Revolutionizing neurotherapeutics: blood-brain barrier-on-a-chip technologies for precise drug delivery.

Introduction: The blood-brain barrier (BBB) is a critical neurovascular unit regulating substances' passage from the bloodstream to the brain. Its selective permeability poses significant challenges in drug delivery for neurological disorders. Conventional methods often fail due to the BBB's complex structure. Aim: The study aims to shed light on their pivotal role in revolutionizing neurotherapeutics and explores the transformative potential of BBB-on-a-Chip technologies in drug delivery research to comprehensively review BBB-on-a-chip technologies, focusing on their design, and substantiate advantages over traditional models. Methods: A detailed analysis of existing literature and experimental data pertaining to BBB-on-a-Chip technologies was conducted. Various models, their physiological relevance, and innovative design considerations were examined through databases like Scopus, EbscoHost, PubMed Central, and Medline. Case studies demonstrating enhanced drug transport through BBB-on-a-Chip models were also reviewed, highlighting their potential impact on neurological disorders. Results: BBB-on-a-Chip models offer a revolutionary approach, accurately replicating BBB properties. These microphysiological systems enable high-throughput screening, real-time monitoring of drug transport, and precise localization of drugs. Case studies demonstrate their efficacy in enhancing drug penetration, offering potential therapies for diseases like Parkinson's and Alzheimer's. Conclusion: BBB-on-a-Chip models represent a transformative milestone in drug delivery research. Their ability to replicate BBB complexities, offer real-time monitoring, and enhance drug transport holds immense promise for neurological disorders. Continuous research and development are imperative to unlock BBB-on-a-Chip models' full potential, ushering in a new era of targeted, efficient, and safer drug therapies for challenging neurological conditions.

Chronic Behavioral and Neurochemical Effects of Four Novel N-Benzyl-2-phenylethylamine Derivatives Recently Identified as "Psychoactive" in Adult Zebrafish Screens.

Potently affecting human and animal brain and behavior, hallucinogenic drugs have recently emerged as potentially promising agents in psychopharmacotherapy. Complementing laboratory rodents, the zebrafish (Danio rerio) is a powerful model organism for screening neuroactive drugs, including hallucinogens. Here, we tested four novel N-benzyl-2-phenylethylamine (NBPEA) derivatives with 2,4- and 3,4-dimethoxy substitutions in the phenethylamine moiety and the -F, -Cl, and -OCF3 substitutions in the ortho position of the phenyl ring of the N-benzyl moiety (34H-NBF, 34H-NBCl, 24H-NBOMe(F), and 34H-NBOMe(F)), assessing their behavioral and neurochemical effects following chronic 14 day treatment in adult zebrafish. While the novel tank test behavioral data indicate anxiolytic-like effects of 24H-NBOMe(F) and 34H-NBOMe(F), neurochemical analyses reveal reduced brain norepinephrine by all four drugs, and (except 34H-NBCl) - reduced dopamine and serotonin levels. We also found reduced turnover rates for all three brain monoamines but unaltered levels of their respective metabolites. Collectively, these findings further our understanding of complex central behavioral and neurochemical effects of chronically administered novel NBPEAs and highlight the potential of zebrafish as a model for preclinical screening of small psychoactive molecules.

The Role of Dietary Peptides Gluten and Casein in the Development of Autism Spectrum Disorder: Biochemical Perspectives.

This paper examines the role of dietary peptides gluten and casein in modulating brain function in individuals with autism spectrum disorder (ASD) from a biochemical perspective. Neurotransmitter systems and neural networks are crucial for brain function, and alterations at the biochemical level can contribute to the characteristic symptoms and behaviors of ASD. The paper explores how dietary peptides influence neurotransmitter systems and neural networks, highlighting their potential as interventions to improve brain function in ASD. The evidence suggests that dietary peptides can impact neurotransmitter synthesis, release, and receptor interactions, disrupting the balance of neurotransmitter systems and affecting neural network function. The findings underscore the potential of dietary interventions in modulating brain function in ASD and call for further research to elucidate the underlying mechanisms and optimize clinical practice. Considering individual dietary sensitivities and preferences, personalized dietary approaches may be necessary for optimal outcomes. Dietary interventions' timing, duration, and integration with other evidence-based treatments are crucial considerations. Safety considerations and regular monitoring are important to ensure the implementation of dietary interventions safely and effectively.

