Aberrant Hippocampal Neuroregenerative Plasticity in Schizophrenia: Reactive Neuroblastosis as a Possible Pathocellular Mechanism of Hallucination.

Hallucination is a sensory perception that occurs in the absence of external stimuli during abnormal neurological disturbances and various mental diseases. Hallucination is recognized as a core psychotic symptom and is particularly more prevalent in individuals with schizophrenia. Strikingly, a significant number of subjects with Alzheimer's disease (AD), Parkinson's disease (PD), Huntington's disease (HD), and other neurological diseases like cerebral stroke and epileptic seizure also experience hallucination. While aberrant neurotransmission has been linked to the neuropathogenic events of schizophrenia, the precise cellular mechanism accounting for hallucinations remains obscure. Neurogenesis is a cellular process of producing new neurons from the neural stem cells (NSC)-derived neuroblasts in the brain that contribute to the regulation of pattern separation, mood, olfaction, learning, and memory in adulthood. Impaired neurogenesis in the hippocampus of the adult brain has been linked to stress, anxiety, depression, and dementia. Notably, many neurodegenerative disorders are characterized by the mitotic and functional activation of neuroblasts and cell cycle re-entry of mature neurons leading to a drastic alteration in neurogenic process, known as reactive neuroblastosis. Considering their neurophysiological properties, the abnormal integration of neuroblasts into the existing neural network or withdrawal of their connections can lead to abnormal synaptogenesis, and neurotransmission. Eventually, this would be expected to result in altered perception accounting for hallucination. Thus, this article emphasizes a hypothesis that aberrant neurogenic processes at the level of reactive neuroblastosis could be an underlying mechanism of hallucination in schizophrenia and other neurological diseases.

BOTOX® counteracts the innate anxiety-related behaviours in correlation with increased activities of key antioxidant enzymes in the hippocampus of ageing experimental mice.

Cholinergic crisis and oxidative stress in the hippocampus of the brain have been known to induce anxiety disorders upon ageing. BOTOX® is a widely used therapeutic form of botulinum neurotoxin that acts by inhibiting the release of acetylcholine (ACh) from the nerve terminals at the neuromuscular junction. BOTOX® can migrate from the muscle to the brain through retrograde axonal transport and modulate neuroplasticity. While a mild dose of BOTOX® has been used to manage various neurological deficits and psychiatric complications including depression, the efficacy and experimental evidence for its anxiolytic effects and antioxidant properties remain limited. In this study, we have investigated the effect of BOTOX® on the innate anxiety-like behaviours in ageing mice upon exposure to different behavioural paradigms like open field test, elevated plus maze and light-dark box test, and estimated the enzymatic activities of key antioxidants in the hippocampus. Results revealed that animals injected with a mild intramuscular dosage of BOTOX® showed reduced level of innate anxiety-related symptoms and increased activities of hippocampal antioxidant enzymes compared to the control group. This study strongly supports that BOTOX® could be implemented to prevent or treat anxiety and hippocampal oxidative stress resulting from ageing, emotional and mood disorders.

Intramuscular Injection of BOTOX® Boosts Learning and Memory in Adult Mice in Association with Enriched Circulation of Platelets and Enhanced Density of Pyramidal Neurons in the Hippocampus.

BOTOX® is a therapeutic form of botulinum neurotoxin. It acts by blocking the release of acetylcholine (ACh) from the synaptic vesicles at the neuromuscular junctions, thereby inhibiting the muscle contraction. Notably, many neurological diseases have been characterized by movement disorders in association with abnormal levels of ACh. Thus, blockade of aberrant release of ACh appears to be a potential therapeutic strategy to mitigate many neurological deficits. BOTOX® has widely been used to manage a number of clinical complications like neuromuscular disorders, migraine and neuropathic pain. While the beneficial effects of BOTOX® against movement disorders have extensively been studied, its possible role in the outcome of cognitive function remains to be determined. Therefore, we investigated the effect of BOTOX® on learning and memory in experimental adult mice using behavioural paradigms such as open field task, Morris water maze and novel object recognition test in correlation with haematological parameters and histological assessments of the brain. Results revealed that a mild dose of BOTOX® treatment via an intramuscular route in adult animals improves learning and memory in association with increased number of circulating platelets and enhanced structural plasticity in the hippocampus. In the future, this minimally invasive treatment could be implemented to ameliorate different forms of dementia resulting from abnormal ageing and various neurocognitive disorders including Alzheimer's disease (AD).

