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Various studies have evidenced the neuroprotective role of PDE4 inhibitors. However, whether PDE4 inhibitor, Piclamilast pharmacological post-treatment is protective during cerebral ischemia reperfusion-induced injury remains unknown. Therefore, this study design included testing the hypothesis that Piclamilast administered at the beginning of a re...
Citations
... 666-15 was purchased from Sigma-Aldrich (5383410001, USA). 666-15 is a potent CREB inhibitor and has been shown to possess efficacious anti-breast cancer activity without toxicity in vivo (Xie F et al., 2017;Peng J et al., 2022), which is dissolved in 1% DMSO in normal saline (vehicle) and intraperitoneally (i.p.) injected at a dose of 10 mg/kg (Kaur A et al., 2022). ...
Background
Depression is a neuropsychiatric disease with high disability rate and mainly caused by the chronic stresses or genetic factors. There is increasing evidences that miRNAs play a critical role in the pathogenesis of depression. However, the underlying molecular mechanism for the pathophysiology of depression of miRNA remains entirely unclear so far.
Methods
We first established a Chronic Social Defeat Stress (CSDS) mice model of depression, and depression-like behaviors of mice were evaluated by a series of behavioral tests. Next, we detected several abundantly expressive miRNAs that had been suggested to be involved in depression in previous reports and found miR-182-5p was selected as a candidate for analysis in the hippocampus, then western blotting and immunofluorescence were used together to examine whether AAV-siR-182-5p treatment alleviated chronic stress-induced decrease in hippocampal Akt/GSK3β/CREB signaling pathway and increase in neurogenesis impairment and neuroinflammation. Furthermore, cAMP-response element binding protein (CREB) inhibitor was adopted to examine if blockade of Akt/GSK3β/CREB signaling pathway abolished the antidepressant actions of AAV-siR-182-5p in mice.
Results
Knock-down of miR-182-5p alleviated depression-like behaviors and impaired neurogenesis of CSDS-induced mice. Intriguingly, the usage of agomiR-182-5p, produced significant increases in immobility times and aggravated neuronal neurogenesis damage of mice. More importantly, it suggested that the 666-15 blocked the reversal effects of AAV-siR-182-5p on the CSDS-induced depressive-like behaviors in the behavioral testing and the neuronal neurogenesis within hippocampus of mice.
Conclusions
These findings indicated that hippocampal miR-182-5p/Akt/GSK3β/CREB signaling pathway participated in the pathogenesis of depression, itmight be given more opportunities for new drug developments based on the miRNA target in the clinic.
... Recently, the neuroprotective effect of piclamilast has been studied. It has been suggested that post-ischemia pharmacological treatment with piclamilast determines an improvement of cerebral ischemia-reperfusion injury in mice [50]. The docking study with piclamilast gave the following resulting poses ( Table 1). ...
Severe acute respiratory syndrome coronavirus-2 (SARS-CoV-2) is an RNA virus belonging to the coronavirus family responsible for coronavirus disease 2019 (COVID-19). It primarily affects the pulmonary system, which is the target of chronic obstructive pulmonary disease (COPD), for which many new compounds have been developed. In this study, phosphodiesterase 4 (PDE4) inhibitors are being investigated. The inhibition of PDE4 enzyme produces anti-inflammatory and bronchodilator effects in the lung by inducing an increase in cAMP concentrations. Piclamilast and rolipram are known selective inhibitors of PDE4, which are unfortunately endowed with common side effects, such as nausea and emesis. The selective inhibition of the phosphodiesterase 4B (PDE4B) subtype may represent an intriguing technique for combating this highly contagious disease with fewer side effects. In this article, molecular docking studies for the selective inhibition of the PDE4B enzyme have been carried out on 21 in-house compounds. The compounds were docked into the pocket of the PDE4B catalytic site, and in most cases, they were almost completely superimposed onto piclamilast. Then, in order to enlarge our study, drug-likeness prediction studies were performed on the compounds under study.
... IL-6 assay estimation for neuroinflammation was done via a marketed available ELISA kit for IL-6 (RayBiotech, USA) at 450 nm. 32 2.5.6. Neuroinflammation Cytokine (IL-10) Immunofluorescence Assay. ...
... IL-10 assay estimation for neuroinflammation was done via a marketed available ELISA kit for IL-10 (RayBiotech, USA) at 450 nm. 32 2.6. Histopathological Analysis. ...
