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Photomicrographs of prefrontal cortex pyramidal neurons at layers III (A, B, and C) and V (A1, B1, and C1) from the Control (A and A1), Isch + Mel (B and B1), and Isch + Veh (C and C1) groups, showing the reduction in dendritic arborization from the apical dendrite (arrows) and in soma size of pyramidal neurons of the Isch + Veh group as compared to the Control. Scale bar = 50 m.
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To analyze the cytoarchitectural characteristics of the remaining pyramidal neurons in the hippocampal CA1 subfield of rats, four months after global cerebral ischemia (GCI) and progesterone treatment.
Dendritic arborization, and density and shape of the dendritic spines of CA1 pyramidal neurons in brains of intact rats, or rats submitted 120 days...
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... ± 0.30; layer V: 14.10 ± 0.38) and to the Isch + Mel (layer III: 10.67 ± 0.19; layer V: 14.27 ± 0.22) groups. Values of this parameter in the Isch + Mel group were similar to those in the Control group both at layer III and V. Representative images of layer III and V pyramidal neurons under the various experimental conditions are presented in Fig. ...
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Purpose: To analyze the cytoarchitectural characteristics of the remaining pyramidal neurons in the hippocampal CA1 subfield of rats, four months after global cerebral ischemia (GCI) and progesterone treatment. Methods: Dendritic arborization, and density and shape of the dendritic spines of CA1 pyramidal neurons in brains of intact rats, or rats s...
Citations
... It has been reported that it promotes axonal myelination [70], decreases the neuritic growth inhibitor Nogo-A [71], regulates cytoskeletal proteins involved in brain plasticity [72], and increases the expression of growth-associated protein 43 (GAP-43) and synaptophysin in CA1, demonstrating that the hormone induces synaptogenesis in this region of the hippocampus [73]. P4 also modulates the expression of neurotrophic factors such as brain-derived neurotrophic factor (BDNF), vascular endothelial growth factor (VEGF), and neudesin (neuron-derived neurotrophic factor, NENF) [74,75], induces compensatory changes in neuronal cytoarchitecture [76], and regulates hippocampal neurogenesis [42,74,77]. ...
... The analysis of the cytoarchitectonic characteristics of the remaining CA1 pyramidal neurons in the ischemic P4-treated rats revealed that they have sinuously branched dendrites with a similar number of bifurcations and whole density of dendritic spines, as well as higher proportional density of mushroom spines than those of the group of intact rats. P4 thus favors the brain's intrinsic capacity to recover and adapt after a severe ischemic episode [76]. In a similar experimental protocol, it was found that P4 is capable of inducing adequate behavioral response to solve learning spatial and memory tasks 21 days after an even more severe episode of global ischemia (30 min). ...
Progesterone (P4) is a neuroactive hormone having pleiotropic effects, supporting its pharmacological potential to treat global (cardiac-arrest-related) cerebral ischemia, a condition associated with an elevated risk of dementia. This review examines the current biochemical, morphological, and functional evidence showing the neuroprotective/neurorestorative effects of P4 against global cerebral ischemia (GCI). Experimental findings show that P4 may counteract pathophysiological mechanisms and/or regulate endogenous mechanisms of plasticity induced by GCI. According to this, P4 treatment consistently improves the performance of cognitive functions, such as learning and memory, impaired by GCI. This functional recovery is related to the significant morphological preservation of brain structures vulnerable to ischemia when the hormone is administered before and/or after a moderate ischemic episode; and with long-term adaptive plastic restoration processes of altered brain morphology when treatment is given after an episode of severe ischemia. The insights presented here may be a guide for future basic research, including the study of P4 administration schemes that focus on promoting its post-ischemia neurorestorative effect. Furthermore, considering that functional recovery is a desired endpoint of pharmacological strategies in the clinic, they could support the study of P4 treatment for decreasing dementia in patients who have suffered an episode of GCI.
... Cerebral ischemia can cause poor spatial memory performance as a result of hippocampal damage and a decrease in synaptic function [71,72]. In the present study, TGCI significantly decreased the number of dendritic spines in neurons that survived the ischemic insult in the DG (granular neurons), CA1, and CA3. ...