Possible Existence of the Hypothalamic-Pituitary-Hippocampal (HPH) Axis: A Reciprocal Relationship Between Hippocampal Specific Neuroestradiol Synthesis and Neuroblastosis in Ageing Brains with Special Reference to Menopause and Neurocognitive Disorders.

The hippocampus-derived neuroestradiol plays a major role in neuroplasticity, independent of circulating estradiol that originates from gonads. The response of hypothalamus-pituitary regions towards the synthesis of neuroestradiol in the hippocampus is an emerging scientific concept in cognitive neuroscience. Hippocampal plasticity has been proposed to be regulated via neuroblasts, a major cellular determinant of functional neurogenesis in the adult brain. Defects in differentiation, integration and survival of neuroblasts in the hippocampus appear to be an underlying cause of neurocognitive disorders. Gonadotropin receptors and steroidogenic enzymes have been found to be expressed in neuroblasts in the hippocampus of the brain. However, the reciprocal relationship between hippocampal-specific neuroestradiol synthesis along neuroblastosis and response of pituitary based feedback regulation towards regulation of estradiol level in the hippocampus have not completely been ascertained. Therefore, this conceptual article revisits (1) the cellular basis of neuroestradiol synthesis (2) a potential relationship between neuroestradiol synthesis and neuroblastosis in the hippocampus (3) the possible involvement of aberrant neuroestradiol production with mitochondrial dysfunctions and dyslipidemia in menopause and adult-onset neurodegenerative disorders and (4) provides a hypothesis for the possible existence of the hypothalamic-pituitary-hippocampal (HPH) axis in the adult brain. Eventually, understanding the regulation of hippocampal neurogenesis by abnormal levels of neuroestradiol concentration in association with the feedback regulation of HPH axis might provide additional cues to establish a neuroregenerative therapeutic management for mood swings, depression and cognitive decline in menopause and neurocognitive disorders.

p57kip2 regulates glial fate decision in adult neural stem cells.

Our recent studies revealed p57kip2 as an intrinsic regulator of late gliogenesis and demonstrated that in oligodendroglial precursor cells p57kip2 inhibition leads to accelerated maturation. Adult neural stem cells have been described as a source of glial progenitors; however, the underlying mechanisms of cell fate specification are still poorly understood. Here, we have investigated whether p57kip2 can influence early events of glial determination and differentiation. We found that Sox2/GFAP double-positive cells express p57kip2 in stem cell niches of the adult brain. Short-hairpin RNA-mediated suppression of p57kip2 in cultured adult neural stem cells was found to strongly reduce astroglial characteristics, while oligodendroglial precursor features were increased. Importantly, this anti-astrogenic effect of p57kip2 suppression dominated the bone morphogenetic protein-mediated promotion of astroglial differentiation. Moreover, we observed that in p57kip2 knockdown cells, the BMP antagonist chordin was induced. Finally, when p57kip2-suppressed stem cells were transplanted into the adult spinal cord, fewer GFAP-positive cells were generated and oligodendroglial markers were induced when compared with control cells, demonstrating an effect of in vivo relevance.

TGF-beta signalling in the adult neurogenic niche promotes stem cell quiescence as well as generation of new neurons.

Members of the transforming growth factor (TGF)-ß family govern a wide range of mechanisms in brain development and in the adult, in particular neuronal/glial differentiation and survival, but also cell cycle regulation and neural stem cell maintenance. This clearly created some discrepancies in the field with some studies favouring neuronal differentiation/survival of progenitors and others favouring cell cycle exit and neural stem cell quiescence/maintenance. Here, we provide a unifying hypothesis claiming that through its regulation of neural progenitor cell (NPC) proliferation, TGF-ß signalling might be responsible for (i) maintaining stem cells in a quiescent stage, and (ii) promoting survival of newly generated neurons and their functional differentiation. Therefore, we performed a detailed histological analysis of TGF-ß1 signalling in the hippocampal neural stem cell niche of a transgenic mouse that was previously generated to express TGF-ß1 under a tetracycline regulatable Ca-Calmodulin kinase promoter. We also analysed NPC proliferation, quiescence, neuronal survival and differentiation in relation to elevated levels of TGF-ß1 in vitro and in vivo conditions. Finally, we performed a gene expression profiling to identify the targets of TGF-ß1 signalling in adult NPCs. The results demonstrate that TGF-ß1 promotes stem cell quiescence on one side, but also neuronal survival on the other side. Thus, considering the elevated levels of TGF-ß1 in ageing and neurodegenerative diseases, TGF-ß1 signalling presents a molecular target for future interventions in such conditions.