Can we gain translational insights into the functional roles of cerebral cortex from acortical rodent and naturally acortical zebrafish models?

Cerebral cortex is found only in mammals and is particularly prominent and developed in humans. Various rodent models with fully or partially ablated cortex are commonly used to probe the role of cortex in brain functions and its multiple subcortical projections, including pallium, thalamus and the limbic system. Various rodent models are traditionally used to study the role of cortex in brain functions. A small teleost fish, the zebrafish (Danio rerio), has gained popularity in neuroscience research, and albeit (like other fishes) lacking cortex, its brain performs well some key functions (e.g., memory, consciousness and motivation) with complex, context-specific and well-defined behaviors. Can rodent and zebrafish models help generate insights into the role of cortex in brain functions, and dissect its cortex-specific (vs. non-cortical) functions? To address this conceptual question, here we evaluate brain functionality in intact vs. decorticated rodents and further compare it in the zebrafish, a naturally occurring acortical species. Overall, comparing cortical and acortical rodent models with naturally acortical zebrafish reveals both distinct and overlapping contributions of neocortex and 'precortical' zebrafish telencephalic regions to higher brain functions. Albeit morphologically different, mammalian neocortex and fish pallium may possess more functional similarities than it is presently recognized, calling for further integrative research utilizing both cortical and decorticated/acortical vertebrate model organisms.

Environmental Risk Factors in Autism Spectrum Disorder: A Narrative Review.

Existing evidence indicates that environmental factors might contribute up to 50% of the variance in autism spectrum disorder (ASD) risk. This structured narrative review offers a comprehensive synthesis of current knowledge on environmental risk factors in ASD, including evaluation of conflicting evidence, exploration of underlying mechanisms, and suggestions for future research directions. Analysis of diverse epidemiological investigations indicates that certain environmental factors, including advanced parental age, preterm birth, delivery complications, and exposure to toxic metals, drugs, air pollutants, and endocrine-disrupting chemicals, are linked to an increased ASD risk through various mechanisms such as oxidative stress, inflammation, hypoxia, and its consequences, changes in neurotransmitters, disruption of signaling pathways and some others. On the other hand, pregnancy-related factors such as maternal diabetes, maternal obesity, and caesarian section show a weaker association with ASD risk. At the same time, other environmental factors, such as vaccination, maternal smoking, or alcohol consumption, are not linked to the risk of ASD. Regarding nutritional elements data are inconclusive. These findings highlight the significance of environmental factors in ASD etiology and emphasize that more focused research is needed to target the risk factors of ASD. Environmental interventions targeting modifiable risk factors might offer promising avenues for ASD prevention and treatment.

The regulatory effects of mesedin and beditin alpha2-adrenoblockers on the functional activity of the nervous, cardiovascular, and endocrine systems in rats under the hypoxic conditions.

One of the reasons of the development of pathologies causing death is hypoxia. The purposes of this study were (1) to study some physiological and biochemical mechanisms of α2-adrenoblockers, which ensure the tissue resistance increase to hypoxia; (2) to offer new drugs contributing to the increase of tissues' stability towards the hypoxic affection; and (3) to submit new medications to surpass by their anti-hypoxic activity of those already used in modern medicine and have some advantages. The reactivity of postsynaptic vascular α2-adrenoceptors was determined on the damaged spinal cord expressed by the blood pressure increase in response to intravenous administration of azepexole that selectively binds to α2-adrenoceptors. Determination of the systemic hemodynamic values and the vascular resistance to the blood flow was performed by the method with plastic microspheres of marked isotopes. pO2 in the blood and the oxygen-transporting function were determined in a sample of 0.1 ml of blood in 30, 90, and 180 min after the α2-adrenoblockers' injections. It has been found that one of the major hemodynamic effects of mesedin and beditin was an improvement in cardiac output, as well as a prolonged increase in coronary blood flow and vasodilation of the heart vessels. Some anti-hypoxic mechanisms of the studied α2-adrenoblockers are an improvement of blood oxygen-transporting function followed by tissue oxygenation and the increased level of corticosterone and resistance to hypoxia. Revealing the mechanisms of action of the postsynaptic α2-adrenoceptors suggests that mesedin and beditin are potentially effective therapeutic means for many hypoxic conditions.