... For example, acute melatonin administration attenuated dendritic spine loss in the hippocampus in TGCI rats [50]. Treatment with progesterone resulted in a similar recovery of dendritic spines and mitigated ischemia-induced learning and memory deficits [72]. Acetyl-l-carnitine treatment before and after 2-vessel occlusion (i.e., a model of ischemia) prevented ischemia-induced dendritic spine loss in the hippocampus, paralleled by the normalization of long-term potentiation in the hippocampus [73]. ...
Evidence for the clinical use of neuroprotective drugs for the treatment of cerebral ischemia (CI) is still greatly limited. Spatial/temporal disorientation and cognitive dysfunction are among the most prominent long-term sequelae of CI. Cannabidiol (CBD) is a non-psychotomimetic constituent of Cannabis sativa that exerts neuroprotective effects against experimental CI. The present study investigated possible neuroprotective mechanisms of action of CBD on spatial memory impairments that are caused by transient global cerebral ischemia (TGCI) in rats. Hippocampal synaptic plasticity is a fundamental mechanism of learning and memory. Thus, we also evaluated the impact of CBD on neuroplastic changes in the hippocampus after TGCI. Wistar rats were trained to learn an eight-arm aversive radial maze (AvRM) task and underwent either sham or TGCI surgery. The animals received vehicle or 10 mg/kg CBD (i.p.) 30 min before surgery, 3 h after surgery, and then once daily for 14 days. On days 7 and 14, we performed a retention memory test. Another group of rats that received the same pharmacological treatment was tested in the object location test (OLT). Brains were removed and processed to assess neuronal degeneration, synaptic protein levels, and dendritic remodeling in the hippocampus. Cannabidiol treatment attenuated ischemia-induced memory deficits. In rats that were subjected to TGCI, CBD attenuated hippocampal CA1 neurodegeneration and increased brain-derived neurotrophic factor levels. Additionally, CBD protected neurons against the deleterious effects of TGCI on dendritic spine number and the length of dendritic arborization. These results suggest that the neuroprotective effects of CBD against TGCI-induced memory impairments involve changes in synaptic plasticity in the hippocampus.
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... For example, a single intravenous injection of melatonin mitigated the loss of dendritic spines of pyramidal neurons in the PFC and hippocampus that survived for up to 120 days after transient global brain ischemia (González-Burgos et al., 2007;García-Chávez et al., 2008). Similar recovery of dendritic spines was conferred by treatment with progesterone and allopregnanolone (Moralí et al., 2012), which also alleviated learning and memory deficits that were caused by ischemia (Moralí et al., 2011). Ischemia-induced dendritic spine deterioration in the hippocampus was prevented by acetyl-L-carnitine administration before and after ischemia, an effect that paralleled the normalization of hippocampal long-term potentiation, indicating the improvement of synaptic function at dendritic spines (Kocsis et al., 2014). ...
Pharmacological interventions that selectively activate serotonin 5-hydroxytryptramine-1A (5-HT1A) heteroreceptors may prevent or attenuate the consequences of brain ischemic episodes. The present study investigated whether the preferential 5-HT1A postsynaptic receptor agonist NLX-101 (a.k.a. F15599) mitigates cognitive and emotional impairments and affects neuroplasticity in mice that are subjected to the bilateral common carotid artery occlusion (BCCAO) model of brain ischemia. The selective serotonin reuptake inhibitor escitalopram (Esc) was used for comparative purposes because it is able to decrease morbidity and improve recovery in stroke patients and ischemic rodents. Sham and BCCAO mice received daily doses of NLX-101 (0.32 mg/kg, i.p) or Esc (20 mg/kg, i.p) for 28 days. During this period, they were evaluated for locomotor activity, anxiety- and despair-related behaviors and hippocampus-dependent cognitive function, using the open field, elevated zero maze, forced swim test and object location test, respectivelly. The mice's brains were processed for biochemical and histological analyses. BCCAO mice exhibited high anxiety and despair-like behaviors and performed worse than controls in the cognitive assessment. BCCAO induced neuronal and dendritic spine loss and decreases in the protein levels of neuronal plasticity markers, including brain-derived neurotrophic factor (BDNF), synaptophysin (SYN), and postsynaptic density protein-95 (PSD-95), in prefrontal cortex (PFC) and hippocampus. NLX-101 and Esc attenuated cognitive impairments and despair-like behaviors in BCCAO mice. Only Esc decreased anxiety-like behaviors due to brain ischemia. Both NLX-101 and Esc blocked the increase in plasma corticosterone levels and, restored BDNF, SYN and PSD-95 protein levels in the hippocampus. Moreover, both compounds impacted positively dentritic remodeling in the hippocampus and PFC of ischemic mice. In the PFC, NLX-101 increased the BDNF protein levels, while Esc in turn, attenuated the decrease in the PSD-95 protein levels induced by BCCAO. The present results suggest that activation of post-synaptic 5-HT1A receptors is the molecular mechanism for serotonergic protective effects in BCCAO. Moreover, post-synaptic biased agonists such as NLX-101 might constitute promising therapeutics for treatment of functional and neurodegenerative outcomes of brain ischemia.
