-termed and adaptive mechanisms during ECT-related convulsive effects.
... The result is that the signal is transferred to the nucleus and CREB is activated . Activated CREB could also continuously promote BDNF expression so that the two form a cyclic response (Coyle and Duman 2003). Therefore, antidepressant drugs could increase BDNF expression and further regulate the expression of key factors, such as MEK, ERK and CREB, to exert antidepressant effects. ...
Context
Fibraurea recisa Pierre. (Menispermaceae) (FR) is a traditional Chinese medicine known as “Huangteng.” The total alkaloids of FR (AFR) are the main active ingredients. However, the pharmacological effects of AFR in the treatment of depression have not been reported.
Objectives
This study investigates the antidepressant effects of AFR by network pharmacology and verification experiments.
Materials and methods
Compound-Target-Pathway (C-P-T) network of FR and depression was constructed through network pharmacology. In vitro, HT-22 cells were treated with corticosterone (CORT) solution (0.35 mg/mL), then AFR (0.05 mg/mL) solution and inhibitor AZD6244 (14 μM/mL) or BAY11-7082 (10 μM/mL) were added, respectively. The cell viability was detected by CCK-8. In vivo, C57BL/6 mice were divided into 5 groups, namely the normal group, the CUMS group, the AFR (400 mg/kg) group, and the 2 groups that were simultaneously administered the inhibitory group AZD6244 (8 mg/kg) and BAY11-7082 (5 mg/kg). Western blotting was used to assess the expression level of the proteins.
Results
AFR could protect HT-22 cells from CORT-induced damage and increase the cell viability from 49.12 ± 3.4% to 87.26 ± 1.5%. Moreover, AFR significantly increased the levels of BDNF (1.3, 1.4-fold), p-ERK (1.4, 1.2-fold) and p-CERB (1.6, 1.3-fold), and decreased the levels of NLRP3 (11.3%, 31.6%), ASC (19.2%, 34.2%) and caspase-1 (18.0%, 27.6%) in HT-22 cells and the hippocampus, respectively.
Discussion and conclusions
AFR can improve depressive-like behaviours and can develop drugs for depression treatment. Further studies are needed to validate its potential in clinical medicine.
... Mpp1 has been reported to regulate neutrophil polarization by AKT1 phosphorylation [74]. Depression can be regarded as an inflammatory disorder, whose pathophysiological mechanism is associated with AKT activity [75]. Mpp1, a skeleton protein in the erythrocyte membrane, belongs to the MAGUK family [76]. ...
Sleep disorder caused by abnormal circadian rhythm is one of the main symptoms and risk factors of depression. As a known hormone regulating circadian rhythms, melatonin (MT) is also namely N-acetyl-5-methoxytryptamine. N-acetylserotonin methyltransferase (Asmt) is the key rate-limiting enzyme of MT synthesis, and has been reportedly associated with depression. Although 50% to 90% of patients with depression have sleep disorders, there are no effective treatment ways in the clinic. Exercise can regulate circadian rhythm and play an important role in depression treatment. In the present study, we showed that Asmt knockout induced depression-like behaviors, which were ameliorated by swimming exercise. Moreover, swimming exercise increased serum levels of MT and 5-hydroxytryptamine (5-HT) in Asmt knockout mice. In addition, the microarray data identified 10 differentially expressed genes (DEGs) in KO mice compared with WT mice, and 29 DEGs in KO mice after swimming exercise. Among the DEGs, the direction and magnitude of change in epidermal growth factor receptor pathway substrate 8-like 1 (Eps8l1) and phospholipase C-β 2 (Plcb2) were confirmed by qRT-PCR partly. Subsequent bioinformatic analysis showed that these DEGs were enriched significantly in the p53 signaling pathway, long-term depression and estrogen signalling pathway. In the protein-protein interaction (PPI) networks, membrane palmitoylated protein 1 (Mpp1) and p53 induced death domain protein 1 (Pidd1) were hub genes to participate in the pathological mechanisms of depression and exercise intervention. These findings may provide new targets for the treatment of depression.
... DISC1 is likely to modulate neuronal and synaptic interactions by influencing neuronal migration, neurodevelopment, neurite growth and cAMP signaling Kamiya et al., 2005;Millar et al., 2005;Miyoshi et al., 2003). All of these factors may be associated with pathophysiology of schizophrenia (Coyle and Duman, 2003). ...
Background
The issue of genetic influence on schizophrenia has received considerable attention. The DISC1 gene has been shown in several studies to play a role in the pathophysiology of schizophrenia. However, the relationship between DISC1 mRNA expression vs. schizophrenia and its clinical symptoms is uncertain.
Methods
Fifty-six subjects (32 patients with schizophrenia and 24 healthy controls) were enrolled. Peripheral blood was obtained from all subjects to exam the DISC1 mRNA expression. Schizophrenia patients were evaluated with Hamilton Rating Scale for Depression (HAMD), Positive and Negative Syndrome Scale (PANSS), Brief Psychiatric Rating Scale (BPRS) and Scale for the Assessment of Negative Symptoms (SANS) scales. Healthy subjects were assessed with HAMD scale.
Results
Patients with schizophrenia had significantly lower levels of the DISC1 mRNA expression than the healthy control (P = 0.002). We also found that lower DISC1 mRNA levels in schizophrenia patients were associated with higher degree of depression in HAMD (P = 0.037), severer positive symptoms in PANSS (P = 0.032) and more negative symptoms in SANS (P = 0.038).
Conclusion
The results showed that schizophrenia patients had lower levels of DISC1 mRNA than healthy individuals, and that the schizophrenia patients with lower DISC1 mRNA levels were more likely to manifest more marked symptoms, including positive, negative, and depressive symptoms. The findings suggest that lower DISC1 expression may be related with the pathogenesis and phenotypes of schizophrenia. Future studies are needed to replicate the results and to further establish its potential role in clinical application of early diagnosis and outcome follow-up.
... MAPKs have been implicated in mood disorders and can scaffold with β-arrestin (21,22). Studies have suggested that MAPK signaling, specifically ERK1/2, in the hippocampus and the basolateral amygdala is required for the acquisition and extinction of fear memory (23,24). ...
G protein–coupled receptors (GPCRs) are implicated in the regulation of fear and anxiety. GPCR signaling involves canonical G protein pathways but can also engage downstream kinases and effectors through scaffolding interactions mediated by β-arrestin. Here, we investigated whether β-arrestin signaling regulates anxiety-like and fear-related behavior in mice in response to activation of the GPCR δ-opioid receptor (δOR or DOR). Administration of β-arrestin–biased δOR agonists to male C57BL/6 mice revealed β-arrestin 2–dependent activation of extracellular signal–regulated kinases 1 and 2 (ERK1/2) in the dorsal hippocampus and amygdala and β-arrestin 1–dependent activation of ERK1/2 in the nucleus accumbens. In mice, β-arrestin–biased agonist treatment was associated with reduced anxiety-like and fear-related behaviors, with some overlapping and isoform-specific input. In contrast, applying a G protein–biased δOR agonist decreased ERK1/2 activity in all three regions as well as the dorsal striatum and was associated with increased fear-related behavior without effects on baseline anxiety. Our results indicate a complex picture of δOR neuromodulation in which β-arrestin 1– and 2–dependent ERK signaling in specific brain subregions suppresses behaviors associated with anxiety and fear and opposes the effects of G protein–biased signaling. Overall, our findings highlight the importance of noncanonical β-arrestin–dependent GPCR signaling in the regulation of these interrelated emotions.
... Several studies have suggested that BDNF/TrkB induction is one of the mechanisms responsible for the therapeutic effects of antipsychotics, mood stabilizers, and antidepressants (Coyle and Duman 2003;Nibuya et al. 1995). For example, it has been shown that the use of lithium modulates the phosphorylation of the TrkB and CREB receptors (Rantamaki et al. 2006). ...
The biological bases of bipolar disorder include aspects related, among others, to neurohormonal pathways, neurotransmission, signal transduction, regulation of gene expression, oxidative stress, neuroplasticity, and changes in the immune system. There is still a gap in understanding its complex neurobiology and, consequently, developing new treatments. Multiple factors probably interact in this complex equation of pathophysiology of bipolar disorder, such as genetic, biochemical, psychosocial, and environmental stress events, correlating with the development and severity of the bipolar disorder. These mechanisms can interact to exacerbate inflammation, impair neurogenesis, and increase oxidative stress damage, cellular mitochondrial dysfunction, changes in neurotrophins and in epigenetic mechanisms, neuroendocrine dysfunction, activation of neuronal death pathways, and dysfunction in neurotransmission systems. In this review, we explore the up-to-date knowledge of the neurobiological underpinnings of bipolar disorders. The difficulty in developing new drugs for bipolar disorder is very much associated with the lack of knowledge about the precise pathophysiology of this disorder. Pharmacological treatment for bipolar patients is vital; to progress to effective medications, it is essential to understand the neurobiology in bipolar patients better and identify novel therapeutic targets.
... Therefore, the protein kinases, such as pERK1/2 investigated in the present study, could be considered as biomarkers reflecting pathophysiological processing of PTSD and the therapeutic efficacy of anti-PTSD treatments, including novel pharmacological therapy, such as atypical antipsychotic drugs. This consideration is also supported by other lines of evidence, confirming that ERK signal system plays a crucial role in protecting against impairments of neuroplasticity and in cellular resilience in the pathophysiology of manicdepressive illness (Manji et al. 2001, Coyle andDuman 2003). The mechanism of involvement of ERK cascade reaction in emotion and cognition is not well understood. ...
The purpose of this study was to determine preventive and protective effects of chronic orally administration with quetiapine (QUE) against anxiety-like behavior and cognitive impairments in rats exposed to the enhanced single prolonged stress (ESPS), an animal model that is used to study post-traumatic stress disorder (PTSD), and to detect changes in the expression of cortical phosphorylated p44/42 extracellular-regulated protein kinase (pERK1/2). Before or after exposure to ESPS paradigm, consisting of 2-h constraint, 20-min forced swimming, etherinduced loss of consciousness, and an electric foot shock, rats were given orally QUE (10 mg/kg daily) for 14 days. Animals were then tested in the open field (OF), elevated plus-maze (EPM), and Morris water maze (MWM). Brains were removed for immunohistochemical staining of pERK1/2. ESPS exposure resulted in pronounced anxiety-like behavior compared to unexposed animals. ESPS-exposed animals also displayed marked learning and spatial memory impairments. However, QUE treatment (both before and after ESPS exposure) significantly ameliorated anxiety-like behavior, learning and spatial memory impairments. ESPS also markedly reduced the expression of pERK1/2 in the prefrontal cortex, medial amygdala nucleus, and cingulate gyrus. Both before and after ESPS exposure QUE treatments significantly elevated the reduced pERK1/2 expression in the three brain regions. QUE has preventive and protective effects against stress-associated symptoms and the changes in pERK1/2 functions may be associated with the pathophysiology of traumatic stress and the therapeutic efficacy of anti-PTSD therapy.