Linking Environmental Chemicals to Neuroinflammation and Autism Spectrum Disorder: Mechanisms and Implications for Prevention.

This article explores the potential link between endocrine-disrupting chemicals (EDCs), neuroinflammation, and the development of autism spectrum disorder (ASD). Neuroinflammation refers to the immune system's response to injury, infection, or disease in the central nervous system. Studies have shown that exposure to EDCs, such as bisphenol A and phthalates, can disrupt normal immune function in the brain, leading to chronic or excessive neuroinflammation. This disruption of immune function can contribute to developing neurological disorders, including ASD. Furthermore, EDCs may activate microglia, increasing pro-inflammatory cytokine production and astroglia-mediated oxidative stress, exacerbating neuroinflammation. EDCs may also modulate the epigenetic profile of cells by methyltransferase expression, thereby affecting neurodevelopment. This article also highlights the importance of reducing exposure to EDCs and advocating for policies and regulations restricting their use. Further research is needed to understand better the mechanisms underlying the link between EDCs, neuroinflammation, and ASD and to develop new treatments for ASD.

Advances in the Treatment of Autism Spectrum Disorder: Current and Promising Strategies.

Autism spectrum disorder (ASD) is an umbrella term for developmental disorders characterized by social and communication impairments, language difficulties, restricted interests, and repetitive behaviors. Current management approaches for ASD aim to resolve its clinical manifestations based on the type and severity of the disability. Although some medications like risperidone show potential in regulating ASD-associated symptoms, a comprehensive treatment strategy for ASD is yet to be discovered. To date, identifying appropriate therapeutic targets and treatment strategies remains challenging due to the complex pathogenesis associated with ASD. Therefore, a comprehensive approach must be tailored to target the numerous pathogenetic pathways of ASD. From currently viable and basic treatment strategies, this review explores the entire field of advancements in ASD management up to cutting-edge modern scientific research. A novel systematic and personalized treatment approach is suggested, combining the available medications and targeting each symptom accordingly. Herein, summarize and categorize the most appropriate ways of modern ASD management into three distinct categories: current, promising, and prospective strategies.

Propionic and valproic acids have an impact on bacteria viability, proton flux and ATPase activity.

Short-chain fatty acids like propionic (PPA) and valproic acids (VP) can alter gut microbiota, which is suggested to play a role in development of autism spectrum disorders (ASD). In this study we investigated the role of various concentrations of PPA and VP in gut enteric gram-negative Escherichia coli K12 and gram-positive Enterococcus hirae ATCC 9790 bacteria growth properties, ATPase activity and proton flux. The specific growth rate (µ) was 0.24 h-1 and 0.82 h-1 in E. coli and E. hirae, respectively. Different concentrations of PPA reduced the value of µ similarly in both strains. PPA affects membrane permeability only in E. hirae. PPA decreased DCCD-sensitive ATPase activity in the presence of K+ ions by 20% in E. coli and 40% in E. hirae suggesting the importance of the FOF1-K+ transport system in the regulation of PPA-disrupted homeostasis. Moreover, the H+ flux during PPA consumption could be the protective mechanism for enteric bacteria. VP has a selective effect on the µ depending on bacteria. The overwhelming effect of VP was detected on the K+-promoted ATPase activity in E. hirae. Taken together it can be suggested that PPA and VP have a disruptive effect on E. coli and E. hirae growth, viability, bioenergetic and biochemical properties, which are connected with the alteration of FOF1-ATPase activity and H+ flux rate or direction.

Towards Novel Potential Molecular Targets for Antidepressant and Antipsychotic Pharmacotherapies.

Depression and schizophrenia are two highly prevalent and severely debilitating neuropsychiatric disorders. Both conventional antidepressant and antipsychotic pharmacotherapies are often inefficient clinically, causing multiple side effects and serious patient compliance problems. Collectively, this calls for the development of novel drug targets for treating depressed and schizophrenic patients. Here, we discuss recent translational advances, research tools and approaches, aiming to facilitate innovative drug discovery in this field. Providing a comprehensive overview of current antidepressants and antipsychotic drugs, we also outline potential novel molecular targets for treating depression and schizophrenia. We also critically evaluate multiple translational challenges and summarize various open questions, in order to foster further integrative cross-discipline research into antidepressant and antipsychotic drug development.

