Cannabinoids modulate proliferation, differentiation, and migration signaling pathways in oligodendrocytes.

Cannabinoid signaling, mainly via CB1 and CB2 receptors, plays an essential role in oligodendrocyte health and functions. However, the specific molecular signals associated with the activation or blockade of CB1 and CB2 receptors in this glial cell have yet to be elucidated. Mass spectrometry-based shotgun proteomics and in silico biology tools were used to determine which signaling pathways and molecular mechanisms are triggered in a human oligodendrocytic cell line (MO3.13) by several pharmacological stimuli: the phytocannabinoid cannabidiol (CBD); CB1 and CB2 agonists ACEA, HU308, and WIN55, 212-2; CB1 and CB2 antagonists AM251 and AM630; and endocannabinoids anandamide (AEA) and 2-arachidonoylglycerol (2-AG). The modulation of cannabinoid signaling in MO3.13 was found to affect pathways linked to cell proliferation, migration, and differentiation of oligodendrocyte progenitor cells. Additionally, we found that carbohydrate and lipid metabolism, as well as mitochondrial function, were modulated by these compounds. Comparing the proteome changes and upstream regulators among treatments, the highest overlap was between the CB1 and CB2 antagonists, followed by overlaps between AEA and 2-AG. Our study opens new windows of opportunities, suggesting that cannabinoid signaling in oligodendrocytes might be relevant in the context of demyelinating and neurodegenerative diseases. Proteomics data are available at ProteomeXchange (PXD031923).

New multifunctional AChE inhibitor drug prototypes protect against Aß-induced memory deficit.

Alzheimer's disease (AD) is the most incident neurodegenerative disorder, characterized by accumulation of extracellular amyloid-ß (Aß), intracellular neurofibrillary tangles, and cognitive impairment. The current available treatments are mainly based on the use of reversible acetylcholinesterase (AChE) inhibitors, which only ameliorate the cognitive deficits. However, it is important to develop disease-modifying drugs with neuroprotective effects in order to hamper the progression of the disease. Here, we describe the effect of four promising new drugs with additional protective characteristics on AD-associated memory changes. C57Bl/6 mice treated with the compounds received an intra-hippocampal injection of Aß1-40 and were submitted to the novel object recognition test, to evaluate memory recovery. All the compounds prevented memory loss. Compounds PQM-56 (4c) and PQM-67 (4g) showed the best profile of memory recovery, representing potential drug candidates for AD treatment.

Cannabinoid signalling in embryonic and adult neurogenesis: possible implications for psychiatric and neurological disorders.

Cannabinoid signalling modulates several aspects of brain function, including the generation and survival of neurons during embryonic and adult periods. The present review intended to summarise evidence supporting a role for the endocannabinoid system on the control of neurogenesis and neurogenesis-dependent functions. Studies reporting participation of cannabinoids on the regulation of any step of neurogenesis and the effects of cannabinoid compounds on animal models possessing neurogenesis-dependent features were selected from Medline. Qualitative evaluation of the selected studies indicated that activation of cannabinoid receptors may change neurogenesis in embryonic or adult nervous systems alongside rescue of phenotypes in animal models of different psychiatric and neurological disorders. The text offers an overview on the effects of cannabinoids on central nervous system development and the possible links with psychiatric and neurological disorders such as anxiety, depression, schizophrenia, brain ischaemia/stroke and Alzheimer's disease. An understanding of the mechanisms by which cannabinoid signalling influences developmental and adult neurogenesis will help foster the development of new therapeutic strategies for neurodevelopmental, psychiatric and neurological disorders.

Cannabidiol, neuroprotection and neuropsychiatric disorders.

Cannabidiol (CBD) is a non-psychotomimetic phytocannabinoid derived from Cannabis sativa. It has possible therapeutic effects over a broad range of neuropsychiatric disorders. CBD attenuates brain damage associated with neurodegenerative and/or ischemic conditions. It also has positive effects on attenuating psychotic-, anxiety- and depressive-like behaviors. Moreover, CBD affects synaptic plasticity and facilitates neurogenesis. The mechanisms of these effects are still not entirely clear but seem to involve multiple pharmacological targets. In the present review, we summarized the main biochemical and molecular mechanisms that have been associated with the therapeutic effects of CBD, focusing on their relevance to brain function, neuroprotection and neuropsychiatric disorders.