... THP attenuates edema, trauma, stress, inflammation, apoptosis, and reduces oxidative stress during trauma or brain injury [31,[171][172][173]. THP is a protective agent in ischemia and maintains blood brain barrier integrity, memory and learning [173][174][175][176]. Finasteride increases apoptotic cell death in the cerebellum and hippocampus [177]. ...
Steroids are important physiological orchestrators of endocrine as well as peripheral and central nervous system functions. One of the key processes for regulation of these molecules lies in their enzymatic processing by a family of 5α-reductase (5α-Rs) isozymes. By catalyzing a key rate-limiting step in steroidogenesis, this family of enzymes exerts a crucial role not only in the physiological control but also in pathological events. Indeed, both 5α-R inhibition and supplementation of 5α-reduced metabolites are currently used or have been proposed as therapeutic strategies for a wide array of pathological conditions. In particular, the potent 5α-R inhibitors finasteride and dutasteride are used in the treatments of benign prostatic hyperplasia (BPH), as well as in male pattern hair loss (MPHL) known as androgenetic alopecia (AGA). Recent preclinical and clinical findings indicate that 5α-R inhibitors evoke not only beneficial, but also adverse effects. Future studies should investigate the biochemical and physiological mechanisms that underlie the persistence of the adverse sexual side effects to determine why a subset of patients is afflicted with such persistence or irreversible adverse effects. Also a better focus of clinical research is urgently needed to better define those subjects who are likely to be adversely affected by such agents. Furthermore, research on the non-sexual adverse effects such as diabetes, psychosis, depression, and cognitive function are needed to better understand the broad spectrum of the effects these drugs may elicit during their use in treatment of AGA or BPH. In this review, we will summarize the state of art on this topic, overview the key unresolved questions that have emerged on the pharmacological targeting of these enzymes and their products, and highlight the need for further studies to ascertain the severity and duration of the adverse effects of 5α-R inhibitors, as well as their biological underpinnings.
... AP is shown to be beneficial in the treatment of traumatic brain injury, attenuating edema, trauma, stress, inflammation, apoptosis, and reducing oxidative stress [76][77][78]. AP is not only a protective agent in ischemia, but also in maintaining blood brain barrier integrity, and in memory and learning [78][79][80][81]. Studies on CNS injury in which asphyxiation was induced in fetal sheep to stimulate neurological stressors, in the presence or absence of finasteride, showed an increase in apoptotic cell death in the cerebellum and hippocampus in the animals treated with finasteride (Fig. 5) [82]. ...
With aging, abnormal benign growth of the prostate results in benign prostate hyperplasia (BPH) with concomitant lower urinary tract symptoms (LUTS). Because the prostate is an androgen target tissue, and transforms testosterone into 5α-dihydrotestosterone (5α-DHT), a potent androgen, via 5α-reductase (5α-R) activity, inhibiting this key metabolic reaction was identified as a target for drug development to treat symptoms of BPH. Two drugs, namely finasteride and dutasteride were developed as specific 5α-reductase inhibitors (5α-RIs) and were approved by the U.S. Food and Drug Administration for the treatment of BPH symptoms. These agents have proven useful in the reducing urinary retention and minimizing surgical intervention in patients with BPH symptoms and considerable literature exists describing the benefits of these agents. In this review we highlight the adverse side effects of 5α-RIs on sexual function, high grade prostate cancer incidence, central nervous system function and on depression. 5α-Rs isoforms (types 1-3) are widely distributed in many tissues including the central nervous system and inhibition of these enzymes results in blockade of synthesis of several key hormones and neuro-active steroids leading to a host of adverse effects, including loss of or reduced libido, erectile dysfunction, orgasmic dysfunction, increased high Gleason grade prostate cancer, observed heart failure and cardiovascular events in clinical trials, and depression. Considerable evidence exists from preclinical and clinical studies, which point to significant and serious adverse effects of 5α-RIs, finasteride and dutasteride, on sexual health, vascular health, psychological health and the overall quality of life. Physicians need to be aware of such potential adverse effects and communicate such information to their patients prior to commencing 5α-RIs therapy.