... It is generally believed that depression is directly related to cellular resilience and impairments of structural plasticity [34]. Effective antidepressant drugs mainly regulate the cell signal transduction pathway to achieve therapeutic goal [35]. Noticeably, preclinical studies have shown that pro-inflammatory factors can even induce major depression in people without a history of mental disorders. ...
The treatments of nervous system diseases (NSDs) have long been difficult issues for researchers because of their complexity of pathogenesis. With the advent of aging society, searching for effective treatments of NSDs has become a hot topic. Ginseng polysaccharides (GP), as the main biologically active substance in ginseng, has various biological properties in immune-regulation, anti-oxidant, anti-inflammation and etc. Considering the association between the effects of GP and the pathogenesis of neurological disorders, many related experiments have been conducted in recent years. In this paper, we reviewed previous studies about the effects and mechanisms of GP on diseases related to nervous system. We found GP play an ameliorative role on NSDs through the regulation of immune system, inflammatory response, oxidative damage and signaling pathway. Structure-activity relationship was also discussed and summarized. In addition, we provided new insights into GP as promising neuroprotective agent for its further development and utilization.
... βArr2 in anxiety behavior. In addition, mitogen activated protein kinases, which have been shown to be involved in mood regulation, can scaffold with βArr (Coyle and Duman 2003;Lefkowitz and Shenoy 2005). ...
Early-life stress is correlated with the development of anxiety-related behavior in adolescence, but underlying mechanisms remain poorly known. The α 1A-adrenergic receptor (AR) is linked to mood regulation and its function is assumed to be regulated by β-arrestins (βArrs) via desensitization and downregulation. Here, we investigated correlation between changes in α 1A-AR and βArr2 levels in the prefrontal cortex (PFC) and hippocampus of adolescent and adult male rats subjected to maternal separation (MS) and their relationship with anxiety-like behavior in adolescence. MS was performed 3 h per day from postnatal days 2-11 and anxiety-like behavior was evaluated in the elevated plus-maze and open field tests. The protein levels were examined using western blot assay. MS decreased α 1A-AR expression and increased βArr2 expression in both brain regions of adolescent rats, while induced reverse changes in adulthood. MS adolescent rats demonstrated higher anxiety-type behavior and lower activity in behavioral tests than controls. Decreased α 1A-AR levels in MS adolescence strongly correlated with reduced time spent in the open field central area, consistent with increased anxiety-like behavior. An anxiety-like phenotype was mimicked by acute and chronic treatment of developing rats with prazosin, an α 1A-AR antagonist, suggesting α 1A-AR downregulation may facilitate anxiety behavior in MS adolescent rats. Together, our results indicate a negative correlation between α 1A-AR neurotransmission and βArr2 levels in both adults and anxious-adolescent rats and suggest that increased βArr2 levels may contribute to posttranslational regulation of α 1A-AR and modulation of anxiety-like behavior in adolescent rats. This may provide a path to develop more effective anxiolytic treatments.
... Multi-component therapy produces "synergies", in which the combined effects are greater than the sum of the individual effects. To our knowledge, the anti-depression mechanisms of active ingredients from TCM can be summed up as following: increasing synaptic availability of monoamines [13], alleviation of the HPA axis dysfunctions [14], regulation of the cAMP signaling pathway [15] and caspases [16], and amelioration of the dysregulation of immune and in ammation [17]. Ginseng has been shown to be a precious herbal medicine with dual activities of immune-regulation and anti-depression. ...
Introduction: The novel coronavirus disease 2019 (COVID-19) is in the midst of worldwide panic. Sudden onset of an immediate life-threatening illness, quarantine and unemployment caused by epidemic are all contributors to depression. Ginseng has been reported to be an effective and safe clinical treatment on both immune-regulation and anti-depression. However, the mechanism of its anti-depression effect has not been fully characterized. In order to provide theoretical guidance for further clinical application in post-pandemic, we investigated active compounds and pharmacological mechanisms of ginseng to exert anti-depressant activity using network pharmacology, and discussed the active ingredients with immune-regulation and anti-depression.
Methods: Information on compounds in ginseng was obtained from public databases, and genes related to depression were gathered using the GeneCards database. Networks of ginseng-associated targets and depression-related genes were constructed through STRING database. Potential targets and pathway enrichment analysis related to the therapeutic efficacy of ginseng for depression were identified using Cytoscape and Database for Annotation, Visualization and Integrated Discovery (DAVID).
Results: Network pharmacological analysis of ginseng in treatment of depression identified 16 active ingredients, 47 potential targets, 32 GO terms, and 8 target gene-regulated major pathways. Among them, kaempferol, beta-sitosterol, stigmasterol, fumarine and frutinone A are bioactive compounds and key chemicals. Core genes in PPI network were AKT1, CASP3, NOS3, TNF, and PPARG. Enrichment results revealed that ginseng could regulate multiple aspects of depression through neuroactive ligand-receptor interaction, HIF-1 signaling pathway, and Serotonergic synapse. More importantly, we found that frutinone A and kaempferol are key ingredients in ginseng with dual activities of immune-regulation and anti-depression.
Conclusions: We discovered that the therapeutic activities of ginseng for depression mainly involve neurotransmitters, neurotrophic factors, neurogenesis, HPA axis and inflammatory response. Pharmacological network analysis can help to explain the potential effects of ginseng for treating depression, indicating that ginseng is a preferable herb clinically for immune-regulation and anti-depression in post-pandemic.
... Neurological damage results in a loss of neuronal cells and prevents the differentiation of NSCs into new neurons, which leads to a series of AD-related cognitive deficits (He and Shen 2009;Robin and others 2014). Lithium, which is used to treat bipolar disorders, promotes hippocampal neurogenesis and improves cognitive functions though the activation of Wnt/β-catenin signaling in the early stages in a mouse model of AD (Coyle and Duman 2003;Fiorentini and others 2010;Valvezan and Klein 2012). Recent studies have reported that valproate acid (VPA) stimulates hippocampal neurogenesis by activating Wnt/β-Catenin signaling in the APP/PS1/Nestin-GFP triple transgenic mouse model of AD (Zeng and others 2019), suggesting that VPA is a potential therapy for the treatment of AD and other related diseases. ...
Neural stem/progenitor cells (NSCs) maintain the ability of self-renewal and differentiation and compose the complex nervous system. Wnt signaling is thought to control the balance of NSC proliferation and differentiation via the transcriptional coactivator β-catenin during brain development and adult tissue homeostasis. Disruption of Wnt signaling may result in developmental defects and neurological diseases. Here, we summarize recent findings of the roles of Wnt/β-catenin signaling components in NSC homeostasis for the regulation of functional brain circuits. We also suggest that the potential role of Wnt/β-catenin signaling might lead to new therapeutic strategies for neurological diseases, including, but not limited to, spinal cord injury, Alzheimer’s disease, Parkinson’s disease, and depression.
... The first and initial step in SSRI's mode of action is the binding to SERT molecules, which are localized at the cell surface of serotonergic neurons (Fig. 1). Thereby, SSRI inhibit SERT-dependent re-uptake of 5-HT back into serotonergic neurons and prolong 5-HT signaling (Nemeroff 1998;Coyle and Duman 2003;Schloss and Henn 2004). SSRI-dependent inhibition of SERT is assumed to elevate 5-HT signaling via enhanced activation of postsynaptic 5-HT receptors. ...
... The LH model has the advantage of screening antidepressant properties of drugs that is needed to recover from depressive-like state than EPM and OFT. Our observation clearly corroborates with the previous findings of the scientists [23][24][25][26][27][28][29][30][31][32][33], and forecasts the rationality of inescapable foot-shocks induced LH model of depression. ...
Major depression has a high prevalence and a high mortality. In order to understand the molecular changes
underlying major depression animal models are needed. The different animal models of depression simulate the etiology
and replicates symptoms, course and treatment of human depression properly. In this study, we investigated stress-induced
depressogenic induction among the rats using Shuttle Box Escape Test, Open Field Test (OFT) and Elevated Plus Maze
(EPM) Test. Fluoxetine hydrochloride (FLX), an antidepressant was administered chronically to determine antidepressant
mediated recovery of their behavioral homeostasis. In addition, all the behavioral tests demonstrated a variety of specific
symptoms like changes in locomotor activity, impaired learning ability and cognition deficit etc. From these findings, we
can conclude that chronic inescapable foot-shocks at 0.8mA intensity for 15 sec duration are the most effective stressor to
produce animal model of depression. After exposure to chronic foot-shocks, FLX mediated recovery strengthen our
findings. In addition, the rats were screened through shuttle box escape test that mimic depressive-like behavior properly in
animals. Our observation clearly corroborates well with the learned helplessness (LH) paradigm. So, the animal models of
depression using electric foot-shock to induce depressive like behavior, have excellent face validity and replicate anhedonia
and anergia in analogy to loss of interest and pleasure.
... Az antidepresszáns hatás kialakításában és így az antidepresszánsok hatásmechanizmusában a TrkBmediált jelátviteli útvonal kulcsfontosságú. 20 Számos in vitro és in vivo tanulmány igazolta, hogy a gyulladás -amely a DM és a depresszió patomechanizmusában egyaránt kulcsfontosságú -hatással van a BDNF expressziójára. 21 Lipopoliszacharid vagy gyulladásos citokinek bejuttatása az agyba nagymértékben csökkenti a BDNF szintjét. ...
... When GSK-3β is active, it induces βcatenin degradation through the phosphorylation of this protein. In contrast, when GSK-3β is inactive, β-catenin accumulates in the cytosol and subsequently moves to the nucleus [52]. Our results indicate that treatment with guanosine was able to increase β-catenin immunocontent (nuclear fraction) in the hippocampus and PFC of mice. ...