Forward Genetics-Based Approaches to Understanding the Systems Biology and Molecular Mechanisms of Epilepsy.

Epilepsy is a highly prevalent, severely debilitating neurological disorder characterized by seizures and neuronal hyperactivity due to an imbalanced neurotransmission. As genetic factors play a key role in epilepsy and its treatment, various genetic and genomic technologies continue to dissect the genetic causes of this disorder. However, the exact pathogenesis of epilepsy is not fully understood, necessitating further translational studies of this condition. Here, we applied a computational in silico approach to generate a comprehensive network of molecular pathways involved in epilepsy, based on known human candidate epilepsy genes and their established molecular interactors. Clustering the resulting network identified potential key interactors that may contribute to the development of epilepsy, and revealed functional molecular pathways associated with this disorder, including those related to neuronal hyperactivity, cytoskeletal and mitochondrial function, and metabolism. While traditional antiepileptic drugs often target single mechanisms associated with epilepsy, recent studies suggest targeting downstream pathways as an alternative efficient strategy. However, many potential downstream pathways have not yet been considered as promising targets for antiepileptic treatment. Our study calls for further research into the complexity of molecular mechanisms underlying epilepsy, aiming to develop more effective treatments targeting novel putative downstream pathways of this disorder.

Understanding CNS Effects of Antimicrobial Drugs Using Zebrafish Models.

Antimicrobial drugs represent a diverse group of widely utilized antibiotic, antifungal, antiparasitic and antiviral agents. Their growing use and clinical importance necessitate our improved understanding of physiological effects of antimicrobial drugs, including their potential effects on the central nervous system (CNS), at molecular, cellular, and behavioral levels. In addition, antimicrobial drugs can alter the composition of gut microbiota, and hence affect the gut-microbiota-brain axis, further modulating brain and behavioral processes. Complementing rodent studies, the zebrafish (Danio rerio) emerges as a powerful model system for screening various antimicrobial drugs, including probing their putative CNS effects. Here, we critically discuss recent evidence on the effects of antimicrobial drugs on brain and behavior in zebrafish, and outline future related lines of research using this aquatic model organism.

Current State of Modeling Human Psychiatric Disorders Using Zebrafish.

Psychiatric disorders are highly prevalent brain pathologies that represent an urgent, unmet biomedical problem. Since reliable clinical diagnoses are essential for the treatment of psychiatric disorders, their animal models with robust, relevant behavioral and physiological endpoints become necessary. Zebrafish (Danio rerio) display well-defined, complex behaviors in major neurobehavioral domains which are evolutionarily conserved and strikingly parallel to those seen in rodents and humans. Although zebrafish are increasingly often used to model psychiatric disorders, there are also multiple challenges with such models as well. The field may therefore benefit from a balanced, disease-oriented discussion that considers the clinical prevalence, the pathological complexity, and societal importance of the disorders in question, and the extent of its detalization in zebrafish central nervous system (CNS) studies. Here, we critically discuss the use of zebrafish for modeling human psychiatric disorders in general, and highlight the topics for further in-depth consideration, in order to foster and (re)focus translational biological neuroscience research utilizing zebrafish. Recent developments in molecular biology research utilizing this model species have also been summarized here, collectively calling for a wider use of zebrafish in translational CNS disease modeling.

Developing Novel Experimental Models of m-TORopathic Epilepsy and Related Neuropathologies: Translational Insights from Zebrafish.

The mammalian target of rapamycin (mTOR) is an important molecular regulator of cell growth and proliferation. Brain mTOR activity plays a crucial role in synaptic plasticity, cell development, migration and proliferation, as well as memory storage, protein synthesis, autophagy, ion channel expression and axonal regeneration. Aberrant mTOR signaling causes a diverse group of neurological disorders, termed 'mTORopathies'. Typically arising from mutations within the mTOR signaling pathway, these disorders are characterized by cortical malformations and other neuromorphological abnormalities that usually co-occur with severe, often treatment-resistant, epilepsy. Here, we discuss recent advances and current challenges in developing experimental models of mTOR-dependent epilepsy and other related mTORopathies, including using zebrafish models for studying these disorders, as well as outline future directions of research in this field.