... Allopregnanolone has been also considered in ischemia. Like PROG, this neuroactive steroid reduces infarction volume, improve blood brain barrier integrity as well as memory and learning (Ishrat et al., 2010; Morali et al., 2012; Sayeed et al., 2006) and as in the case of traumatic brain injury, allopregnanolone is generally more effective than PROG (Sayeed et al., 2006). Moreover, also in this case allopregnanolone specifically decreases mitochondrial cytochrome c release (Sayeed et al., 2009). ...
... Ventricular fibrillation was allowed to persist for 15 min, during which mechanical ventilation was ceased, and after which the cats were resuscitated. Global ischemia has also been induced in rats via a 4-vessel occlusion model (Morali et al., 2005(Morali et al., , 2012Ozacmak and Sayan, 2009;Zhao et al., 2011) in which the vertebral arteries are permanently occluded via cauterization, while the common carotid arteries are transiently occluded for 15 min with microvascular clamps. Bilateral carotid artery occlusion (BCAO) has been used to induce partial global ischemia in mice (Aggarwal et al., 2008). ...
... Mice treated with PROG following tMCAO showed improved performance on the MWM compared to vehicle-treated controls (Gibson and Murphy, 2004). This finding was replicated in rats treated with PROG before tMCAO (Cai et al., 2008) and following 4-vessel occlusion (Morali et al., 2012). The latter study also showed improvement on a 9-arm radial maze test, a measure of reference and working memory. ...
... ALLO has been utilized in a few experiments to treat ischemia. Like PROG, ALLO was shown to reduce infarction volume (Ishrat et al., 2010;Sayeed et al., 2006), improve BBB integrity (Ishrat et al., 2010), and improve learning and memory (Morali et al., 2012). As in TBI, results suggest that ALLO may be more potent than PROG when treating ischemia (Sayeed et al., 2006). ...
The sex hormone Progesterone has been shown to improve outcomes in animal models of a number of neurologic diseases, including traumatic brain injury, ischemia, spinal cord injury, peripheral nerve injury, demyelinating disease, neuromuscular disorders, and seizures. Evidence suggests it exerts its neuroprotective effects through several pathways, including reducing edema, improving neuronal survive, and modulating inflammation and apoptosis. In this review, we summarize the functional outcomes and pathophysiologic mechanisms attributed to Progesterone treatment in neurologic disease. We then comment on the breadth of evidence for the use of Progesterone in each neurologic disease family. Finally, we provide support for further human studies using Progesterone to treat several neurologic diseases.
... For administration of P 4 or vehicle, a catheter (Clay Adams, PE-50) was inserted into the right internal jugular vein. Rats were subjected to sham procedures, or to global ischemia during 13 min by a 4-VO model [20][21][22] routinely used in our laboratory [15][16][17]. Only rats remaining unconscious, with complete loss of the righting reflex during ischemia and for 20-50 min afterwards, as a neurological sign of having suffered a severe ischemia [19,21,28], were included in the study. ...
... Thus, P 4 administration in the same dose and treatment schedule as used in this study has been shown to be neuroprotective after global ischemia since, in spite of a limited preservation (20-40%) of CA1 pyramidal neurons [15,16], the functional integrity of the hippocampus was preserved, as shown by a better performance of spatial learning and memory in progesterone-than in non-treated animals, and similar to that of control rats [16]. Similar cytoarchitectural characteristics of remaining CA1 pyramidal neurons as those of intact rats [17] may have contributed to functional preservation. ...