Although guanosine is an endogenous nucleoside that displays antidepressant-like properties in several animal models, the mechanism underlying its antidepressant-like effects is not well characterized. The present study aimed at investigating the involvement of ERK/GSK-3β and Nrf2/HO-1 signaling pathways in the antidepressant-like effect of guanosine in the mouse tail suspension test (TST). The immobility time in the TST was taken as an indicative of antidepressant-like responses and the locomotor activity was assessed in the open-field test. Biochemical analyses were performed by Western blotting in the hippocampus and prefrontal cortex (PFC). The combined treatment with sub-effective doses of guanosine (0.01 mg/kg, p.o.) and lithium chloride (a non-selective GSK-3β inhibitor, 10 mg/kg, p.o.) or AR-A014418 (selective GSK-3β inhibitor, 0.01 μg/site, i.c.v.) produced a synergistic antidepressant-like effect in the TST. The antidepressant-like effect of guanosine (0.05 mg/kg, p.o.) was completely prevented by the treatment with MEK1/2 inhibitors U0126 (5 μg/site, i.c.v.), PD98059 (5 μg/site, i.c.v.), or zinc protoporphyrin IX (ZnPP) (HO-1 inhibitor, 10 μg/site, i.c.v). Guanosine administration (0.05 mg/kg, p.o.) increased the immunocontent of β-catenin in the nuclear fraction and Nrf2 in the cytosolic fraction in the hippocampus and PFC. The immunocontent of HO-1 was also increased in the hippocampus and PFC. Altogether, the results provide evidence that the antidepressant-like effect of guanosine in the TST involves the inhibition of GSK-3β, as well as activation of MAPK/ERK and Nrf2/HO-1 signaling pathways, highlighting the relevance of these molecular targets for antidepressant responses.
... On the other hand, genetic association studies revealed association of EDs with Brain-Derived Neurotropic Factor (BDNF), Serotonin transporter, Monoamine oxidase A (MAO-A), cannabinoid receptor and potassium channel (KCNN3) genes. Evidence suggests that BDNF playsan important role in the patho physiology of psychiatric diseases, including mood disorders, and in the mechanism of action of therapeutic agents [5], [6]. ...
Eating disorders are central reason of physical and psycho-social morbidity. Several factors have been identified as being associated with the prevalence and progression of eating disorders in humans. Scientific investigation was carried out to assess the usage of terms in manuscript titles of nearly 900 published articles followed by network analysis and network centralities using R programming. The tm package, term document matrix function was utilized to create a term document matrix (TDM) from the corpus. A binary word matrix comprising 17 terms was created based on higher probability of occurring a term in a column. An agglomerative hierarchical clustering technique using ward clustering algorithm was presented. A data frame from the TDM was created to store data and used to plot word cloud based on word frequencies. An undirected network graph was plotted based on terms that appeared in the term matrix. Centralization measures such as Degree centrality, Closeness, Eigenvector and betweenness Centrality were reported.
... However, upregulation of hindgut cAMP/cGMP phosphodiesterases might depress reabsorption rates by reducing cytosolic cAMP or cGMP (Schooley et al., 2012). Upregulation of a putative cAMP phosphodiesterase and downregulation of inositol monophosphatase (which is required for IP3 recycling) in the Malpighian tubules of cold-acclimated crickets could contribute to reduced excretion rates (Coyle and Duman, 2003). If these transcriptional shifts reflect altered secondary messenger abundance, we could perhaps quantify their contribution to altered transport function by selective inhibition in the hindgut and Malpighian tubules ex vivo (Sharma et al., 1975;Genain et al., 1995;Sarkar et al., 2005). ...
Water and ion homeostasis has emerged as an important factor limiting chill-susceptible insects at low temperatures; loss of this homeostasis in the cold likely contributes to chronic chilling injury, and reestablishment of homeostasis is required for recovery from chilling. Both plastic and interspecific variation in cold tolerance correlates with enhanced defense of water and ion homeostasis during cold exposure, however the mechanisms are poorly understood. Using Gryllus crickets, I generated and tested hypotheses about the mechanisms underlying this variation in transport function. I first related interspecific variation in cold tolerance to water and ion balance in early chill coma. A rapid influx of Na+ to the hemolymph suggests that Na+ first leaks from the tissues, and could drive migration of Na+ and water to the gut. Gryllus veletis (a more cold-tolerant species) may avoid or slow this Na+ leak by maintaining lower hemolymph Na+ content and lower osmotic pressure between the gut and hemolymph, compared to G. pennsylvanicus. Plasticity in defense of water and ion homeostasis during cold exposure is thought to involve enhanced active transport function and/or decreased permeability of ionoregulatory tissues. Using G. pennsylvanicus I identified specific candidate mechanisms related to these transport function modifications by comparing the hindgut and Malpighian tubule transcriptomes of warm- and cold-acclimated individuals. Cold acclimation modified the expression of hindgut and Malpighian tubule ion transporters, and hindgut structural (cytoskeletal and cell junction) genes. Rectal macromorphology and rectal pad scalariform complex ultrastructure were unchanged (suggesting that modified permeability does not involve these structural elements), however cytoskeletal modifications do protect rectal pad actin stability during cold shock. Cold acclimation decreases excretion rate (i.e. active transport) across the Malpighian tubules, which may be driven by modified activity of Na+-K+ ATPase but not of V-ATPase. Increased expression of hindgut Na+-K+ ATPase did not alter the activity of this enzyme in the rectum. Overall I show that cold acclimation modifies active transport function in the Malpighian tubules and modifies rectal pad structure to enhance cytoskeletal stability during cold exposure.
... 35 In addition, there is a growing body of evidence to support the idea that disturbed synaptic transmission contributes to the pathophysiology of mood disorders. 36,37 Post-mortem studies have reported reduced complexin expression levels in cases of bipolar disorder and major depression. 38 Herein, the expression of complexin 2 was increased in the stress resilience rats than stress sensitive rats. ...
Stress plays a crucial role in the development of major depressive disorder, but the molecular mechanism underlying the susceptibility vs. resilience to stress remains unclear. To better understand these mechanisms, we used chronic unpredictable mild stress to develop a depressive rat model. We categorized them into stress resistant rats and stress sensitive rats by their performance in behavioral tests, including forced swim test and sucrose preference test. Brain regions were dissected, and prefrontal cortex (PFC) proteins extracted from stress resistant and stress sensitive rats were analyzed using label-free liquid chromatography-tandem mass spectrometry. Three hundred and four proteins were up-regulated and 323 proteins were down-regulated among the 1482 different proteins from stress resistant rats compared with that of the stress sensitive rats. Western blotting, immunohistochemical staining and electron microscopy were used to validate the results of the proteomic analysis. Some proteins differentially expressed in stress resistant and sensitive rats were found to be associated with several neurobiological processes, particularly with neurotransmission regulation. The results provide possible novel insights into the molecular mechanisms for stress resilience.
... Valproic acid (VPA) is an established drug that is used in the long-term treatment of epilepsy [2]. VPA is a broad--spectrum inhibitor of HDACs that has been shown to mediate neuronal protection through the activation of signaling transduction pathways [5] and through the inhibition of proapoptotic factors [19]. A previous study showed that VPA suppresses the growth and increases the differentiation of different tumor cell lines [2] and induces neural progenitor cells to differentiate into neurons [11]. ...
Introduction:
Epigenetic mechanisms regulate the transcription of genes, which can affect the differentiation of MSCs. The aim of the current work is to determine how the histone deacetylase inhibitors TSA and VPA affect the expression of neuronal lineage genes in a culture of rat MSCs (rMSCs).
Materials and methods:
We analyzed the expression of early neuron marker gene (Tubb3), mature neuron markers genes (Vacht, Th, Htr2a) and the oligodendrocyte progenitor marker gene (GalC). Moreover, changes in the gene expression after three different periods of exposure to TSA and VPA were investigated for the first time.
Results:
After six days of exposition to TSA and VPA, the expression of Tubb3 and GalC decreased, while the expression of Th increased. The highest increase of VAChT expression was observed after three days of TSA and VPA treatment. A decrease in Htr2a gene expression was observed after TSA treatment and an increase was observed after VPA treatment. We also observed that TSA and VPA inhibited cell proliferation and the formation of neurospheres in the rMSCs culture.
Discussion:
The central findings of our study are that TSA and VPA affect the expression of neuronal lineage genes in an rMSCs culture. After exposure to TSA or VPA, the expression of early neuronal gene decreases but equally the expression of mature neuron genes increases. After TSA and VPA treatment ER of the oligodendrocyte progenitor marker decreased. TSA and VPA inhibit cell proliferation and the formation of neurospheres in rMSCs culture.
... decrease of CPLX1 has also been reported in the brain of depressive disorder [59]. Besides, imbalance of synaptic function in some cases such as AD led to the pathophysiology of mood disorders [60,61]. Previous studies showed that the expression of synaptic vesicle protein such as CPLX1 and CPLX2 was decreased in depression [62]. ...
Alzheimer's disease (AD) is a devastating neurodegenerative disease accompanied by neuropsychiatric symptoms, such as anxiety and depression. The levels of melatonin decrease in brains of AD patients. The potential effect of melatonin on anxiety and depression behaviors in AD and the underlying mechanisms remain unclear. In this study, we treated 10-month-old triple transgenic mice of AD (3xTg-AD) with melatonin (10 mg/kg body weight/day) for 1 month and explored the effects of melatonin on anxiety and depression-like behaviors in 3xTg-AD mice and the protein expression of hippocampal tissues. The behavioral test showed that melatonin ameliorated anxiety and depression-like behaviors of 3xTg-AD mice as measured by open field test, elevated plus maze test, forced swimming test, and tail suspension test. By carrying out two-dimensional fluorescence difference gel electrophoresis (2D-DIGE) coupled with mass spectrometry, we revealed a total of 46 differentially expressed proteins in hippocampus between the wild-type (WT) mice and non-treated 3xTg-AD mice. A total of 21 differentially expressed proteins were revealed in hippocampus between melatonin-treated and non-treated 3xTg-AD mice. Among these differentially expressed proteins, glutathione S-transferase P 1 (GSTP1) (an anxiety-associated protein) and complexin-1 (CPLX1) (a depression-associated protein) were significantly down-regulated in hippocampus of 3xTg-AD mice compared with the WT mice. The expression of these two proteins was modulated by melatonin treatment. Our study suggested that melatonin could be used as a potential candidate drug to improve the neuropsychiatric behaviors in AD via modulating the expression of the proteins (i.e. GSTP1 and CPLX1) involved in anxiety and depression behaviors
... In some developed countries, the lifetime prevalence of depression in general population Antidepressants instantly effect on brain functioning by exerting their impact on monoamines, but still pharmacotherapy treatment of depression is consider as time consuming 1 , it indicates that along with enhancing monoamine level, some other mechanisms also participates in restoring the normal mood by antidepressants [2][3][4] . Serotonin (5-hydroxytryptamine, 5-HT), a biogenic monoamine, familiar to modulate numerous functions like anxiety 5 , control of mood, food intake and sexual behavior 6 . ...