Electrochemical failure of the brain cortex is more deleterious when it is accompanied by low perfusion.

BACKGROUND AND PURPOSE: Clinical and experimental evidence suggests that spreading depolarization facilitates neuronal injury when its duration exceeds a certain time point, termed commitment point. We here investigated whether this commitment point is shifted to an earlier period, when spreading depolarization is accompanied by a perfusion deficit. METHODS: Electrophysiological and cerebral blood flow changes were studied in a rat cranial window model followed by histological and immunohistochemical analyses of cortical damage. RESULTS: In group 1, brain topical application of artificial cerebrospinal fluid (ACSF) with high K(+) concentration ([K(+)](ACSF)) for 1 hour allowed us to induce a depolarizing event of fixed duration with cerebral blood flow fluctuations around the baseline (short-lasting initial hypoperfusions followed by hyperemia). In group 2, coapplication of the NO-scavenger hemoglobin ([Hb](ACSF)) with high [K(+)](ACSF) caused a depolarizing event of similar duration, to which a severe perfusion deficit was coupled (=spreading ischemia). In group 3, intravenous coadministration of the L-type calcium channel antagonist nimodipine with brain topical application of high [K(+)](ACSF)/[Hb](ACSF) caused spreading ischemia to revert to spreading hyperemia. Whereas scattered neuronal injury occurred in the superficial cortical layers in the window areas of groups 1 and 3, necrosis of all layers with partial loss of the tissue texture and microglial activation were observed in group 2. CONCLUSIONS: The results suggest that electrochemical failure of the cortex is more deleterious when it is accompanied by low perfusion. Thus, the commitment point of the cortex is not a universal value but depends on additional factors, such as the level of perfusion.

Resveratrol Mediated Regulation of Hippocampal Neuroregenerative Plasticity via SIRT1 Pathway in Synergy with Wnt Signaling: Neurotherapeutic Implications to Mitigate Memory Loss in Alzheimer's Disease.

Alzheimer's disease (AD) is a major form of dementia. Abnormal amyloidogenic event-mediated degeneration of cholinergic neurons in the cognitive centers of the brain has been attributed to neuropathological sequelae and behavioral deficits in AD. Besides, impaired adult neurogenesis in the hippocampus has experimentally been realized as an underlying cause of dementia regardless of neurodegeneration. Therefore, nourishing the neurogenic process in the hippocampus has been considered an effective therapeutic strategy to mitigate memory loss. In the physiological state, the Wnt pathway has been identified as a potent mitogenic generator in the hippocampal stem cell niche. However, downstream components of Wnt signaling have been noticed to be downregulated in AD brains. Resveratrol (RSV) is a potent Sirtuin1 (SIRT1) enhancer that facilitates neuroprotection and promotes neurogenesis in the hippocampus of the adult brain. While SIRT1 is an important positive regulator of Wnt signaling, ample reports indicate that RSV treatment strongly mediates the fate determination of stem cells through Wnt signaling. However, the possible therapeutic roles of RSV-mediated SIRT1 enhancement on the regulation of hippocampal neurogenesis and reversal of memory loss through the Wnt signaling pathway have not been addressed yet. Taken together, this review describes RSV-mediated effects on the regulation of hippocampal neurogenesis via the activation of SIRT1 in synergy with the Wnt signaling. Further, the article emphasizes a hypothesis that RSV treatment can provoke the activation of quiescent neural stem cells and prime their neurogenic capacity in the hippocampus via Wnt signaling in AD.

Ranitidine Alleviates Anxiety-like Behaviors and Improves the Density of Pyramidal Neurons upon Deactivation of Microglia in the CA3 Region of the Hippocampus in a Cysteamine HCl-Induced Mouse Model of Gastrointestinal Disorder.