Cannabidiol and Alzheimer's disease.

Alzheimer's disease (AD) stands as the most prevalent form of neuropsychiatric disorder among the elderly population, impacting a minimum of 50 million individuals worldwide. Current pharmacological treatments rely on the prescribing cholinesterase inhibitors and memantine. However,recently anecdotal findings based on low-quality real-world data had prompted physicians, patients, and their relatives to consider the use of cannabinoids, especially Cannabidiol (CBD), for alleviating of AD symptoms. CBD the primary non-psychotomimetic compound found in the Cannabis sp. plant, exhibits promising therapeutic potential across various clinical contexts. Pre-clinical and in vitro studies indicate that CBD could mitigate cognitive decline and amyloid-beta-induced neurodegeneration by modulating oxidative stress and neuroinflammation. In addition, CBD demonstrates significant effects in promoting neuroplasticity, particularly in brain regions such as the hippocampus. However, the available clinical evidence presents conflicting results, and no randomized placebo-controlled trials have been published to date. In conclusion, although pre-clinical and in vitro studies offer encouraging insights into the potential benefits of CBD in AD models, new and well-designed clinical trials are imperative to ascertain the clinical relevance of CBD use in the management of AD symptoms, especially in comparison to conventional treatments.

Cannabidiol: Pharmacodynamics and pharmacokinetic in the context of neuropsychiatric disorders.

In this chapter we explored the growing interest in cannabinoids, particularly cannabidiol (CBD), over the last two decades due to their potential therapeutic applications in neurodegenerative and psychiatric disorders. CBD, a major non-psychotomimetic compound derived from Cannabis sativa, is highlighted as a safer alternative to other cannabinoids like Δ9-tetrahydrocannabinol (THC). Clinical trials have been investigating CBD formulations for conditions such as schizophrenia, multiple sclerosis, Alzheimer's, Parkinson's diseases, and stress-related disorders. However, limited access to CBD-approved formulations primarily due to their high-cost and concerns about the quality of market-available products, challenges regulatory agencies globally. The pharmacokinetics of CBD, especially after oral administration, present challenges with erratic absorption and low bioavailability. CBD's "promiscuous" pharmacodynamics involve interactions with various targets beyond the endocannabinoid system, complicating precise dosing in therapeutic interventions. This chapter delves into CBD's dose-response curves, revealing complexities that pose challenges in clinical practice. Nanobiotechnology emerges as a promising solution, with recent developments showing improved bioavailability, stability, and reduced toxicity through nanoencapsulation of CBD. While this phytocannabinoid holds immense promise in neuropsychopharmacology, we provided a comprehensive overview of the current state of CBD research and suggests potential future directions regarding the pharmacology of CBD, harnessing the benefits of this intriguing compound.

The Gut Microbiome in the First One Thousand Days of Neurodevelopment: A Systematic Review from the Microbiome Perspective.

Evidence shows that the gut microbiome in early life is an essential modulator of physiological processes related to healthy brain development, as well as mental and neurodegenerative disorders. Here, we conduct a systematic review of gut microbiome assessments on infants (both healthy and with conditions that affect brain development) during the first thousand days of life, associated with neurodevelopmental outcomes, with the aim of investigating key microbiome players and mechanisms through which the gut microbiome affects the brain. Bacteroides and Bifidobacterium were associated with non-social fear behavior, duration of orientation, cognitive and motricity development, and neurotypical brain development. Lachnospiraceae, Streptococcus, and Faecalibacterium showed variable levels of influence on behavior and brain development. Few studies described mechanistic insights related to NAD salvage, aspartate and asparagine biosynthesis, methanogenesis, pathways involved in bile acid transformation, short-chain fatty acids production, and microbial virulence genes. Further studies associating species to gene pathways and robustness in data analysis and integration are required to elucidate the functional mechanisms underlying the role of microbiome-gut-brain axis in early brain development.