Serotonergic neurotransmission corresponds with the locomotive activity and the elevation in its neurotransmission has an influence on it. Conversely, reduced brain 5-HT undermines the behavioral performance. Serotonin is known to play a central role in physiological responses but also involves regulating mood and behavior. It is the by-product of Tryptophan which is classify as essential amino acid. The present study was therefore destining to evaluate the effects of repeated administration of tryptophan in rat model of depression. Present study revealed that oral administration of tryptophan at the dose of 100 mg/kg for 14 days increased locomotive activity in familiar but decreased in novel environments on repeated administration but not on single administration. Repeated administration of tryptophan were reported to elicit anxiolytic effects in light dark box and elevated plus maze. Results suggest that Anxiolytic effects produced upon repeated administration but not on single administration.
... Activation of GSK-3β induces β-catenin degradation through the phosphorylation of this protein. In contrast, inhibition of GSK-3β culminates in dephosphorylation and stabilization of β-catenin, resulting in its accumulation, and subsequent translocation to the nucleus to induce transcription in cooperation with transcription factors, inducing antiapoptotic effects and stimulating axonogenesis [59]. Our results showed that only the group incubated with folic acid plus glutamate presented increased β-catenin expression, similar to the results of GSK-3β phosphorylation at Ser 9. Therefore, folic acid may promote cell survival against glutamate damage through β-catenin accumulation, perhaps as a consequence of its inhibitory effect on GSK-3β activity. ...
Folic acid (folate) is a vitamin of the B-complex group crucial for neurological function. Considering that excitotoxicity and cell death induced by glutamate are involved in many disorders, the potential protective effect of folic acid on glutamate-induced cell damage in rat hippocampal slices and the possible intracellular signaling pathway involved in such effect were investigated. The treatment of hippocampal slices with folic acid (100 μM) significantly abrogated glutamate (1 mM)-induced reduction of cell viability measured by MTT reduction assay and inhibited glutamate-induced D-[³H]-aspartate release. To investigate the putative intracellular signaling pathways implicated in the protective effect of folic acid, we used a PI3K inhibitor, LY294002, which abolished the protective effects of folic acid against glutamate-induced cell damage and D-[³H] aspartate release. Moreover, hippocampal slices incubated with folic acid alone for 30 min presented increased phosphorylation of GSK-3β at Ser9, indicating an inhibition of the activity of this enzyme. Furthermore, folic acid in the presence of glutamate insult in hippocampal slices maintained for an additional period of 6 h in fresh culture medium without glutamate and/or folic acid induced phosphorylation of GSK-3β and β-catenin expression. In addition, glutamate-treated hippocampal slices showed increased iNOS expression that was reversed by folic acid. In conclusion, the results of this study show that the protective effect of folic acid against glutamate-induced excitotoxicity may involve the modulation of PI3K/GSK-3β/β-catenin pathway and iNOS inhibition.
Treatments are only partially effective in major depressive disorders (MDD) but no biomarker exists to predict symptom improvement in patients. Animal models are essential tools in the development of antidepressant medications, but while recent genetic studies have demonstrated the polygenic contribution to MDD, current models are limited to either mimic the effect of a single gene or environmental factor. We developed in the past a model of depressive-like behaviors in mice (H/Rouen), using selective breeding based on behavioral reaction after an acute mild stress in the tail suspension test. Here, we propose a new mouse model of depression (H-TST) generated from a more complex genetic background and based on the same selection process. We first demonstrated that H/Rouen and H-TST mice had similar phenotypes and were more sensitive to glutamate-related antidepressant medications than selective serotonin reuptake inhibitors. We then conducted an exome sequencing on the two mouse models and showed that they had damaging variants in 174 identical genes, which have also been associated with MDD in humans. Among these genes, we showed a higher expression level of Tmem161b in brain and blood of our two mouse models. Changes in TMEM161B expression level was also observed in blood of MDD patients when compared with controls, and after 8-week treatment with duloxetine, mainly in good responders to treatment. Altogether, our results introduce H/Rouen and H-TST as the two first polygenic animal models of MDD and demonstrate their ability to identify biomarkers of the disease and to develop rapid and effective antidepressant medications.
Valproate is among the most prescribed drugs for bipolar disorder; however, 87% of patients do not report full long-term treatment response (LTTR) to this medication. One of valproate's suggested mechanisms of action involves the brain-derived neurotrophic factor (BDNF), expressed in the brain areas regulating emotions, such as the prefrontal cortex. Nonetheless, data about the role of BDNF in LTTR and its implications in the structure of the dorsolateral prefrontal cortex (dlPFC) is scarce. We explore the association of BDNF variants and dorsolateral cortical thickness (CT) with LTTR to valproate in bipolar disorder type I (BDI). Twenty-eight BDI patients were genotyped for BDNF polymorphisms rs1519480, rs6265, and rs7124442, and T1-weighted 3D brain scans were acquired. LTTR to valproate was evaluated with Alda's scale. A logistic regression analysis was conducted to evaluate LTTR according to BDNF genotypes and CT. We evaluated CT differences by genotypes with analysis of covariance. LTTR was associated with BDNF rs1519480 and right dlPFC thickness. Insufficient responders with the CC genotype had thicker right dlPFC than TC and TT genotypes. Full responders reported thicker right dlPFC in TC and TT genotypes. In conclusion, different patterns of CT related to BDNF genotypes were identified, suggesting a potential biomarker of LTTR to valproate in our population.
Recently, psychedelics have emerged as promising therapeutics for numerous neuropsychiatric disorders. While their potential in the clinic has yet to be fully elucidated, understanding their molecular and biological mechanisms is imperative as these compounds are becoming widely used both in therapeutic and recreational contexts. This review examines the current understanding of basic biology, pharmacology, and structural biology in an attempt to reveal both the knowns and unknowns within the field.
https://www.mdpi.com/books/book/6617-induced-impairment-of-neurogenesis-and-brain-diseases
Major depressive disorders are among the most common psychiatric diseases featuring an insufficient serotonin signaling as the most prominent core patho-mechanism. Therefore, selective serotonin re-uptake inhibitors are firstly employed to restore serotonin neurotransmission in depressed patients. One member of this class of antidepressants, which selectively targets the serotonin transporter, is citalopram. Citalopram was first synthesized in 1972 and consists of equal molecular amounts of the isomers R-citalopram and S-citalopram, generally referred to as escitalopram, which exerts the antidepressant effect. Underlying citalopram’s mode of action is an allosteric mechanism, by which citalopram modulates its own binding to the primary binding site at the serotonin transporter. The following chapter will provide an overview of recent findings on the molecular binding characteristics determining citalopram’s docking to the serotonin transporter and the allosteric modulation of the citalopram-induced antidepressant response. Here, the focus will be on the acute citalopram-induced effects, which result in dose-dependent internalization of serotonin transporter molecules and diminished neuronal activity of serotonergic neurons.
It has been postulated that common molecular changes resulting from treatment with antipsychotic drugs are involved in their therapeutic mechanisms of action. There are studies showing antipsychotic drug treatment causes changes in rat cortical gene expression. Hence, in this study, we sort to identify common changes in gene expression caused by two antipsychotic drugs because such changes could be related to their therapeutic mechanisms of action. In this study, RNA in rat cortex was measured using Affymetrix GeneChip® Rat Genome 230 2.0 Arrays after treatment with vehicle, haloperidol or chlorpromazine in drinking water for 28 days (n = 10 per group). Panther Gene Ontology Classification System was used to identify biological consequences of changes in gene expression after drug treatment. Using criteria for differential gene expression established using our current data sets, compared to vehicle, chlorpromazine and haloperidol treatment changed levels of cortical RNA for 454 and 102 genes, respectively. Moreover, at the level of significance of p < 0.05 treatment with both drugs cause highly correlated fold changes in the expression of 154 genes that includes enzymes and regulators of their activity, receptors and receptor signalling pathways, regulators of gene translation and transcription, components of the cytoskeleton, molecular transporters and regulators of protein trafficking across membranes. We conclude that changing gene expression is an important mechanism of action of antipsychotic drugs and some of these changes are involved in the therapeutic benefits of those drugs.
ObjetivoIdentificar factores de riesgo, genéticos, clínicos y ambientales, para el desarrollo de demencias, movimientos anormales y trastornos afectivos, en población adulta mayor de tres barrios de la Localidad Cuarta de Bogotá.MetodologíaEstudio Piloto, analítico de tipo transversal, diseñado para la identificación clínica y de factores de riesgo en una muestra intencional con participación voluntaria de 250 individuos, realizado en dos etapas: primera, de tamización, con base en diagnóstico interdisciplinario (Medicina, Enfermería y Psicología); segunda, de confirmación diagnóstica por especialistas (Neurología y Psiquiatría). Diferentes instrumentos neuro-psicológicos y pruebas de genética molecular y bioquímicas fueron realizadas a los participantes.ResultadosSe estudiaron individuos de ambos sexos, con edad promedio de 68,3 años, y también algunos de sus familiares. El 65,5% de la población de estudio está afectada por alguna de las entidades valoradas, con una mayor frecuencia de los trastornos afectivos (35,0%), seguida por alteración de las funciones cognitivas (23,3%). Los estudios genéticos permitieron identificar varios polimorfismos en genes, que pueden estar influyendo en la aparición de estas enfermedades.ConclusionesEstudio poblacional interdisciplinario en una de las localidades de Bogotá, D.C, de estratos uno y dos, para identificar trastornos cognitivos, afectivos y de movimientos anormales, con instrumentos clínicos y de biología molecular, lo que permite avanzar en la caracterización de perfiles genéticos de nuestra población y sus aplicaciones en programas de Salud Pública.
The growth arrest and DNA damage-inducible (Gadd) 45 proteins have been associated with numerous cellular mechanisms including cell cycle control, DNA damage sensation and repair, genotoxic stress, neoplasia, and molecular epigenetics. The genes were originally identified in in vitro screens of irradiation- and interleukin-induced transcription and have since been implicated in a host of normal and aberrant central nervous system processes. These include early and postnatal development, injury, cancer, memory, aging, and neurodegenerative and psychiatric disease states. The proteins act through a variety of molecular signaling cascades including the MAPK cascade, cell cycle control mechanisms, histone regulation, and epigenetic DNA demethylation. In this review, we provide a comprehensive discussion of the literature implicating each of the three members of the Gadd45 family in these processes.