Brain-derived neurotrophic factor (BDNF) in perinatal depression: Side show or pivotal factor?

Perinatal depression is the most common psychiatric complication of pregnancy, with its detrimental effects on maternal and infant health widely underrated. There is a pressing need for specific molecular biomarkers, with pregnancy-related decline in brain-derived neurotrophic factor (BDNF) in the blood and downregulation of TrkB receptor in the brain reported in clinical and preclinical studies. In this review, we explore the emerging role of BDNF in reproductive biology and discuss evidence suggesting its deficiency as a risk factor for perinatal depression. With the increasing evidence for restoration of serum BDNF levels by antidepressant therapy, the strengthening association of perinatal depression with deficiency of BDNF supports its potential as a surrogate endpoint for preclinical and clinical studies.

Automated and combined HIV, HBV, HCV, and syphilis testing among illegal gold miners in French Guiana using a standardized dried blood device.

Blood spotted onto filter paper can be easily collected outside healthcare facilities and shipped to a central laboratory for serological testing. However, dried blood testing generally requires manual processing for pre-analytical steps. In this study, we used a standardized blood collection device combined with an automated elution system to test illegal gold miners living in French Guiana for human immunodeficiency virus (HIV), hepatitis B virus (HBV), hepatitis C virus (HCV) and syphilis. We included 378 participants, 102 females and 266 males, in three illegal gold mining resting sites. Blood collected on the Ser-Col device (Labonovum) was eluted using an automated system (SCAUT Ser-Col automation, Blok System Supply) and an automated analyzer (Alinity i, Abbott). Ser-Col results were compared to both plasma results, considered the gold standard, and to Dried blood Spot (DBS) results, considered the reference sampling method using dried blood. In plasma samples, two participants (0.5%) tested positive for HIV, six (1.5%) tested positive for hepatitis B surface antigen (HBsAg), eight were weakly positive for anti-HCV antibodies but negative for HCV RNA, and 47 tested positive for treponemal antibodies (12.4%), including 20 females (19.6%) and 27 males (9.8%, p= 0.010179). We observed a full concordance of Ser-Col and DBS results for HIV diagnosis compared to plasma results. Ser-Col and DBS samples tested positive in five HBsAg carriers and negative for one participant with a low HBsAg level in plasma (0.5 IU/mL). All participants tested negative for HCV in Ser-Col and DBS samples, including the eight participants who tested low positive for HCV antibodies and HCV RNA negative in plasma. Among syphilis seropositive participants, 41 (87.2%) and 40 (85.1%) tested positive for treponemal antibodies in Ser-Col and DBS samples, respectively. The Ser-Col method allows automated dried blood testing of HIV, HBV, HCV and syphilis with performances comparable to DBS. Automated approaches to test capillary blood transported on dried blood devices may facilitate large-scale surveys and improve testing of populations living in remote areas.

Effects of ß-amyloid (1-42) Administration on the Main Neurogenic Niches of the Adult Brain: Amyloid-Induced Neurodegeneration Influences Neurogenesis.

Alzheimer's disease (AD) is the most prevalent neurodegenerative disorder and warrants further study as well as timely treatment. Additionally, the mechanisms of the brain's intrinsic defense against chronic injury are not yet fully understood. Herein, we examined the response of the main neurogenic niches to amyloid exposure and the associated changes in structure and synaptic activity. Flow cytometry of Nestin-, Vimentin-, Nestin/Vimentin-, NeuN-, GFAP-, NeuN/GFAP-, NSE-, BrdU-, Wnt-, BrdU/Wnt-, VEGF-, Sox14-, VEGF/Sox14-, Sox10-, Sox2-, Sox10/Sox2-, Bax-, and Bcl-xL-positive cells was performed in the subventricular zone (SVZ), hippocampus, and cerebral cortex of rat brains on 90th day after intracerebroventricular (i.c.v.) single injection of a fraction of ß-amyloid (Aß) (1-42). The relative structural changes in these areas and disruptions to synaptic activity in the entorhinal cortex-hippocampus circuit were also evaluated. Our flow analyses revealed a reduction in the numbers of Nestin-, Vimentin-, and Nestin/Vimentin-positive cells in neurogenic niches and the olfactory bulb. These changes were accompanied by an increased number of BrdU-positive cells in the hippocampus and SVZ. The latter changes were strongly correlated with changes in the numbers of VEGF- and VEGF/Sox14-positive cells. The morphological changes were characterized by significant neural loss, a characteristic shift in entorhinal cortex-hippocampus circuit activity, and decreased spontaneous alternation in a behavioral test. We conclude that although an injection of Aß (1-42) induced stem cell proliferation and triggered neurogenesis at a certain stage, this process was incomplete and led to neural stem cell immaturity. We propose the idea of enhancing adult neurogenesis as a promising strategy for preventing dementia at healthy elderly people andpeople at high risk for developing AD, or treating patients diagnosed with AD.