Elevated levels of histamine cause over-secretion of gastric hydrochloric acid (HCl), leading to gastrointestinal (GI) disorders and anxiety. Ranitidine is an antihistamine drug widely used in the management of GI disorders, as it works by blocking the histamine-2 receptors in parietal cells, thereby reducing the production of HCl in the stomach. While some reports indicate the neuroprotective effects of ranitidine, its role against GI disorder-related anxiety remains unclear. Therefore, we investigated the effect of ranitidine against anxiety-related behaviors in association with changes in neuronal density in the hippocampal cornu ammonis (CA)-3 region of cysteamine hydrochloride-induced mouse model of GI disorder. Results obtained from the open field test (OFT), light and dark box test (LDBT), and elevated plus maze (EPM) test revealed that ranitidine treatment reduces anxiety-like behaviors in experimental animals. Nissl staining and immunohistochemical assessment of ionized calcium-binding adapter molecule (Iba)-1 positive microglia in cryosectioned brains indicated enhanced density of pyramidal neurons and reduced activation of microglia in the hippocampal CA-3 region of brains of ranitidine-treated experimental mice. Therefore, this study suggests that ranitidine mediates anxiolytic effects, which can be translated to establish a pharmacological regime to ameliorate anxiety-related symptoms in humans.

Pathogenomic Signature and Aberrant Neurogenic Events in Experimental Cerebral Ischemic Stroke: A Neurotranscriptomic-Based Implication for Dementia.

BACKGROUND: Cerebral ischemic stroke is caused due to neurovascular damage or thrombosis, leading to neuronal dysfunction, neuroinflammation, neurodegeneration, and regenerative failure responsible for neurological deficits and dementia. The valid therapeutic targets against cerebral stroke remain obscure. Thus, insight into neuropathomechanisms resulting from the aberrant expression of genes appears to be crucial. OBJECTIVE: In this study, we have elucidated how neurogenesis-related genes are altered in experimental stroke brains from the available transcriptome profiles in correlation with transcriptome profiles of human postmortem stroke brain tissues. METHODS: The transcriptome datasets available on the middle cerebral artery occlusion (MCAo) rat brains were obtained from the Gene Expression Omnibus, National Center for Biotechnology Information. Of the available datasets, 97 samples were subjected to the meta-analysis using the network analyst tool followed by Cytoscape-based enrichment mapping analysis. The key differentially expressed genes (DEGs) were validated and compared with transcriptome profiling of human stroke brains. RESULTS: Results revealed 939 genes are differently expressed in the brains of the MCAo rat model of stroke, in which 30 genes are key markers of neural stem cells, and regulators of neurogenic processes. Its convergence with DEGs from human stroke brains has revealed common targets. CONCLUSION: This study has established a panel of highly important DEGs to signify the potential therapeutic targets for neuroregenerative strategy against pathogenic events associated with cerebral stroke. The outcome of the findings can be translated to mitigate neuroregeneration failure seen in various neurological and metabolic disease manifestations with neurocognitive impairments.

A Mild Dose of Aspirin Promotes Hippocampal Neurogenesis and Working Memory in Experimental Ageing Mice.

Aspirin has been reported to prevent memory decline in the elderly population. Adult neurogenesis in the hippocampus has been recognized as an underlying basis of learning and memory. This study investigated the effect of aspirin on spatial memory in correlation with the regulation of hippocampal neurogenesis and microglia in the brains of ageing experimental mice. Results from the novel object recognition (NOR) test, Morris water maze (MWM), and cued radial arm maze (cued RAM) revealed that aspirin treatment enhances working memory in experimental mice. Further, the co-immunohistochemical assessments on the brain sections indicated an increased number of doublecortin (DCX)-positive immature neurons and bromodeoxyuridine (BrdU)/neuronal nuclei (NeuN) double-positive newly generated neurons in the hippocampi of mice in the aspirin-treated group compared to the control group. Moreover, a reduced number of ionized calcium-binding adaptor molecule (Iba)-1-positive microglial cells was evident in the hippocampus of aspirin-treated animals. Recently, enhanced activity of acetylcholinesterase (AChE) in circulation has been identified as an indicative biomarker of dementia. The biochemical assessment in the blood of aspirin-treated mice showed decreased activity of AChE in comparison with that of the control group. Results from this study revealed that aspirin facilitates hippocampal neurogenesis which might be linked to enhanced working memory.

SARS-CoV-2-Mediated Neuropathogenesis, Deterioration of Hippocampal Neurogenesis and Dementia.