Anxiogenic doses of rapamycin prevent URB597-induced anti-stress effects in socially defeated mice.

Repeated exposure to psychosocial stress modulates the endocannabinoid system, particularly anandamide (AEA) signaling in brain regions associated with emotional distress. The mTOR protein regulates various neuroplastic processes in the brain disrupted by stress, including adult hippocampal neurogenesis. This kinase has been implicated in multiple effects of cannabinoid drugs and the anti-stress behavioral effects of psychoactive drugs. Therefore, our hypothesis is that enhancing AEA signaling via pharmacological inhibition of the fatty acid amide hydrolase (FAAH) enzyme induces an anti-stress behavioral effect through an mTOR-dependent mechanism. To test this hypothesis, male C57Bl6 mice were exposed to social defeat stress (SDS) for 7 days and received daily treatment with either vehicle or different doses of the FAAH inhibitor, URB597 (0.1; 0.3; 1 mg/Kg), alone or combined with rapamycin. The results suggested that URB597 induced an inverted U-shaped dose-response curve in mice subjected to SDS (with the intermediate dose of 0.3 mg/kg being anxiolytic, and the higher tested dose of 1 mg/Kg being anxiogenic). In a second independent experiment, rapamycin treatment induced an anxiogenic-like response in control mice. However, in the presence of rapamycin, the anxiolytic dose of URB597 treatment failed to reduce stress-induced anxiety behaviors in mice. SDS exposure altered the hippocampal expression of the mTOR scaffold protein Raptor. Furthermore, the anxiogenic dose of URB597 decreased the absolute number of migrating doublecortin (DCX)-positive cells in the dentate gyrus, suggesting an anti-anxiety effect independent of newly generated/immature neurons. Therefore, our results indicate that in mice exposed to repeated psychosocial stress, URB597 fails to counteract the anxiogenic-like response induced by the pharmacological dampening of mTOR signaling.

Cardiovascular and kidney diseases are positively associated with neuroinflammation and reduced brain-derived neurotrophic factor in patients with severe COVID-19.

Even though respiratory dysfunctions are the primary symptom associated with SARS-CoV-2 infection, cerebrovascular events, and neurological symptoms are described in many patients. However, the connection between the neuroimmune profile and the lung's inflammatory condition during COVID-19 and its association with the neurological symptoms reported by COVID-19 patients still needs further exploration. The present study characterizes the SARS-CoV-2 infectivity profile in postmortem nervous and lung tissue samples of patients who died due to severe COVID-19, and the pro-inflammatory factors present in both nervous and lung tissue samples, via a proteomic profiling array. Additionally, Brain-Derived Neurotrophic Factor (BDNF) levels and intracellular pathways related to neuroplasticity/neuroprotection were assessed in the samples. Out of the 16 samples analyzed, all samples but 1 were positive for the viral genome (genes E or N2, but only 3.9% presented E and N2) in the olfactory brain pathway. The E or N2 gene were also detected in all lung samples, with 43.7% of the samples being positive for the E and N2 genes. In the E/N2 positive brain samples, the Spike protein of SARS-CoV-2 co-localized with TUJ-1+ (neuron-specific class III beta-tubulin) and GFAP+ (glial fibrillary acidic protein) astrocytes. IL-6, but not IL-10, expression was markedly higher in most nervous tissue samples compared to the lung specimens. While intracellular adhesion molecule-1 (ICAM-1), interleukin-8 (IL-8), macrophage migration inhibitory factor (MIF), and plasminogen activator inhibitor 1 (PAI-1) were increased in lung samples from SARS-Cov-2 patients, only MIF and IL-18 were detected in nervous tissue samples. Correlation analysis suggested that high levels of IL-6 are followed by increased levels of IL-10 in the brain, but not in lung samples. Our analysis also demonstrated that the presence of comorbidities, such as cardiovascular disease, hypertension, and hypothyroidism, is associated with neuroinflammation, while chronic kidney conditions predict the presence of neurological symptoms, which correlate with lower levels of BDNF in the brain samples. Our results corroborate the hypothesis that a pro-inflammatory state might further impair neural homeostasis and induce brain abnormalities found in COVID-19 patients.