The synergy of ß amyloid 1-42 and oxidative stress in the development of Alzheimer's disease-like neurodegeneration of hippocampal cells.

Alzheimer's disease (AD) is a type of dementia that affects memory, thinking and behavior. Symptoms eventually become severe enough to interfere with daily tasks. Understanding the etiology and pathogenesis of AD is necessary for the development of strategies for AD prevention and/or treatment, and modeling of this pathology is an important step in achieving this goal. ß-amyloid peptide (Aß) injection is a widely used approach for modeling AD. Nevertheless, it has been reported that the model constructed by injection of Aß in combination with a prooxidant cocktail (ferrous sulfate, Aß, and buthionine sulfoximine (BSO) (FAB)) best reflects the natural development of this disease. The relationship between oxidative stress and Aß deposition and their respective roles in Aß-induced pathology in different animal models of AD have been thoroughly investigated. In the current paper, we compared the effects of Aß 1-42 alone with that of Aß-associated oxidative stress induced by the FAB cocktail on the neurodegeneration of hippocampal cells in vitro. We constructed a FAB-induced AD model using rat primary hippocampal cells and analyzed the contribution of each compound. The study mainly focused on the prooxidant aspects of AD pathogenesis. Moreover, cellular bioenergetics was assessed and routine metabolic tests were performed to determine the usefulness of this model. The data clearly show that aggregated Aß1-42 alone is significantly less toxic to hippocampal cells. Aggregated Aß damages neurons, and glial cells proliferate to remove Aß from the hippocampus. External prooxidant agents (Fe2+) or inhibition of internal antioxidant defense by BSO has more toxic effects on hippocampal cells than aggregated Aß alone. Moreover, hippocampal cells fight against Aß-induced damage more effectively than against oxidative damage. However, the combination of Aß with external oxidative damage and inhibition of internal antioxidant defense is even more toxic, impairs cellular defense systems, and may mimic the late phase of AD-associated cell damage. Our findings strongly indicate a critical role for the combination of Aß and oxidative stress in the development of neurodegeneration in vitro.

Kinetics of anti-nucleocapsid IgG response in COVID-19 immunocompetent convalescent patients.

The comprehension of a long-term humoral immune response against SARS-CoV-2 can shed light on the treatment and vaccination strategies of COVID-19 disease, improving the knowledge about this virus infection and/or re-infection. We assessed the IgG antibodies against SARS-CoV-2 nucleocapsid (N) protein (anti-SARS-CoV-2 (N) IgG) in 1441 COVID-19 convalescent patients within 15 months longitudinal study from middle-developed country. The main inclusion criteria was positive RT- PCR result on nasopharyngeal swab samples at least one month before antibody testing and absence of any induced or inherited immunodeficiency. 92.7% of convalescent patients' serum contained anti-SARS-CoV-2 (N) IgG and only 1.3% of patients had a delayed antibody response. In the majority of convalescent patients' the durability of antibodies lasted more than one year. The kinetics of anti-SARS-CoV-2 (N) IgG took a bell-shaped character-increased first 25-30 weeks, then started to decrease, but were still detectable for more than 15 months. We found that on the one hand anti-SARS-CoV-2 humoral response level correlates with disease severity, on the other, in particular, the level of peak antibodies correlates with age-older patients develop more robust humoral response regardless of sex, disease severity and BMI.