A significant portion of COVID-19 patients and survivors display marked clinical signs of neurocognitive impairments. SARS-CoV-2-mediated peripheral cytokine storm and its neurotropism appear to elicit the activation of glial cells in the brain proceeding to neuroinflammation. While adult neurogenesis has been identified as a key cellular basis of cognitive functions, neuroinflammation-induced aberrant neuroregenerative plasticity in the hippocampus has been implicated in progressive memory loss in ageing and brain disorders. Notably, recent histological studies of post-mortem human and experimental animal brains indicate that SARS-CoV-2 infection impairs neurogenic process in the hippocampus of the brain due to neuroinflammation. Considering the facts, this article describes the prominent neuropathogenic characteristics and neurocognitive impairments in COVID-19 and emphasizes a viewpoint that neuroinflammation-mediated deterioration of hippocampal neurogenesis could contribute to the onset and progression of dementia in COVID-19. Thus, it necessitates the unmet need for regenerative medicine for the effective management of neurocognitive deficits in COVID-19.

Liposome encapsulated clodronate mediated elimination of pathogenic macrophages and microglia: A promising pharmacological regime to defuse cytokine storm in COVID-19.

The emergence of new SARS-CoV-2 variants continues to pose an enormous public health concern. The SARS-CoV-2 infection disrupted host immune response accounting for cytokine storm has been linked to multiorgan failure and mortality in a significant portion of positive cases. Abruptly activated macrophages have been identified as the key pathogenic determinant of cytokine storm in COVID-19. Besides, reactive microglia have been known to discharge a surplus amount of proinflammatory factors leading to neuropathogenic events in the brains of SARS-CoV-2 infected individuals. Considering the fact, depletion of activated macrophages and microglia could be proposed to eradicate the life-threatening cytokine storm in COVID-19. Clodronate, a non-nitrogenous bisphosphonate drug has been identified as a potent macrophage and microglial depleting agent. While recent advancement in the field of liposome encapsulation technology offers the most promising biological tool for drug delivery, liposome encapsulated clodronate has been reported to effectively target and induce prominent phagocytic cell death in activated macrophages and microglia compared to free clodronate molecules. Thus, in this review article, we emphasize that depletion of activated macrophages and microglial cells by administration of liposome encapsulated clodronate can be a potential therapeutic strategy to diminish the pathogenic cytokine storm and alleviate multiorgan failure in COVID-19. Moreover, recently developed COVID-19 vaccines appear to render the chronic activation of macrophages accounting for immunological dysregulation in some cases. Therefore, the use of liposome encapsulated clodronate can also be extended to the clinical management of unforeseen immunogenic reactions resulting from activated macrophages associated adverse effects of COVID-19 vaccines.

Single injection of very mild dose botulinum toxin in the vastus lateralis improves testicular spermatogenesis and sperm motility in ageing experimental mice.

BACKGROUND: Botulinum toxin (BoNT) is a widely used therapeutic agent that blocks the excessive release of acetylcholine at the neuromuscular junction. Previously, repeated intracremasteric injections and slight overdose of BoNT have been reported to induce adverse effects in the testicular parameter of experimental rodents. However, a mild dose of BoNT is highly beneficial against skin ageing, neuromuscular deficits, overactive urinary bladder problems, testicular pain and erectile dysfunctions. Considering the facts, the possible therapeutic benefits of BoNT on the testis might be achieved at a very minimal dosage and via a distal route of action. Therefore, we revisited the effect of BoNT, but with a trace amount injected into the vastus lateralis of the thigh muscle, and analyzed histological parameters of the testis, levels of key antioxidants and sperm parameters in ageing experimental mice. RESULTS: Experimental animals injected with 1 U/kg bodyweight of BoNT showed enhanced spermatogenesis in association with increased activities of key antioxidants in the testis, leading to enhanced amount of the total sperm count and progressive motility. CONCLUSIONS: This study signifies that a mild intramuscular dose of BoNT can be considered as a potent treatment strategy to manage and prevent male infertility.

Omeprazole treatment manifests anxiolytic effects in a cysteamine hydrochloride induced mouse model of gastrointestinal disorder.