Due to their difficulty of pathogenesis, nervous system disease (NSD) therapies have long been challenging problems for researchers. With the rise of an ageing population, the quest for successful NSD therapies has become a hot topic. Polysaccharides demonstrated numerous biological effects in anti-oxidation, anti-inflammation, and immune regulation.In recent years, several studies have been conducted in light of the connection between the properties of polysaccharides and the pathogenesis of neurological conditions. In this review, we aim to discuss the most recent reports on the beneficial properties and mechanisms of polysaccharides for nervous system-related diseases.
Psychedelic drugs including psilocybin, N,N'-dimethyltryptamine (DMT) and lysergic acid diethylamide (LSD) are undergoing a renaissance as potentially useful drugs for various neuropsychiatric diseases, with a rapid onset of therapeutic activity. Notably, phase II trials have shown that psilocybin can produce statistically significant clinical effects following one or two administrations in depression and anxiety. These findings have inspired a 'gold rush' of commercial interest, with nearly 60 companies already formed to explore opportunities for psychedelics in treating diverse diseases. Additionally, these remarkable phenomenological and clinical observations are informing hypotheses about potential molecular mechanisms of action that need elucidation to realize the full potential of this investigative space. In particular, despite compelling evidence that the 5-HT2A receptor is a critical mediator of the behavioural effects of psychedelic drugs, uncertainty remains about which aspects of 5-HT2A receptor activity in the central nervous system are responsible for therapeutic effects and to what degree they can be isolated by developing novel chemical probes with differing specificity and selectivity profiles. Here, we discuss this emerging area of therapeutics, covering both controversies and areas of consensus related to the opportunities and perils of psychedelic and psychedelic-inspired therapeutics. We highlight how basic science breakthroughs can guide the discovery and development of psychedelic-inspired medications with the potential for improved efficacy without hallucinogenic or rewarding actions.
Bipolar disorder (BD) is a heterogeneous, multifactorial disease associated with many neurobiological components impacting etiology and pathophysiology. Current research implicates several intracellular signaling systems in the neuroprogression of BD: Ca²⁺ signaling, GSK3-β/Wnt pathways, DAG/PKC pathways, BDNF, and therapeutic mechanisms (in the context of lithium pharmacotherapy), all of which are linked by mitochondrial dysfunction. BD is associated with abnormalities in synaptic/neuroplasticity, neurogeneration, and neuronal cell survival. Key signaling mechanisms implicated in these processes and in the prophylactic mechanism of mood stabilizers are described in the following sections. For each topic, we provide evidence of its alteration in BD as well as an explanation of intracellular signaling mechanisms.
There still are huge unmet needs for improved treatments in bipolar disorder (BD). Attempts were made to decipher the neurobiology of BD and develop new therapeutic targets. Lithium is still considered as gold standard for BD, and increasing studies highlight lithium’s various effects on neurotrophic factors, neurotransmitters, and second messenger systems which all contribute to neuroplasticity. Cellular studies suggested that mitochondrial-mediated pathway involving BCL-2 and calcium regulation, phosphatidylinositol-3 kinase (PI3K)/protein kinase B (Akt) signaling pathway, and extracellular regulated kinase (ERK)–mitogen-activated protein kinase (ERK/MAPK) pathway might be promising therapeutic targets. Visualization and assessment of diverse changes of neuroplasticity with higher space and time resolution became possible with development of neuroimaging techniques. Theoretically, these detrimental cascades leading to decreased neuroplasticity can be counteracted simultaneously by inhibiting glycogen synthase kinase-3 β (GSK-3β) activity. Thus increased number of studies indicate that GSK-3β, by modulating neuroplasticity of BD brain, could be an important and viable target for treatment of BD.
The discovery and development of effective medicines for the treatment of psychiatric disorders such as schizophrenia and depression has been heralded as one of the great medical achievements of the past century. Indeed, the profound impact of these medicines on our understanding of the pathophysiology underlying these diseases, the treatment of psychiatric patients and even our social perception of mental illnesses cannot be underestimated. However, there is still an urgent medical need for even more effective, safe and well-tolerated treatments. For example, currently available treatments for schizophrenia address mainly the positive symptoms and largely neglect the negative symptoms and cognitive disfunction which greatly impact overall morbidity. Similarly, whilst the current first line antidepressants show significantly improved side effect profiles compared to the first generation therapies, there still up to 40% of patients who are treatment resistant, and even in the patient population which responds well, the onset of action is slow at typically 2-3 weeks. The aim of this book is to provide the first point of call for those involved or just interested in this rapidly expanding and increasingly fragmented field of research and drug discovery. The editors will combine their wide ranging experience and extensive network of contacts with leading scientists and opinion leaders in this field to provide an authoritative reference text covering the evolution, major advances, challenges and future directions in drug discovery and medicinal chemistry for major psychiatric disorders.
Background
Lithium remains the first-line treatment for bipolar disorder (BD), but patients respond to it variably. While a myriad of studies have attributed many genes and signaling pathways to lithium responsiveness, a comprehensive study with an integrated conclusion is still lacking.Objective
We aim to present an integrated mechanism for the therapeutic actions of lithium in BD.Methods
First, a list of lithium responsiveness-associated genes (LRAGs) was collected by searching in the literature. Thereafter, gene set enrichment analysis together with gene–gene interaction network analysis was performed, in order to find the cellular and molecular events related to the LRAGs.ResultsGene set enrichment analyses showed that the chromosomal regions 3p26, 4p21, 5q34 and 7p13 could be novel associated loci for lithium responsiveness in BD. Also, expression pattern analysis of the LRAGs showed their enrichment in adulthood stages and different cell lineages of brain, blood and immune system. Most of the LRAGs exhibited enriched expression in central parts of human brain, suggesting major contribution of these parts in lithium responsiveness. Beside the prediction of several biological processes and signaling pathways related to lithium responsiveness, an interaction network between these processes was constructed that was found to be regulated by a set of microRNAs. Proteins of the network were mainly classified as transcription factors and kinases, which also highlighted the crucial role of glycogen synthase kinase 3β (GSK3β) in lithium responsiveness.Conclusions
The predicted cellular and molecular events in this study could be considered as mechanisms and also determinants of lithium responsiveness in BD.
Depression is a widespread psychological disorder that affects up to 20% of the world's population. Traditional Chinese medicine (TCM), with its unique curative effect in depression treatment, is gaining increasing attention as the discovery of novel antidepressant drug has become the pursuit of pharmaceutical. This article summarizes the work done on the natural products from TCM that have been reported to conceive antidepressant effects in the past two decades, which can be classified according to various mechanisms including increasing synaptic concentrations of monoamines, alleviating the hypothalamic-pituitary-adrenal (HPA) axis dysfunctions, lightening the impairment of neuroplasticity, fighting towards immune and inflammatory dysregulation. The antidepressant active ingredients identified can be generally divided into saponins, flavonoids, alkaloids, polysaccharides and others. Albiflorin, Baicalein, Berberine chloride, beta-Asarone, cannabidiol, Curcumin, Daidzein, Echinocystic acid (EA), Emodin, Ferulic acid, Gastrodin, Genistein, Ginsenoside Rb1, Ginsenoside Rg1, Ginsenoside Rg3, Hederagenin, Hesperidin, Honokiol, Hyperoside, Icariin, Isoliquiritin, Kaempferol, Liquiritin, L-theanine, Magnolol, Paeoniflorin, Piperine, Proanthocyanidin, Puerarin, Quercetin, Resveratrol (trans), Rosmarinic acid, Saikosaponin A, Senegenin, Tetrahydroxystilbene glucoside and Vanillic acid are Specified in this review. Simultaneously, chemical structures of the active ingredients with antidepressant activities are listed and their sources, models, efficacy and mechanisms are described. Chinese compound prescription and extracts that exert antidepressant effects are also introduced, which may serve as a source of inspiration for further development. In the view of present study, the antidepressant effect of certain TCMs are affirmative and encouraging. However, there are a lot of work needs to be done to evaluate the exact therapeutic effects and mechanisms of those active ingredients, specifically, to establish a unified standard for diagnosis and evaluation of curative effect.
As pointed out in Sects. 1.5, 3.1, and 3.2 the pattern formation perspective is part of a broad perspective that addresses how system of the animate and inanimate worlds can form qualitatively new states and how transitions between qualitatively different states take place. In this context, aggregate phase transitions (e.g., transitions from ice to water), phase transitions in non-equilibrium systems of the inanimate world (e.g., emergence of roll patterns in fluids and gases heated from below), and transitions between qualitatively different movement patterns of humans and animals (e.g., walk to trot gait transitions in horses) have been considered on an equal footing. It has been pointed out that when an individual stands up from a chair and starts to walk, then the sit-to-stand and stand-to-walk transitions from a physics perspective are considered as counterparts to aggregate phase transitions such as ice-to-water and water-to-gas transitions.
Apoptosis and autophagy are highly coordinated mechanisms to maintain cellular homeostasis against various intrinsic and/or extrinsic stresses in eukaryotic cells. Since the early 1990s, our knowledge of the molecular mechanisms and the physiological functions of apoptosis have increased substantially. Dysfunction of apoptosis leads to various diseases, including cancers and degenerative diseases. Therefore, small molecules that induce apoptosis or synthetic lethality with mutated genes have been examined for the development of cancer-specific apoptosis-inducing agents; conversely, small molecules that suppress apoptosis have been identified for protective agents against neuronal cell death.
On the other hand, autophagy is an evolutionarily conserved pathway involved in the degradation of intracellular components and is critical for the maintenance of cellular homeostasis. The mechanisms and functions of autophagy have been revealed by genetic studies in yeast, which identified a series of autophagy-related genes. Many small molecules that have been discovered to induce or inhibit autophagy also provide insight into the mechanisms and functions of the autophagic process. In this chapter, we introduce several small molecules identified by synthetic lethality screening, apoptosis inhibitors, and autophagy modulators.
Reduced serotonin (5-HT) neurotransmission is postulated to underlie the pathogenesis of depression. The serotonin transporter (SERT) and 5-HT1A auto-receptors act in concert to ensure homeostasis of serotonin (5-HT) neurotransmission and regulation of their cell surface expression represent efficient mechanisms to maintain this homeostasis. Thus, we investigated the changes in the subcellular distribution of SERT and 5-HT1A receptors (5-HT1AR) in the rat olfactory bulbectomy model of depression using immuno-gold labelling and electron microscopy, and examined the effect of chronic treatment with the antidepressant, fluoxetine, a serotonin reuptake inhibitor, on the subcellular distribution of SERT and 5-HT1AR. The density of plasma membrane labelling of 5-HT1A auto-receptors on dendrites of dorsal raphe neurons was increased after bulbectomy, but the 5-HT1A hetero-receptor membrane labelling on dendrites of CA3 hippocampal neurons was not. The density of membrane labelling of SERTs was increased both in dendrites of dorsal raphe neuron and axon terminals in the hippocampus after bulbectomy. However, the proportion of 5-HT1AR and SERT membrane labelling relative to total labelling were unchanged, suggesting an increase in protein levels. The increases in 5-HT1AR and SERTs membrane labelling induced by bulbectomy were reversed by chronic fluoxetine treatment, and these changes were associated with a reduction in the relative proportion of membrane versus total labelling, consistent with a protein shift between subcellular compartments. Our findings support the hypothesis that changes in efficacy of serotonergic neurotransmission in this model of depression depends on both activity and density of cell surface-expressed SERT and 5-HT1A auto-receptors.
