Exploring Astrocytes Involvement and Glutamate Induced Neuroinflammation in Chlorpyrifos-Induced Paradigm Of Autism Spectrum Disorders (ASD).

Autism spectrum disorders (ASD) are neurodevelopmental disorders manifested mainly in children, with symptoms ranging from social/communication deficits and stereotypies to associated behavioral anomalies like anxiety, depression, and ADHD. While the patho-mechanism is not well understood, the role of neuroinflammation has been suggested. Nevertheless, the triggers giving rise to this neuroinflammation have not previously been explored in detail, so the present study was aimed at exploring the role of glutamate on these processes, potentially carried out through increased activity of inflammatory cells like astrocytes, and a decline in neuronal health. A novel chlorpyrifos-induced paradigm of ASD in rat pups was used for the present study. The animals were subjected to tests assessing their neonatal development and adolescent behaviors (social skills, stereotypies, sensorimotor deficits, anxiety, depression, olfactory, and pain perception). Markers for inflammation and the levels of molecules involved in glutamate excitotoxicity, and neuroinflammation were also measured. Additionally, the expression of reactive oxygen species and markers of neuronal inflammation (GFAP) and function (c-Fos) were evaluated, along with an assessment of histopathological alterations. Based on these evaluations, it was found that postnatal administration of CPF had a negative impact on neurobehavior during both the neonatal and adolescent phases, especially on developmental markers, and brought about the generation of ASD-like symptoms. This was further corroborated by elevations in the expression of glutamate and downstream calcium, as well as certain cytokines and neuroinflammatory markers, and validated through histopathological and immunohistochemical results showing a decline in neuronal health in an astrocyte-mediated cytokine-dependent fashion. Through our findings, conclusive evidence regarding the involvement of glutamate in neuroinflammatory pathways implicated in the development of ASD-like symptoms, as well as its ability to activate further downstream processes linked to neuronal damage has been obtained. The role of astrocytes and the detrimental effect on neuronal health are also concluded. The significance of our study and its findings lies in the evaluation of the involvement of chlorpyrifos-induced neurotoxicity in the development of ASD, particularly in relation to glutamatergic dysfunction and neuronal damage.

Repurposing Niclosamide as a plausible neurotherapeutic in autism spectrum disorders, targeting mitochondrial dysfunction: a strong hypothesis.

Autism Spectrum Disorders (ASD) are a complex set of neurodevelopmental manifestations which present in the form of social and communication deficits. Affecting a growing proportion of children worldwide, the exact pathogenesis of this disorder is not very well understood, and multiple signaling pathways have been implicated. Among them, the ERK/MAPK pathway is critical in a number of cellular processes, and the normal functioning of neuronal cells also depends on this cascade. As such, recent studies have increasingly focused on the impact this pathway has on the development of autistic symptoms. Improper ERK signaling is suspected to be involved in neurotoxicity, and the same might be implicated in autism spectrum disorders (ASD), through a variety of effects including mitochondrial dysfunction and oxidative stress. Niclosamide, an antihelminthic and anti-inflammatory agent, has shown potential in inhibiting this pathway, and countering the effects shown by its overactivity in inflammation. While it has previously been evaluated in other neurological disorders like Alzheimer's Disease and Parkinson's Disease, as well as various cancers by targeting ERK/MAPK, it's efficacy in autism has not yet been evaluated. In this article, we attempt to discuss the potential role of the ERK/MAPK pathway in the pathogenesis of ASD, specifically through mitochondrial damage, before moving to the therapeutic potential of niclosamide in the disorder, mediated by the inhibition of this pathway and its detrimental effects of neuronal development.

Exploring sulforaphane as neurotherapeutic: targeting Nrf2-Keap & Nf-Kb pathway crosstalk in ASD.

Autism spectrum disorders (ASD) are a family of complex neurodevelopmental disorders, characterized mainly through deficits in social behavior and communication. While the causes giving rise to autistic symptoms are numerous and varied, the treatment options and therapeutic avenues are still severely limited. Nevertheless, a number of signalling pathways have been implicated in the pathogenesis of the disease, and targeting these pathways might provide insight into potential treatments and future strategies. Importantly, alterations in inflammation, oxidative stress, and mitochondrial dysfunction have been noted in the brains of ASD patients, and among the pathways involved in these processes is the Nrf2 cascade. This particular pathway has been hypothesized to be involved in inducing both, inflammatory and anti-inflammatory/neuroprotective effects in the brain, sparking an interest in its use in ASD. Sulforaphane, a sulfur-containing phytochemical present mainly in cruciferous plants like broccoli and cabbage, has shown efficacy in activating the Nrf2 signaling pathway, which in turn brings about a protective effect on neuronal cells, especially against mitochondrial dysfunction. Its efficacy against ASD has not yet been evaluated, and in this paper, we attempt to discuss the therapeutic potential of this agent in the therapy of autism, with special emphasis on the role of the Nrf2 pathway in the disorder.

Taurine as a potential therapeutic agent interacting with multiple signaling pathways implicated in autism spectrum disorder (ASD): An in-silico analysis.

Autism spectrum disorders (ASD) are a complex sequelae of neurodevelopmental disorders which manifest in the form of communication and social deficits. Currently, only two agents, namely risperidone and aripiprazole have been approved for the treatment of ASD, and there is a dearth of more drugs for the disorder. The exact pathophysiology of autism is not understood clearly, but research has implicated multiple pathways at different points in the neuronal circuitry, suggesting their role in ASD. Among these, the role played by neuroinflammatory cascades like the NF-KB and Nrf2 pathways, and the excitotoxic glutamatergic system, are said to have a bearing on the development of ASD. Similarly, the GPR40 receptor, present in both the gut and the blood brain barrier, has also been said to be involved in the disorder. Consequently, molecules which can act by interacting with one or multiple of these targets might have a potential in the therapy of the disorder, and for this reason, this study was designed to assess the binding affinity of taurine, a naturally-occurring amino acid, with these target molecules. The same was scored against these targets using in-silico docking studies, with Risperidone and Aripiprazole being used as standard comparators. Encouraging docking scores were obtained for taurine across all the selected targets, indicating promising target interaction. But the affinity for targets actually varied in the order NRF-KEAP > NF-κB > NMDA > Calcium channel > GPR 40. Given the potential implication of these targets in the pathogenesis of ASD, the drug might show promising results in the therapy of the disorder if subjected to further evaluations.

Major depressive disorder (mdd): emerging immune targets at preclinical level.

BACKGROUND: Major depressive disorder is a mental health disorder that is characterized by a persistently low mood and loss of interest. MDD is affecting over 3.8% of the global population as a major health problem. Its etiology is complex, and involves the interaction between a number of factors, including genetic predisposition and the presence of environmental stresses. AREAS COVERED: The role of the immune and inflammatory systems in depression has been gaining interest, with evidence suggesting the potential involvement of pro-inflammatory molecules like TNF, interleukins, prostaglandins, and other cytokines, among others, has been put forth. Along with this, the potential of agents, from NSAIDs to antibiotics, are being evaluated in therapy for depression. The current review will discuss emerging immune targets at the preclinical level. EXPERT OPINION: With increasing evidence to show that immune and inflammatory mediators are implicated in MDD, increasing research toward their potential as drug targets is encouraged. At the same time, agents acting on these mediators and possessing anti-inflammatory potential are also being evaluated as future therapeutic options for MDD, and increasing focus toward non-conventional drugs which can act through these mechanisms is important as regards the future prospects of the use of anti-inflammatory agents in depression.