Omeprazole, a proton pump inhibitor (PPI), has widely been used to treat various gastrointestinal (GI) disorders. Notably, many clinical symptoms of GI disorders have been known to be associated with anxiety. In recent years, an exponentially increased number of subjects with abnormal ageing, neurological deficits, and psychiatric problems simultaneously exhibit GI dysfunctions as well as anxiety. Considering the fact, drugs that are used to treat GI disorders can be speculated to mitigate anxiety-related symptoms, and vice versa. Although, omeprazole treatment has been reported to result in development of anxiety and neurocognitive decline, ample reports suggest that omeprazole treatment is beneficial for the positive regulation of neuroplasticity. While underlying mechanisms of omeprazole-mediated neurological alterations remain obscure, the available scientific data on the omeprazole induced adverse effects in the brain appear to be inadequate, uncertain, and controversial. Hence, this study revisited the effect of omeprazole treatment on the degree of anxiety-like behaviours in a cysteamine hydrochloride (HCl) induced mouse model of GI disorder using open field test (OFT), light-dark box (LDB) test and elevated plus maze (EPM). Results revealed that omeprazole treatment mitigates anxiety-related behaviours in the cysteamine HCl induced animal model of GI disorder. Thus, this study assuredly supports and validates the anxiolytic properties of omeprazole. However, the adverse effects associated with inappropriate intake of omeprazole may not completely be excluded. Therefore, this study advocates the future direction in determining the long-term effects of omeprazole on the brain functions.

NF-κB signalling as a pharmacological target in COVID-19: potential roles for IKKß inhibitors.

Coronavirus disease 2019 (COVID-19) has been characterized by lymphopenia as well as a proinflammatory cytokine storm, which are responsible for the poor prognosis and multiorgan defects. The transcription factor nuclear factor-κB (NF-κB) modulates the functions of the immune cells and alters the gene expression profile of different cytokines in response to various pathogenic stimuli, while many proinflammatory factors have been known to induce NF-κB signalling cascade. Besides, NF-κB has been known to potentiate the production of reactive oxygen species (ROS) leading to apoptosis in various tissues in many diseases and viral infections. Though the reports on the involvement of the NF-κB signalling pathway in COVID-19 are limited, the therapeutic benefits of NF-κB inhibitors including dexamethasone, a synthetic form of glucocorticoid, have increasingly been realized. Considering the fact, the abnormal activation of the NF-κB resulting from severe acute respiratory syndrome coronavirus-2 (SARS-CoV-2) infection might be associated with the pathogenic profile of immune cells, cytokine storm and multiorgan defects. Thus, the pharmacological inactivation of the NF-κB signalling pathway can strongly represent a potential therapeutic target to treat the symptomatology of COVID-19. This article signifies pharmacological blockade of the phosphorylation of inhibitor of nuclear factor kappa B kinase subunit beta (IKKß), a key downstream effector of NF-κB signalling, for a therapeutic consideration to attenuate COVID-19.

Repurposing of histone deacetylase inhibitors: A promising strategy to combat pulmonary fibrosis promoted by TGF-ß signalling in COVID-19 survivors.

Coronavirus disease 2019 (COVID-19) has rapidly spread around the world causing global public health emergency. In the last twenty years, we have witnessed several viral epidemics such as severe acute respiratory syndrome coronavirus (SARS-CoV), Influenza A virus subtype H1N1 and most recently Middle East respiratory syndrome coronavirus (MERS-CoV). There were tremendous efforts endeavoured globally by scientists to combat these viral diseases and now for SARS-CoV-2. Several drugs such as chloroquine, arbidol, remdesivir, favipiravir and dexamethasone are adopted for use against COVID-19 and currently clinical studies are underway to test their safety and efficacy for treating COVID-19 patients. As per World Health Organization reports, so far more than 16 million people are affected by COVID-19 with a recovery of close to 10 million and deaths at 600,000 globally. SARS-CoV-2 infection is reported to cause extensive pulmonary damages in affected people. Given the large number of recoveries, it is important to follow-up the recovered patients for apparent lung function abnormalities. In this review, we discuss our understanding about the development of long-term pulmonary abnormalities such as lung fibrosis observed in patients recovered from coronavirus infections (SARS-CoV and MERS-CoV) and probable epigenetic therapeutic strategy to prevent the development of similar pulmonary abnormalities in SARS-CoV-2 recovered patients. In this regard, we address the use of U.S. Food and Drug Administration (FDA) approved histone deacetylase (HDAC) inhibitors therapy to manage pulmonary fibrosis and their underlying molecular mechanisms in managing the pathologic processes in COVID-19 recovered patients.