Lead contamination in human milk affects infants' language trajectory: results from a prospective cohort study.

Infants growing up in low- and middle-income countries are at increased risk of suffering adverse childhood experiences, including exposure to environmental pollution and lack of cognitive stimulation. In this study, we aimed to examine the levels of metals in the human milk of women living in São Paulo City, Brazil, and determine the effects on infants' neurodevelopment. For such, a total of 185 human milk samples were analyzed for arsenic (As), lead (Pb), mercury (Hg), and cadmium (Cd) using inductively coupled plasma mass spectrometry (ICP-MS). We applied the Bayley scales of infant and toddler development Third Edition (Bayley-III) to assess developmental milestones. In our analysis, we found a mean (standard deviation) concentration of As in human milk equal to 2.76 (4.09) µg L-1, followed by Pb 2.09 (5.36) and Hg 1.96 (6.68). Cd was not detected. We observed that infants exposed to Pb presented language trajectories lower than non-exposed infants (ß = -0.413; 95% CI -0.653, -0.173) after adjustment for infant age, maternal education, socioeconomic status, infant sex, and sample weights. Our results report As, Pb, and Hg contamination in human milk, and that infant exposure to Pb decreased infants' language development. These results evidence maternal-child environmental exposure and its detrimental impact on infants' health.

The anxiolytic effect of cannabidiol on chronically stressed mice depends on hippocampal neurogenesis: involvement of the endocannabinoid system.

Cannabidiol (CBD), the main non-psychotomimetic component of the plant Cannabis sativa, exerts therapeutically promising effects on human mental health such as inhibition of psychosis, anxiety and depression. However, the mechanistic bases of CBD action are unclear. Here we investigate the potential involvement of hippocampal neurogenesis in the anxiolytic effect of CBD in mice subjected to 14 d chronic unpredictable stress (CUS). Repeated administration of CBD (30 mg/kg i.p., 2 h after each daily stressor) increased hippocampal progenitor proliferation and neurogenesis in wild-type mice. Ganciclovir administration to GFAP-thymidine kinase (GFAP-TK) transgenic mice, which express thymidine kinase in adult neural progenitor cells, abrogated CBD-induced hippocampal neurogenesis. CBD administration prevented the anxiogenic effect of CUS in wild type but not in GFAP-TK mice as evidenced in the novelty suppressed feeding test and the elevated plus maze. This anxiolytic effect of CBD involved the participation of the CB1 cannabinoid receptor, as CBD administration increased hippocampal anandamide levels and administration of the CB1-selective antagonist AM251 prevented CBD actions. Studies conducted with hippocampal progenitor cells in culture showed that CBD promotes progenitor proliferation and cell cycle progression and mimics the proliferative effect of CB1 and CB2 cannabinoid receptor activation. Moreover, antagonists of these two receptors or endocannabinoid depletion by fatty acid amide hydrolase overexpression prevented CBD-induced cell proliferation. These findings support that the anxiolytic effect of chronic CBD administration in stressed mice depends on its proneurogenic action in the adult hippocampus by facilitating endocannabinoid-mediated signalling.

Further evidence for an anti-inflammatory role of artesunate in experimental cerebral malaria.