Chronic organ ophosphorus pesticides (OP) exposure is associated with an increased risk of depression, and there is an urgent need to find an effective treatment for the depressive-like symptoms caused by OP. The main purpose of this study was to investigate whether combined lithium chloride (LiCl) and astaxanthin (AST) treatment would manifest synergetic antidepressant effects on mice with chronic OP exposure, and to determine the role of the Akt/GSK3?/CREB signaling pathway. Our results showed that chronic omethoate exposure significantly increased immobility time in behavioral tests and induced neuron damage in HE staining. The expression of p-GSK3?, p-CREB, p-PI3K and p-Akt in hippocampus after OP exposure were significantly down-regulated, while the influences were reversed by LiCl and AST treatment. Moreover, the combined application of AST and LiCl had synergistic therapeutic effects compared to LiCl and AST treatment alone, the expression of p-GSK3?, p-CREB, p-PI3K and p-Akt after combined LiCl-AST treatment were significantly higher than that with single drug application. These results showed that the combination of LiCl and AST could efficiently ameliorate depressive-like behavior induced by omethoate, and Akt/GSK3?/CREB signaling pathway might be responsible for the neuroprotective effect.
In spite of our increased knowledge of adult neurogenesis, Cajal’s dogma of no new neurons is still fundamentally correct when viewed in the context of the brain’s intrinsic repair mechanisms. In the embryo, neurogenesis operates to generate all of the basic brain structures and circuitry. At birth, all areas of the brain down-regulate neurogenesis and, in the adult, most areas have stopped producing neurons altogether with fine tuning of the neuronal morphology and synaptic connections as the only evidence for plasticity. Evidence for persistent neurogenesis within several anatomically distinct loci in the adult brain has started to question this dogma. In spite of this evidence, the paucity of large scale neuron replacement following disease or injury leaves the dogma relatively intact. Looking forward, it seems clear that successful therapeutic mobilization of neural progenitor cells will depend on the precise modulation of local signaling responsible for recruitment of endogenous stem cells, the fate choice and migration of these cells, and their integration into the preexisting circuitry of the adult brain.
Bei einem Schizophrenen hatten Cerletti und Bini die Elektrokonvulsionstherapie (EKT) erstmals 1938 erfolgreich angewandt [181. Es war kein Zufall, dass die Behandlung gerade bei einem wahnhaften, halluzinierenden, denkzerfahrenen und apathischen Patienten so erfolgreich war; bis heute gehören schwere Wahnformen, Katatonie und jede Art von psychotischer motorischer Hemmung oder Erregung und unbeherrschbare Aggressivität mit Selbst-und Fremdgefährdung zu den psychiatrischen Krankheitsbildern, die den Einsatz der EKT geradezu verlangen. Die therapeutischen Erfolge sind in der Regel sehr gut. Bei Therapieresistenz auf entsprechende Psychopharmakotherapie kommt der Verzicht auf die Anwendung der EKT in diesen Fällen praktisch einem Kunstfehler gleich.*
Regulation of gene transcription via the cAMP-mediated second messenger pathway has been implicated in the actions of antidepressant drugs, but studies to date have not demonstrated such an effect in vivo. To directly study the regulation of cAMP response element (CRE)-mediated gene transcription by antidepressants, transgenic mice with a CRE-LacZ reporter gene construct were administered one of three different classes of antidepressants: a norepinephrine selective reuptake inhibitor (desipramine), a serotonin selective reuptake inhibitor (fluoxetine), or a monoamine oxidase inhibitor (tranylcypromine). Chronic, but not acute, administration of these antidepressants significantly increased CRE-mediated gene transcription, as well as the phosphorylation of CRE binding protein (CREB), in several limbic brain regions thought to mediate the action of antidepressants, including the cerebral cortex, hippocampus, amygdala, and hypothalamus. These results demonstrate that chronic antidepressant treatment induces CRE-mediated gene expression in a neuroanatomically differentiated pattern and further elucidate the molecular mechanisms underlying the actions of these widely used therapeutic agents.
Studies at the basic and clinical levels demonstrate that neuronal atrophy and cell death occur in response to stress and in the brains of depressed patients. Although the mechanisms have yet to be fully elucidated, progress has been made in characterizing the signal transduction cascades that control neuronal atrophy and programmed cell death and that may be involved in the action of antidepressant treatment. These pathways include the cyclic adenosine monophosphate and neurotrophic factor signal transduction cascades. It is notable that these same pathways have been demonstrated to play a pivotal role in cellular models of neural plasticity. This overlap of plasticity and cell survival pathways, together with studies demonstrating that neuronal activity enhances cell survival, suggests that neuronal atrophy and death could result from a disruption of the mechanisms underlying neural plasticity. The role of these pathways and failure of neuronal plasticity in stress-related mood disorders are discussed.
Recent studies suggest that stress-induced atrophy and loss of hippocampal neurons may contribute to the pathophysiology of depression. The aim of this study was to investigate the effect of antidepressants on hippocampal neurogenesis in the adult rat, using the thymidine analog bromodeoxyuridine (BrdU) as a marker for dividing cells. Our studies demonstrate that chronic antidepressant treatment significantly increases the number of BrdU-labeled cells in the dentate gyrus and hilus of the hippocampus. Administration of several different classes of antidepressant, but not non-antidepressant, agents was found to increase BrdU-labeled cell number, indicating that this is a common and selective action of antidepressants. In addition, upregulation of the number of BrdU-labeled cells is observed after chronic, but not acute, treatment, consistent with the time course for the therapeutic action of antidepressants. Additional studies demonstrated that antidepressant treatment increases the proliferation of hippocampal cells and that these new cells mature and become neurons, as determined by triple labeling for BrdU and neuronal- or glial-specific markers. These findings raise the possibility that increased cell proliferation and increased neuronal number may be a mechanism by which antidepressant treatment overcomes the stress-induced atrophy and loss of hippocampal neurons and may contribute to the therapeutic actions of antidepressant treatment.
The mood-stabilizing agents lithium and valproic acid (VPA) increase DNA binding activity and transactivation activity of
AP-1 transcription factors, as well as the expression of genes regulated by AP-1, in cultured cells and brain regions involved
in mood regulation. In the present study, we found that VPA activated extracellular signal-regulated kinase (ERK), a kinase
known to regulate AP-1 function and utilized by neurotrophins to mediate their diverse effects, including neuronal differentiation,
neuronal survival, long term neuroplasticity, and potentially learning and memory. VPA-induced activation of ERK was blocked
by the mitogen-activated protein kinase/ERK kinase inhibitor PD098059 and dominant-negative Ras and Raf mutants but not by
dominant-negative stress-activated protein kinase/ERK kinase and mitogen-activated protein kinase kinase 6 mutants. VPA also
increased the expression of genes regulated by the ERK pathway, including growth cone-associated protein 43 and Bcl-2, promoted
neurite growth and cell survival, and enhanced norepinephrine uptake and release. These data demonstrate that VPA is an ERK
pathway activator and produces neurotrophic effects.
Valproic acid is widely used to treat epilepsy and bipolar disorder and is also a potent teratogen, but its mechanisms of
action in any of these settings are unknown. We report that valproic acid activates Wntdependent gene expression, similar
to lithium, the mainstay of therapy for bipolar disorder. Valproic acid, however, acts through a distinct pathway that involves
direct inhibition of histone deacetylase (IC50 for HDAC1 = 0.4 mm). At therapeutic levels, valproic acid mimics the histone deacetylase inhibitor trichostatin A, causing hyperacetylation
of histones in cultured cells. Valproic acid, like trichostatin A, also activates transcription from diverse exogenous and
endogenous promoters. Furthermore, valproic acid and trichostatin A have remarkably similar teratogenic effects in vertebrate
embryos, while non-teratogenic analogues of valproic acid do not inhibit histone deacetylase and do not activate transcription.
Based on these observations, we propose that inhibition of histone deacetylase provides a mechanism for valproic acid-induced
birth defects and could also explain the efficacy of valproic acid in the treatment of bipolar disorder.
Stress-induced structural remodeling in the adult hippocampus, involving debranching and shortening of dendrites and suppression of neurogenesis, provides a cellular basis for understanding the impairment of neural plasticity in the human hippocampus in depressive illness. Accordingly, reversal of structural remodeling may be a desirable goal for antidepressant therapy. The present study investigated the effect of tianeptine, a modified tricyclic antidepressant, in the chronic psychosocial stress model of adult male tree shrews (Tupaia belangeri), a model with high validity for research on the pathophysiology of major depression. Animals were subjected to a 7-day period of psychosocial stress to elicit stress-induced endocrine and central nervous alterations before the onset of daily oral administration of tianeptine (50 mg/kg). The psychosocial stress continued throughout the treatment period of 28 days. Brain metabolite concentrations were determined in vivo by proton magnetic resonance spectroscopy, cell proliferation in the dentate gyrus was quantified by using BrdUrd immunohistochemistry, and hippocampal volume was measured post mortem. Chronic psychosocial stress significantly decreased in vivo concentrations of N-acetyl-aspartate (-13%), creatine and phosphocreatine (-15%), and choline-containing compounds (-13%). The proliferation rate of the granule precursor cells in the dentate gyrus was reduced (-33%). These stress effects were prevented by the simultaneous administration of tianeptine yielding normal values. In stressed animals treated with tianeptine, hippocampal volume increased above the small decrease produced by stress alone. These findings provide a cellular and neurochemical basis for evaluating antidepressant treatments with regard to possible reversal of structural changes in brain that have been reported in depressive disorders.