COVID-19 and Parkinson's disease: Defects in neurogenesis as the potential cause of olfactory system impairments and anosmia.

Anosmia, a neuropathogenic condition of loss of smell, has been recognized as a key pathogenic hallmark of the current pandemic SARS-CoV-2 infection responsible for COVID-19. While the anosmia resulting from olfactory bulb (OB) pathology is the prominent clinical characteristic of Parkinson's disease (PD), SARS-CoV-2 infection has been predicted as a potential risk factor for developing Parkinsonism-related symptoms in a significant portion of COVID-19 patients and survivors. SARS-CoV-2 infection appears to alter the dopamine system and induce the loss of dopaminergic neurons that have been known to be the cause of PD. However, the underlying biological basis of anosmia and the potential link between COVID-19 and PD remains obscure. Ample experimental studies in rodents suggest that the occurrence of neural stem cell (NSC) mediated neurogenesis in the olfactory epithelium (OE) and OB is important for olfaction. Though the occurrence of neurogenesis in the human forebrain has been a subject of debate, considerable experimental evidence strongly supports the incidence of neurogenesis in the human OB in adulthood. To note, various viral infections and neuropathogenic conditions including PD with olfactory dysfunctions have been characterized by impaired neurogenesis in OB and OE. Therefore, this article describes and examines the recent reports on SARS-CoV-2 mediated OB dysfunctions and defects in the dopaminergic system responsible for PD. Further, the article emphasizes that COVID-19 and PD associated anosmia could result from the regenerative failure in the replenishment of the dopaminergic neurons in OB and olfactory sensory neurons in OE.

Testicular Atrophy and Hypothalamic Pathology in COVID-19: Possibility of the Incidence of Male Infertility and HPG Axis Abnormalities.

Coronavirus disease 2019 (COVID-19), which resulted from the pandemic outbreak of the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), causes a massive inflammatory cytokine storm leading to multi-organ damage including that of the brain and testes. While the lungs, heart, and brain are identified as the main targets of SARS-CoV-2-mediated pathogenesis, reports on its testicular infections have been a subject of debate. The brain and testes are physiologically synchronized by the action of gonadotropins and sex steroid hormones. Though the evidence for the presence of the viral particles in the testicular biopsies and semen samples from COVID-19 patients are highly limited, the occurrence of testicular pathology due to abrupt inflammatory responses and hyperthermia has incresingly been evident. The reduced level of testosterone production in COVID-19 is associated with altered secretion of gonadotropins. Moreover, hypothalamic pathology which results from SARS-CoV-2 infection of the brain is also evident in COVID-19 cases. This article revisits and supports the key reports on testicular abnormalities and pathological signatures in the hypothalamus of COVID-19 patients and emphasizes that testicular pathology resulting from inflammation and oxidative stress might lead to infertility in a significant portion of COVID-19 survivors. Further investigations are required to monitor the reproductive health parameters and HPG axis abnormalities related to secondary pathological complications in COVID-19 patients and survivors.

Prolactin prevents chronic stress-induced decrease of adult hippocampal neurogenesis and promotes neuronal fate.

Chronic exposure to stress results in a reduction of hippocampal neurogenesis and of hippocampal volume. We examined whether prolactin (PRL), a regulator of the stress response and stimulator of neurogenesis in the subventricular zone, influences neurogenesis in the hippocampal dentate gyrus (DG) of chronically stressed adult C57BL/6 male mice. Chronically stressed (4 h daily immobilization for 21 d) or nonstressed mice were treated with either ovine PRL or vehicle between days 1-14. BrdU was injected daily between days 1-7 to evaluate cell survival and fate, or twice on day 21 to evaluate cell proliferation. Hippocampal cell proliferation was unchanged by either stress exposure or PRL at the end of the treatments. In contrast, the number of cells in the DG that incorporated BrdU during the first phase of the experiment and survived to the end of the experiment was decreased in vehicle-treated stressed mice compared with PRL- or vehicle-treated nonstressed control mice. Stressed animals receiving PRL had significantly more BrdU-labeled cells than vehicle-treated stressed mice at this time point. Cell fate analysis revealed a higher percentage of neurons in PRL- compared with vehicle-treated stressed mice. The results demonstrate that PRL protects neurogenesis in the DG of chronically stressed mice and promotes neuronal fate.