BACKGROUND: Cerebral malaria (CM) is a clinical syndrome resulting from Plasmodium falciparum infection. A wide range of clinical manifestations follow the disease including cognitive dysfunction, seizures and coma. CM pathogenesis remains incompletely understood and without treatment this condition is invariably fatal. Artesunate has been accepted as the most effective drug for treating severe malaria. Besides its antiparasitic activity, an anti-inflammatory property has also been reported. In the current study, the immunomodulatory role of artesunate was investigated using a Plasmodium berghei ANKA model of CM, trough evaluation of behavioural changes and cytokines expression in hippocampus and in frontal cortex. METHODS: C57Bl/6 mice were infected with P. berghei by intraperitoneal route, using a standardized inoculation of 106 parasitized erythrocytes. Memory function was evaluated using the step-down inhibitory avoidance test. The mRNA expression of IFN-γ, IL-1ß, IL-6 and TNF in the frontal cortex and hippocampus of control and infected mice on day 5 post-infection were estimated by quantitative real time PCR. Plasmodium berghei -infected mice also received intraperitoneally a single dose of artesunate (32 mg/kg) on day 4 post-infection, and 24 hours after treatment behavioural and immunological analysis were performed. The protein levels of cytokines IL-2, IL-6, IL-10, IL-17, IFN-γ, TNF in the serum, frontal cortex and hippocampus of controls and P. berghei -infected mice treated or not treated with artesunate were determined using a cytometric bead array (CBA) kit. The survival and neurological symptoms of CM were also registered. RESULTS: CM mice presented a significant impairment of aversive memory compared to controls on day 5 post-infection. A higher mRNA expression of pro-inflammatory cytokines was found in the hippocampus and frontal cortex of infected mice. A single dose of artesunate was also able to decrease the expression of inflammatory cytokines in the hippocampus and frontal cortex of P. berghei-infected mice. In parallel, a significant improvement in neurological symptoms and survival were observed in artesunate treated mice. CONCLUSIONS: In summary, the current study provided further evidence that CM affects key brain areas related to cognition process. In addition, different patterns of cytokine expression during the course of CM could be modulated by a single administration of the anti-malarial artesunate.

Does the "Entourage Effect" in Cannabinoids Exist? A Narrative Scoping Review.

Background: The concept of an "entourage" effect in the cannabis and cannabinoids' field was first introduced in the late 1990s, during a period when most research on medical cannabinoids focused on the effects of isolated cannabinoids, such as cannabidiol and Δ9-tetrahydrocannabinol. Over the past decade, however, with the increased understanding of the endocannabinoid system, the discovery of other phytocannabinoids and their potential therapeutic uses, the term has gained widespread use in scientific reviews and marketing campaigns. Objective: Critically review the application of the term "entourage effect (EE)" in the literature and its endorsement by certain sectors of the cannabis market. Also, explore the perspectives for further interpretation and elaboration of the term based on current evidence, aiming to contribute to a more nuanced understanding of the concept and its implications for cannabinoid-based medicine. Methods: A comprehensive review of the literature was conducted to evaluate the current state of knowledge regarding the entourage effect. Relevant studies and scientific reviews were analyzed to assess the evidence of clinical efficacy and safety, as well as the regulation of cannabinoid-containing product production. Results: The EE is now recognized as a synergistic phenomenon in which multiple components of cannabis interact to modulate the therapeutic actions of the plant. However, the literature provides limited evidence to support it as a stable and predictable phenomenon. Hence, there is also limited evidence to support clinical efficacy, safety, and appropriate regulation for cannabinoid-containing products based on a "entourage" hypothesis. Conclusion: The EE has significant implications for the medical use of cannabinoid-containing products and their prescription. Nevertheless, a critical evaluation of the term's application is necessary. Further research and evidence are needed to establish the clinical efficacy, safety, and regulatory framework for these products. It's crucial that regulators, the pharmaceutical industry, the media, and health care providers exercise caution and avoid prematurely promoting the entourage effect hypothesis as a scientific proven phenomenon for cannabinoids and other cannabis-derived compound combinations.

The chronic pharmacological antagonism of the CB1 receptor is not involved in the behavioral effects of antidepressants administered in mice submitted to chronic unpredictable stress.