... So it is possible that glutamatergic excitotoxicity plays a role in the vulnerability of CA1 neurons. Expressions of this vulnerability include the reduced dendritic branching, dendritic arbor retraction, loss of dendrites and changes of spine density and morphology in the CA1 subfield caused by inflammatory factors (Sakić et al., 1998), hypobaric hypoxia (Titus et al., 2007), old age (Markham et al., 2005), global cerebral ischemia (Moralí et al., 2012), neurodegeneration of Alzheimer's transgenic mice (Merino-Serrais et al., 2011), hypertension (Sánchez et al., 2011) and type I diabetes mellitus (Beauquis et al., 2010). It has been also recognized that the strong dendritic remodeling and atrophy caused in the CA3 region by chronic stress and glucocorticoid treatment may be also present in rat CA1 pyramidal cells (Christian et al., 2011;Donohue et al., 2006;Lambert et al., 1998). ...
Increased neuronal vulnerability has been described in the brain of spontaneously hypertensive rats (SHR), models of primary hypertension. Previous data indicate that estradiol treatment corrects several dysfunctions of the hippocampus and hypothalamus of SHR. Considering this evidence we analyzed the dendritic arborization and spine density of the CA1 subfield in SHR and Wistar-Kyoto (WKY) normotensive rats with and without estradiol treatment. Five month old male SHR and WKY rats received single estradiol or cholesterol pellets (sham treatment) for 2 weeks. A substantial rise of circulating estradiol (> 25 fold) and testicular atrophy was present in all estradiol-receiving rats. In both SHR and WKY rats, estradiol decreased blood pressure by ~ 20 mmHg; however, a moderate hypertension persisted in SHR (164 mmHg). Using a modified Golgi impregnation technique, apical and basal dendrites of the CA1 subfield were subjected to Sholl analysis. Spine density was also statistically analyzed. Apical dendritic length was significantly lower in SHR compared to WKY rats (p<0.01), whereas estradiol treatment increased dendritic length in the SHR group only (SHR vs SHR + estradiol; p<0.01). Apical dendritic length plotted against the shell distances 20-100, 120-200 and 220-300 μm, revealed that changes were more pronounced in the range 120-200 μm between SHR vs. WKY rats (p<0.05) and SHR vs. SHR + estradiol (p<0.05). Instead, basal dendrites were not significantly modified by hypertension or steroid treatment. Spine density of apical dendrites was lower in SHR than WKY (p<0.05) and was up-regulated in the SHR + estradiol group compared to the SHR group (p<0.001). Similar changes were obtained for basal dendritic spines. These data suggest that changes of neuronal processes in SHR are plastic events restorable by estradiol treatment. In conjunction with previous results, the present data reveal new targets of estradiol neuroprotection in the brain of hypertensive rats.
... Progesterone-induced anticonvulsant effects seem to be mediated via its metabolite allopregnanolone, which activates GABA A receptors (Frye et al., 2002;Reddy, 2010). In contrast, doses of both sex hormones resulting in supraphysiological concentrations may enhance seizure susceptibility and these effects may be due to enhanced NMDA-mediated transmission due to increased dendritic spine density by either estradiol or progesterone (Morali et al., 2012;Woolley and McEwen, 1993). ...
... In addition, chronic administration of allopregnanolone contributes to a paradoxical hyperexcitability state by increasing the expression of α4 subunit of GABA A receptors (denotes the extrasynaptic receptors insensitive to benzodiazepines) (Smith et al., 2007). The hyperexcitability could be also related to progesterone-induced increase in dendritic spine density with mushroom like spines (Morali et al., 2012), which is similar to estradiol effects (Woolley and McEwen, 1994) and to positive modulation of NMDA receptors and glutamate release (Giuliani et al., 2011). Finally, epileptiform activity causes changes in GABA A receptor subunit composition, which then in turn leads to decreased sensitivity of the GABA A receptors to ligands, including neurosteroids (Joshi et al., 2011). ...
Epilepsy is the third most common chronic neurological disorder. Clinical and experimental evidence supports the role of sex and influence of sex hormones on seizures and epilepsy as well as alterations of the endocrine system and levels of sex hormones by epileptiform activity. Conversely, seizures are sensitive to changes in sex hormone levels, which in turn may affect the seizure-induced neuronal damage. The effects of reproductive hormones on neuronal excitability and seizure-induced damage are complex to contradictory and depend on different mechanisms, which have to be accounted for in data interpretation. Both estradiol and progesterone/allopregnanolone may have beneficial effects for patients with epilepsy. Individualized hormonal therapy should be considered as adjunctive treatment in patients with epilepsy to improve seizure control as well as quality of life. This article is part of a Special Issue entitled Hormones & Neurotrauma.