Current treatments for depression are inadequate for many individuals, and progress in understanding the neurobiology of depression is slow. Several promising hypotheses of depression and antidepressant action have been formulated recently. These hypotheses are based largely on dysregulation of the hypothalamic-pituitary-adrenal axis and hippocampus and implicate corticotropin-releasing factor, glucocorticoids, brain-derived neurotrophic factor, and CREB. Recent work has looked beyond hippocampus to other brain areas that are also likely involved. For example, nucleus accumbens, amygdala, and certain hypothalamic nuclei are critical in regulating motivation, eating, sleeping, energy level, circadian rhythm, and responses to rewarding and aversive stimuli, which are all abnormal in depressed patients. A neurobiologic understanding of depression also requires identification of the genes that make individuals vulnerable or resistant to the syndrome. These advances will fundamentally improve the treatment and prevention of depression.
Previous studies demonstrated that antidepressant treatment increases the expression of brain-derived neurotrophic factor (BDNF) in rat hippocampus. The present study was conducted to test the hypothesis that BDNF in the hippocampus produces an antidepressant effect in behavioral models of depression, the learned helplessness (LH) and forced swim test (FST) paradigms. A single bilateral infusion of BDNF into the dentate gyrus of hippocampus produced an antidepressant effect in both the LH and FST that was comparable in magnitude with repeated systemic administration of a chemical antidepressant. These effects were observed as early as 3 d after a single infusion of BDNF and lasted for at least 10 d. Similar effects were observed with neurotrophin-3 (NT-3) but not nerve growth factor. Infusions of BDNF and NT-3 did not influence locomotor activity or passive avoidance. The results provide further support for the hypothesis that BDNF contributes to the therapeutic action of antidepressant treatment.
Lithium, carbamazepine and valproic acid are effective mood-stabilizing treatments for bipolar affective disorder. The molecular mechanisms underlying the actions of these drugs and the illness itself are unknown. Berridge and colleagues suggested that inositol depletion may be the way that lithium works in bipolar affective disorder, but others have suggested that glycogen synthase kinase (GSK3) may be the relevant target. The action of valproic acid has been linked to both inositol depletion and to inhibition of histone deacetylase (HDAC). We show here that all three drugs inhibit the collapse of sensory neuron growth cones and increase growth cone area. These effects do not depend on GSK3 or HDAC inhibition. Inositol, however, reverses the effects of the drugs on growth cones, thus implicating inositol depletion in their action. Moreover, the development of Dictyostelium is sensitive to lithium and to valproic acid, but resistance to both is conferred by deletion of the gene that codes for prolyl oligopeptidase, which also regulates inositol metabolism. Inhibitors of prolyl oligopeptidase reverse the effects of all three drugs on sensory neuron growth cone area and collapse. These results suggest a molecular basis for both bipolar affective disorder and its treatment.
Recent studies have indicated that exogenously administered neurotrophins produce antidepressant-like behavioral effects. We have here investigated the role of endogenous brain-derived neurotrophic factor (BDNF) and its receptor trkB in the mechanism of action of antidepressant drugs. We found that trkB.T1-overexpressing transgenic mice, which show reduced trkB activation in brain, as well as heterozygous BDNF null (BDNF(+/)-) mice, were resistant to the effects of antidepressants in the forced swim test, indicating that normal trkB signaling is required for the behavioral effects typically produced by antidepressants. In contrast, neurotrophin-3(+/)- mice showed a normal behavioral response to antidepressants. Furthermore, acute as well as chronic antidepressant treatment induced autophosphorylation and activation of trkB in cerebral cortex, particularly in the prefrontal and anterior cingulate cortex and hippocampus. Tyrosines in the trkB autophosphorylation site were phosphorylated in response to antidepressants, but phosphorylation of the shc binding site was not observed. Nevertheless, phosphorylation of cAMP response element-binding protein was increased by antidepressants in the prefrontal cortex concomitantly with trkB phosphorylation and this response was reduced in trkB.T1-overexpressing mice. Our data suggest that antidepressants acutely increase trkB signaling in a BDNF-dependent manner in cerebral cortex and that this signaling is required for the behavioral effects typical of antidepressant drugs. Neurotrophin signaling increased by antidepressants may induce formation and stabilization of synaptic connectivity, which gradually leads to the clinical antidepressive effects and mood recovery.
Understanding the biology of the pharmacological stabilization of mood will undoubtedly serve to provide significant insight into the pathophysiology of manic-depressive illness (MDI). Accumulating evidence from our laboratories and those of other researchers has identified the family of protein kinase C isozymes as a shared target in the brain for the long-term action of both lithium and valproate. In rats chronically treated with lithium, there is a reduction in the hippocampus of the expression of two protein kinase isozymes, α and ε, as well as a reduction in the expression of a major PKC substrate, MARCKS, which has been implicated in long-term neuroplastic events in the developing and adult brain. In addition, we have been invesigating the down-stream impact of these mood stabilzizers on another kinase system, GSK-3β and on the AP-1 family of transcription factors. Further studies have generated promising preliminary data in support of the antimanic action of tamoxifen, and antiestrogen that is also a PKC inhibitor. Future studies must address the therapuetic relevance of these protein targets in the brain using innovative strategies in both animal and clinical investigations to ultimately create opportunities for the discovery of the next generations of mood stabilizers for the treatment of MDI.
Abstract : Differential display of mRNA was used to identify concordant changes in gene expression induced by two mood-stabilizing agents, lithium and valproate (VPA). Both treatments, on chronic administration, increased mRNA levels of the transcription factor polyomavirus enhancer-binding protein (PEBP) 2β in frontal cortex (FCx). Both treatments also increased the DNA binding activity of PEBP2αβ and robustly increased the levels of bcl-2 (known to be transcriptionally regulated by PEBP2) in FCx. Immunohistochemical studies revealed a marked increase in the number of bcl-2-immunoreactive cells in layers 2 and 3 of FCx. These novel findings represent the first report of medication-induced increases in CNS bcl-2 levels and may have implications not only for mood disorders, but also for long-term treatment of various neurodegenerative disorders.
AFRC Unit of Insect Neurophysiology and Pharmacology Department of Zoology Cambridge CB2 3EJ England tSmith Kline & French Research Ltd. The Frythe, Welwyn Hertfordshire AL6 9AR England *MRC Molecular Neurobiology Unit University of Cambridge Medical School Cambridge CB2 2QH England Lithium, with an atomic weight of 6.9, is the smallest of the alkali metals, yet this simple ion can exert a profound ef- fect on both human behavior and early embryonic devel- opment. Manic-depressive psychosis, characterized by dramatic swings in mood, can be effectively controlled by maintaining a serum level of Li+ of ~1 mM. Despite its therapeutic success, little is known about the way Li+ can modify neurotransmission within the central nervous sys- tem (CNS). Many of the proposed mechanisms have sug- gested an inhibitory effect on components of various neu- rotransmitter signaling pathways, such as cyclic AMP formation, cyclic GMP formation, G proteins, or inositol phosphate metabolism (Hallcher and Sherman, 1960; Berridge et al., 1962). Only the latter provides a plausible explanation of the Li+ conundrum, i.e., the reason this ion
Lithium, one of the most effective drugs for the treatment of bipolar (manic-depressive) disorder, also has dramatic effects on morphogenesis in the early development of numerous organisms. How lithium exerts these diverse effects is unclear, but the favored hypothesis is that lithium acts through inhibition of inositol monophosphatase (IMPase). We show here that complete inhibition of IMPase has no effect on the morphogenesis of Xenopus embryos and present a different hypothesis to explain the broad action of lithium. Our results suggest that lithium acts through inhibition of glycogen synthase kinase-3 beta (GSK-3 beta), which regulates cell fate determination in diverse organisms including Dictyostelium, Drosophila, and Xenopus. Lithium potently inhibits GSK-3 beta activity (Ki = 2 mM), but is not a general inhibitor of other protein kinases. In support of this hypothesis, lithium treatment phenocopies loss of GSK-3 beta function in Xenopus and Dictyostelium. These observations help explain the effect of lithium on cell-fate determination and could provide insights into the pathogenesis and treatment of bipolar disorder.
Mood disorders are among the most common neuropsychiatric illnesses, yet little is known about their neurobiology. Recent neuroimaging studies have found that the volume of the subgenual part of Brodmann's area 24 (sg24) is reduced in familial forms of major depressive disorder (MDD) and bipolar disorder (BD). In this histological study, we used unbiased stereological techniques to examine the cellular composition of area sg24 in two different sets of brains. There was no change in the number or size of neurons in area sg24 in mood disorders. In contrast, the numbers of glia were reduced markedly in both MDD and BD. The reduction in glial number was most prominent in subgroups of subjects with familial MDD (24%, P = 0.01) or BD (41%, P = 0.01). The glial reduction in subjects without a clear family history was lower in magnitude and not statistically significant. Consistent with neuroimaging findings, cortical volume was reduced in area sg24 in subjects with familial mood disorders. Schizophrenic brains studied as psychiatric controls had normal neuronal and glial numbers and cortical volume. Glial and neuronal numbers also were counted in area 3b of the somatosensory cortex in the same group of brains and were normal in all psychiatric groups. Glia affect several processes, including regulation of extracellular potassium, glucose storage and metabolism, and glutamate uptake, all of which are crucial for normal neuronal activity. We thus have identified a biological marker associated with familial mood disorders that may provide important clues regarding the pathogenesis of these common psychiatric conditions.
Differential display of mRNA was used to identify concordant changes in gene expression induced by two mood-stabilizing agents, lithium and valproate (VPA). Both treatments, on chronic administration, increased mRNA levels of the transcription factor polyomavirus enhancer-binding protein (PEBP) 2beta in frontal cortex (FCx). Both treatments also increased the DNA binding activity of PEBP2 alphabeta and robustly increased the levels of bcl-2 (known to be transcriptionally regulated by PEBP2) in FCx. Immunohistochemical studies revealed a marked increase in the number of bcl-2-immunoreactive cells in layers 2 and 3 of FCx. These novel findings represent the first report of medication-induced increases in CNS bcl-2 levels and may have implications not only for mood disorders, but also for long-term treatment of various neurodegenerative disorders.
Understanding the biology of the pharmacological stabilization of mood will undoubtedly serve to provide significant insight into the pathophysiology of manic-depressive illness (MDI). Accumulating evidence from our laboratories and those of other researchers has identified the family of protein kinase C isozymes as a shared target in the brain for the long-term action of both lithium and valproate. In rats chronically treated with lithium, there is a reduction in the hippocampus of the expression of two protein kinase isozymes, alpha and epsilon, as well as a reduction in the expression of a major PKC substrate, MARCKS, which has been implicated in long-term neuroplastic events in the developing and adult brain. In addition, we have been investigating the down-stream impact of these mood stabilizers on another kinase system, GSK-3 beta and on the AP-1 family of transcription factors. Further studies have generated promising preliminary data in support of the antimanic action of tamoxifen, and antiestrogen that is also a PKC inhibitor. Future studies must address the therapeutic relevance of these protein targets in the brain using innovative strategies in both animal and clinical investigations to ultimately create opportunities for the discovery of the next generations of mood stabilizers for the treatment of MDI.