Several pieces of evidence suggest that the monoaminergic theory of depression cannot fully explain all behavioral and neuroplastic changes observed after antidepressant chronic treatment. Other molecular targets, such as the endocannabinoid system, have been associated with the chronic effects of these drugs. In the present study, we hypothesized that the behavioral and neuroplastic effects observed after repeated treatment with the antidepressants (AD) Escitalopram (ESC) or venlafaxine (VFX) in chronically stressed mice depend on CB1 receptor activation. Male mice submitted to the chronic unpredictable stress (CUS) paradigm for 21 days were treated with Esc (10 mg/kg) or VFX (20 mg/kg) once a day in the presence or not of AM251 (0.3 mg/kg), a CB1 receptor antagonist/inverse agonist. At the end of the CUS paradigm, we conducted behavior tests to evaluate depressive- and anxiety-like behaviors. Our results demonstrated that chronic blockade of the CB1 receptor does not attenuate the antidepressant- or the anxiolytic-like effects of ESC nor VFX. ESC increased the expression of CB1 in the hippocampus, but AM251 did not change the pro-proliferative effects of ESC in the dentate gyrus or the increased expression of synaptophysin induced by this AD in the hippocampus. Our results suggest that CB1 receptors are not involved in behavioral and hippocampal neuroplastic effects observed after repeated antidepressant treatment in mice submitted to CUS.

Effect of two oral formulations of cannabidiol on responses to emotional stimuli in healthy human volunteers: pharmaceutical vehicle matters.

OBJECTIVE: To compare plasma concentrations of cannabidiol (CBD) following oral administration of two formulations of the drug (powder and dissolved in oil), and to evaluate the effects of these distinct formulations on responses to emotional stimuli in healthy human volunteers. METHODS: In a randomized, double-blind, placebo-controlled, parallel-group design, 45 healthy male volunteers were randomly assigned to three groups of 15 subjects that received either 150 mg of CBD powder; 150 mg of CBD dissolved in corn oil; or placebo. Blood samples were collected at different times after administration, and a facial emotion recognition task was completed after 150 min. RESULTS: There were no significant differences across groups in the subjective and physiological measures, nor in the facial emotion recognition task. However, groups that received the drug showed statistically significant differences in baseline measures of plasma CBD, with a significantly greater difference in favor of the oil formulation. CONCLUSION: When administered as a single 150-mg dose, neither formulation of oral CBD altered responses to emotional stimuli in healthy subjects. The oil-based CBD formulation resulted in more rapid achievement of peak plasma level, with an approximate fourfold increase in oral bioavailability.

Cannabidiol for the treatment of autism spectrum disorder: hope or hype?

RATIONALE: Autism spectrum disorder (ASD) is defined as a group of neurodevelopmental disorders whose symptoms include impaired communication and social interaction, restricted and repetitive patterns of behavior, and varying levels of intellectual disability. ASD is observed in early childhood and is one of the most severe chronic childhood disorders in prevalence, morbidity, and impact on society. It is usually accompanied by attention deficit hyperactivity disorder, anxiety, depression, sleep disorders, and epilepsy. The treatment of ASD has low efficacy, possibly because it has a heterogeneous nature, and its neurobiological basis is not clearly understood. Drugs such as risperidone and aripiprazole are the only two drugs available that are recognized by the Food and Drug Administration, primarily for treating the behavioral symptoms of this disorder. These drugs have limited efficacy and a high potential for inducing undesirable effects, compromising treatment adherence. Therefore, there is great interest in exploring the endocannabinoid system, which modulates the activity of other neurotransmitters, has actions in social behavior and seems to be altered in patients with ASD. Thus, cannabidiol (CBD) emerges as a possible strategy for treating ASD symptoms since it has relevant pharmacological actions on the endocannabinoid system and shows promising results in studies related to disorders in the central nervous system. OBJECTIVES: Review the preclinical and clinical data supporting CBD's potential as a treatment for the symptoms and comorbidities associated with ASD, as well as discuss and provide information with the purpose of not trivializing the use of this drug.

Case Report: Cannabidiol-Induced Skin Rash: A Case Series and Key Recommendations.