Alzheimer's disease (AD) is a progressive neurodegenerative disorder causing immense suffering for the patients. Dopamine D2 and 5-hydroxytryptamine receptor 1A (5-HT1A) receptors' activation has been reported to play a crucial role in managing neurological outcomes in the brain and other health disorders. This study aimed to investigate the role of aripiprazole, a dopamine D2 and 5-HT1A selective receptors' activator, in the restoration of memory deficit induced by streptozotocin in mice. The cognitive functions of animals were determined using the Morris water maze. Brain sections were stained with hematoxylin and eosin and Congo red to examine the structural deviations. Brain oxidative stress (thiobarbituric acid reactive substance and glutathione), acetylcholinesterase activity, IL-6, and IL-10 were measured to assess biochemical alterations. Activation of D2 and 5-HT1A with aripiprazole attenuated STZ-induced cognitive deficit, increased brain GSH levels, reduced TBARS levels, AChE activity, IL-6 levels, and IL-10 levels and prevented STZ-induced brain anomalies in mice. Hence, the present study concluded that aripiprazole mitigated STZ-induced memory impairment and can be used as an efficacious therapeutic target for the management of AD.
Obesity, a prominent risk factor for the development of heart attacks and several cardiovascular ailments. Obesity ranks as the second most significant avoidable contributor to mortality, whereas stroke stands as the second leading cause of death on a global scale. While changes in lifestyle have been demonstrated to have significant impacts on weight management, the long-term weight loss remains challenging, and the global prevalence of obesity continues to rise. The pathophysiology of obesity has been extensively studied during the last few decades, and an increasing number of signal transduction pathways have been linked to obesity preclinically. This review is focused on signaling pathways, and their respective functions in regulating the consumption of fatty food as well as accumulation of adipose tissue, and the resulting morphological and cognitive changes in the brain of individuals with obesity. We have also emphasized the recent progress in the mechanisms behind the emergence of obesity, as elucidated by both experimental and clinical investigations. The mounting understanding of signaling transduction may shed light on the future course of obesity research as we move into a new era of precision medicine.
Hypoxia-inducible factor 1 has been identified as an important therapeutic target in psychiatric illnesses. Hypoxia is a condition in which tissues do not receive enough oxygen, resulting in less oxidative energy production. HIF-1, the master regulator of molecular response to hypoxia, is destabilized when oxygen levels fall. HIF-1, when activated, increases the gene transcription factors that promote adaptive response and longevity in hypoxia. HIF-regulated genes encode proteins involved in cell survival, energy metabolism, angiogenesis, erythropoiesis, and vasomotor control. Multiple genetic and environmental variables contribute to the pathophysiology of psychiatric disease. This review focuses on the most recent findings indicating the role of oxygen deprivation in CNS damage, with strong attention on HIF-mediated pathways. Several pieces of evidence suggested that, in the case of hypoxia, induction and maintenance of HIF-1 target genes may help reduce nerve damage. Major new insights into the molecular mechanisms that control HIF's sensitivity to oxygen are used to make drugs that can change the way HIF works as a therapeutic target for some CNS diseases.
Several experimental studies have linked adenosine’s neuroprotective role in cerebral ischemia. During ischemia, adenosine is formed due to intracellular ATP breakdown into ADP, further when phosphate is released from ADP, the adenosine monophosphate is formed. It acts via A1, A2, and A3 receptors found on neurons, blood vessels, glial cells, platelets, and leukocytes. It is related to various effector systems such as adenyl cyclase and membrane ion channels via G-proteins. Pharmacological manipulation of adenosine receptors by agonists (CCPA, ADAC, IB-MECA) increases ischemic brain damage in various in vivo and in vitro models of cerebral ischemia whereas, agonist can also be neuroprotective. Mainly, receptor antagonists (CGS15943, MRS1706) indicated neuroprotection. Later, various studies also revealed that the downregulation or upregulation of specific adenosine receptors is necessary during the recovery of cerebral ischemia by activating several downstream signaling pathways. In the current review, we elaborate on the dual roles of adenosine and its receptor subtypes A1, A2, and A3 and their involvement in the pathobiology of cerebral ischemic injury. Adenosine-based therapies have the potential to improve the outcomes of cerebral injury patients, thereby providing them with a more optimistic future.
Graphical abstract
Parkinson's disease (PD) is a neurodegenerative disorder that alters either motor or non-motor activities. Dopamine-based medications can help alleviate symptoms at an early stage, but the disease worsens due to fewer neuroprotective drugs. PD's pathogenic mechanism involves α-synuclein accumulations, lipid peroxidation damage, iron deposition, and enhanced oxidative stress. An iron-dependent method of programmed cell death known as ferroptosis, which results from the dangerous accumulation of lipid peroxides, is similar to PD. The interesting fact is that α-synuclein has been functionally connected to iron or lipid metabolism, suggesting that dysregulated α-syn may interact with other PD clinical traits associated with ferroptosis. Treatments aimed at restoring dopamine levels in the brain are already available; however, they only alleviate symptoms and do not stop the progression of neurodegeneration. Ferroptosis-related mechanisms that could be targeted for treatment will be discussed in this review. Researchers have found that anti-ferroptosis molecules such as iron chelators and anti-oxidants protect the brains of PD animal models and humans. The ferroptosis pathway in PD and the treatment prospects of addressing the molecular pathways engaged in ferroptosis are both examined in this review.