Recent preclinical studies have shown that lithium (Li) robustly increases the levels of the major neuroprotective protein, bcl-2, in rat brain and in cells of human neuronal origin. These effects are accompanied by striking neuroprotective effects in vitro and in the rodent central nervous system in vivo. We have undertaken the present study to determine if lithium exerts neurotrophic/ neuroprotective effects in the human brain in vivo.
Using quantitative proton magnetic resonance spectroscopy, N-acetyl-aspartate (NAA) levels (a putative marker of neuronal viability and function) were investigated longitudinally in 21 adult subjects (12 medication-free bipolar affective disorder patients and 9 healthy volunteers). Regional brain NAA levels were measured at baseline and following 4 weeks of lithium (administered in a blinded manner).
A significant increase in total brain NAA concentration was documented (p < .0217). NAA concentration increased in all brain regions investigated, including the frontal, temporal, parietal, and occipital lobes.
This study demonstrates for the first time that Li administration at therapeutic doses increases brain NAA concentration. These findings provide intriguing indirect support for the contention that chronic lithium increases neuronal viability/function in the human brain, and suggests that some of Li's long-term beneficial effects may be mediated by neurotrophic/neuroprotective events.
Rodent studies have shown that lithium exerts neurotrophic or neuroprotective effects. We used three-dimensional magnetic resonance imaging and brain segmentation to study pharmacologically-induced increases in grey matter volume with chronic lithium use in patients with bipolar mood disorder. Grey-matter volume increased after 4 weeks of treatment. The increases in grey matter probably occurred because of neurotrophic effects.
Major depressive disorders, long considered to be of neurochemical origin, have recently been associated with impairments in signaling pathways that regulate neuroplasticity and cell survival. Agents designed to directly target molecules in these pathways may hold promise as new therapeutics for depression.
Recent studies have demonstrated that chronic antidepressant treatment increases the expression of the cyclic amp (cAMP) response element binding protein (CREB) in rat hippocampus. The study presented here was conducted to determine if CREB is a relevant target that produces an antidepressant-like effect.
We employed the herpes simplex virus (HSV)-mediated gene transfer technique to overexpress CREB and determined its effect on the learned helplessness and forced swim tests, two established models used for pharmacological screening of antidepressant drugs.
In the learned helplessness model, rats that received bilateral microinjection of HSV-CREB into the dentate gyrus showed significantly fewer escape failures in the subsequent conditioned avoidance test than those injected with control vector (HSV-LacZ). In contrast, microinjection of HSV-CREB in either the CA1 pyramidal cell layer of hippocampus or the prefrontal cortex did not produce an antidepressant response. In the forced swim test, CREB expression in the dentate gyrus resulted in a significantly shorter immobility time than those injected with HSV-LacZ.
These results demonstrate that over-expression of CREB in hippocampus results in an antidepressant effect and suggest that CREB may serve as a potential molecular target for novel therapeutic agents.
Tissue-specific overexpression of the glycogen synthase kinase-3 (GSK-3) ortholog shaggy (sgg) shortens the period of the Drosophila circadian locomotor activity cycle. The short period phenotype was attributed to premature nuclear translocation of the PERIOD/TIMELESS heterodimer. Reducing SGG/GSK-3 activity lengthens period, demonstrating an intrinsic role for the kinase in circadian rhythmicity. Lowered sgg activity decreased TIMELESS phosphorylation, and it was found that GSK-3 beta specifically phosphorylates TIMELESS in vitro. Overexpression of sgg in vivo converts hypophosphorylated TIMELESS to a hyperphosphorylated protein whose electrophoretic mobility, and light and phosphatase sensitivity, are indistinguishable from the rhythmically produced hyperphosphorylated TIMELESS of wild-type flies. Our results indicate a role for SGG/GSK-3 in TIMELESS phosphorylation and in the regulated nuclear translocation of the PERIOD/TIMELESS heterodimer.
The cAMP signaling pathway, and its downstream neurotrophic factor BDNF, are major targets of antidepressant medications. Abnormalities in this pathway have previously been reported in postmortem brain of subjects with mood disorders. This study was designed to test whether the diagnosis of a mood disorder, or treatment with an antidepressant or mood stabilizer was associated with changes in hippocampal BDNF in postmortem brain.
Frozen postmortem anterior hippocampus sections were obtained from the Stanley Foundation Neuropathology Consortium. Tissue from subjects with major depression, bipolar disorder, schizophrenia and nonpsychiatric control subjects were stained for BDNF using immunohistochemistry.
Increased BDNF expression was found in dentate gyrus, hilus and supragranular regions in subjects treated with antidepressant medications at the time of death, compared with antidepressant-untreated subjects. Furthermore, there was a trend toward increased BDNF expression in hilar and supragranular regions in depressed subjects treated with antidepressants, compared with the subjects not on these medications at the time of death.
These findings are consistent with recent studies measuring CREB levels in this same subject sample, and support current animal and cellular models of antidepressant function.
Lithium, the major drug used to treat manic depressive illness, robustly protects cultured rat brain neurons from glutamate excitotoxicity mediated by N-methyl-D-aspartate (NMDA) receptors. The lithium neuroprotection against glutamate excitotoxiciy is long-lasting, requires long-term pretreatment and occurs at therapeutic concentrations of this drug. The neuroprotective mcchanisms involve inactivation of NMDA receptors, decreased expression of pro-apoptotic proteins, p53 and Bax, enhanced expression of the cytoprotective protein, Bcl-2, and activation of the cell survival kinase, Akt. In addition, lithium pretreatment suppresses glutamate-induced loss of the activities of Akt, cyclic AMP-response element binding protein (CREB), c-Jun - N-terminal kinase (JNK) and p38 kinase. Lithium also reduces brain damage in animal models of neurodegenerative diseases in which excitotoxicity has been implicated. In the rat model of stroke using middle cerebral artery occlusion, lithium markedly reduces neurologic deficits and decreases brain infarct volume even when administered after the onset of ischemia. In a rat Huntington's disease model, lithium significantly reduces brain lesions resulting from intrastriatal infusion of quinolinic acid, an excitotoxin. Our results suggest that lithium might have utility in the treatment of neurodegenerative disorders in addition to its common use for the treatment of bipolar depressive patients.
Brain-derived neurotrophic factor (BDNF) is a major neurotrophin in the brain and abnormal regulation of BDNF may contribute to the pathophysiology of mood disorders. In the present study, we examined if alterations in the activity of glycogen synthase kinase-3-beta (GSK3beta) or treatment with mood stabilizers modulated BDNF-mediated signal transduction pathways in differentiated human neuroblastoma SH-SY5Y cells. BDNF increased the phosphorylation of the forkhead transcription factor FKHRL1 through activation of the phosphatidylinositol 3-kinase (PI3K)/Akt signaling pathway, and the phosphorylation of the cyclic AMP response element binding protein (CREB) through activation of extracellular signal-regulated kinase1/2 (ERK1/2). BDNF also increased serine(9) -phosphorylation of GSK3beta, which inhibits GSK3beta activity. Overexpression of GSK3beta did not affect BDNF-induced phosphorylation of Akt, ERK1/2, or FKHRL1, but abolished CREB phosphorylation induced by BDNF. This inhibition of BDNF-induced CREB phosphorylation in GSK3beta-overexpressing SH-SY5Y cells was blocked by treatment with lithium. In contrast to lithium, sodium valproate and lamotrigine did not affect BDNF-mediated signaling, whereas carbamazepine induced a rapid and prolonged phosphorylation of ERK1/2 and CREB in the absence or the presence of BDNF. Therefore, increased GSK3beta selectively attenuates BDNF-induced CREB phosphorylation, and lithium and carbamazepine can facilitate activation of CREB.
Gene finding in genetically complex diseases has been difficult as a result of many factors that have diagnostic and methodologic considerations. For bipolar disorder and schizophrenia, numerous family, twin, and adoption studies have identified a strong genetic component to these behavioral psychiatric disorders. Despite difficulties that include diagnostic differences between sample populations and the lack of statistical significance in many individual studies, several promising patterns have emerged, suggesting that true susceptibility loci for schizophrenia and bipolar disorder may have been identified. In this review, the genetic epidemiology of these disorders is covered as well as linkage findings on chromosomes 4, 12, 13, 18, 21, and 22 in bipolar disorder and on chromosomes 1, 6, 8, 10, 13, 15, and 22 in schizophrenia. The sequencing of the human genome and identification of numerous single nucleotide polymorphisms (SNP) should substantially enhance the ability of investigators to identify disease-causing genes in these areas of the genome.
We review the literature on the cellular changes that underlie the structural impairments observed in brains of animals exposed to stress and in subjects with depressive disorders. We discuss the molecular, cellular and structural adaptations that underlie the therapeutic responses of different classes of antidepressants and contribute to the adaptive plasticity induced in the brain by these drugs.
We review results from various clinical and basic research studies.
Studies demonstrate that chronic antidepressant treatment increases the rate of neurogenesis in the adult hippocampus. Studies also show that antidepressants up-regulate the cyclic adenosine monophosphate (cAMP) and the neurotrophin signaling pathways involved in plasticity and survival. In vitro and in vivo data provide direct evidence that the transcription factor, cAMP response element-binding protein (CREB) and the neurotrophin, brain derived-neurotrophic factor (BDNF) are key mediators of the therapeutic response to antidepressants.
These results suggest that depression maybe associated with a disruption of mechanisms that govern cell survival and neural plasticity in the brain. Antidepressants could mediate their effects by increasing neurogenesis and modulating the signaling pathways involved in plasticity and survival.
Brain-derived neurotrophic factor (BDNF) modulates hippocampal plasticity and hippocampal-dependent memory in cell models and in animals. We examined the effects of a valine (val) to methionine (met) substitution in the 5' pro-region of the human BDNF protein. In human subjects, the met allele was associated with poorer episodic memory, abnormal hippocampal activation assayed with fMRI, and lower hippocampal n-acetyl aspartate (NAA), assayed with MRI spectroscopy. Neurons transfected with met-BDNF-GFP showed lower depolarization-induced secretion, while constitutive secretion was unchanged. Furthermore, met-BDNF-GFP failed to localize to secretory granules or synapses. These results demonstrate a role for BDNF and its val/met polymorphism in human memory and hippocampal function and suggest val/met exerts these effects by impacting intracellular trafficking and activity-dependent secretion of BDNF.
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