Cannabidiol (CBD) is a non-psychotomimetic constituent of the Cannabis plant, with potential therapeutic properties for many physical and neuropsychiatric conditions. Isolated CBD has been suggested to have favorable safety and tolerability. Although CBD-related rash is described, few case reports are well documented in the literature, and usually, CBD was used concomitantly with other medications. Thus, we report four women who presented a skin rash after ongoing CBD use. Other causes of these skin rashes were ruled out after conducting an extensive viral and serological detection panel, and three patients had their lesions biopsied. Two patients were re-exposed to the vehicle (MCT) without developing a new skin rash. Therefore, clinicians must be aware of this potential adverse effect of CBD use.

Genetic Ablation of the Inducible Form of Nitric Oxide in Male Mice Disrupts Immature Neuron Survival in the Adult Dentate Gyrus.

Inducible nitric oxide synthase (iNOS) is an enzyme upregulated in the brain during neuroimmune stimuli which is associated with an oxidative and pro-inflammatory environment in several brain regions, including the hippocampal formation and the prefrontal cortex. The dentate gyrus of the hippocampal formation is the site of a process known as adult hippocampal neurogenesis (AHN). Although many endogenous and extrinsic factors can modulate AHN, the exact participation of specific proinflammatory mediators such as iNOS in these processes remains to be fully elucidated. Here, we investigated how the total genetic ablation of iNOS impacts the hippocampal neurogenic niche and microglial phenotype and if these changes are correlated to the behavioral alterations observed in iNOS knockout (K.O.) mice submitted or not to the chronic unpredictable stress model (CUS - 21 days protocol). Contrary to our initial hypothesis, at control conditions, iNOS K.O. mice displayed no abnormalities on microglial activation in the dentate gyrus. However, they did exhibit impaired newborn cells and immature neuron survival, which was not affected by CUS. The reduction of AHN in iNOS K.O. mice was accompanied by an increased positive coping response in the tail suspension test and facilitation of anxiety-like behaviors in the novelty suppressed feeding. Next, we investigated whether a pro-neurogenic stimulus would rescue the neurogenic capacity of iNOS K.O. mice by administering in control and CUS groups the antidepressant escitalopram (ESC). The chronic treatment with ESC could not rescue the neurogenic capacity or the behavioral changes observed in iNOS K.O. mice. Besides, in the ventromedial prefrontal (vmPFC) cortex there was no change in the expression or the chronic activation of PV neurons (evaluated by double labeling PV with FOSB) in the prelimbic (PrL) or infralimbic subregions. FOSB expression, however, increased in the PrL of iNOS K.O. mice. Our results suggest that iNOS seems essential for the survival of newborn cells and immature neurons in the hippocampus and seem to partially explain the anxiogenic-like behavior observed in iNOS K.O. mice. On the other hand, the iNOS ablation appears to result in increased activity of the PrL which could explain the antidepressant-like behaviors of iNOS K.O mice.

Zebrafish as a Translational Model: An Experimental Alternative to Study the Mechanisms Involved in Anosmia and Possible Neurodegenerative Aspects of COVID-19?

The Coronavirus disease-2019 (COVID-19) presents a variability of clinical symptoms, ranging from asymptomatic to severe respiratory and systemic conditions. In a cohort of patients, the Severe Acute Respiratory Syndrome Coronavirus (SARS-CoV-2), beyond the classical respiratory manifestations, induces anosmia. Evidence has suggested SARS-CoV-2-induced anosmia can be the result of neurodegeneration of the olfactory pathway. Neurologic symptoms associated with COVID-19 have been reported; however, the precise mechanism and possible long-lasting effects remain poorly investigated. Preclinical models are valuable tools for describing and testing new possible treatments for neurologic disorders. In this way, the zebrafish (Danio rerio) organism model represents an attractive tool in the field of neuroscience, showing economic and logistic advantages besides genetic and physiologic similarities with mammalian, including the brain structure and functions. Besides, its external embryonic development, high availability of eggs, and fast development allows easy genetic manipulation and fast replications. In the present review, we suggest that the zebrafish model can be advantageous to investigate the neurologic features of COVID-19.