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.

Enhanced Bioavailability and Higher Uptake of Brain-Targeted Surface Engineered Delivery System of Naringenin developed as a Therapeutic for Autism Spectrum Disorder.

BACKGROUND: Neuroinflammation resulting from oxidative and nitrosative stress is associated with various neurological disorders and involves the generation of pro-inflammatory cytokines and microglial activation. Dietary phytochemicals are safer and more valuable adjunct neurotherapeutic agents which can be added to the therapeutic regimen. These compounds provide neuroprotection by the modulation of various signaling pathways. INTRODUCTION: Naringenin (NGN) is a phytochemical having low oral bioavailability because of poor solubility, and adding to this limitation is enhanced efflux by P-glycoprotein transporters in neuroinflammatory diseases. METHODS: Hence, as a solution for these limitations, naringenin encapsulated poly-lactic-co-glycolic acid (PLGA) nanocarriers were developed using the nanoprecipitation technique and coated with 1% glutathione (GSH) and 1% Tween 80 to enhance brain delivery. RESULTS: Coated and uncoated NGN-PLGA nanoparticles (NGN-PLGA-NPs) were spherical, monodispersed, stable, and non-toxic, with a particle size of less than 200 nm. They had negative zeta-potential values, 80% entrapment efficiency, and sustained drug release of 81.8% (uncoated), 80.13%, and 78.43% (coated) in 24 hours. FT-IR, DSC, PXRD, and NMR confirmed the drug encapsulation and coating over nanoparticles. In vivo brain uptake showed greater fluorescence intensity of the coated nanoparticles in the brain than uncoated nanoparticles. In addition, there was a 2.33-fold increase in bioavailability after coating compared to naringenin suspension and enhanced brain uptake. CONCLUSION: Present studies indicate sustained and targeted brain delivery of naringenin via the ligandcoated delivery system by inhibiting enhanced P-glycoprotein (P-gp) efflux occurring in autism spectrum disorders due to neuroinflammation.

Nitric oxide pathway as a plausible therapeutic target in autism spectrum disorders.

BACKGROUND: The nitric oxide pathway has been \pivotal in exploring neurodevelopmental disorders. Pathogenesis of autism spectrum disorders (ASD) is also suspected to involve a number of biological cascades triggered by nitric oxide-induced neurotoxicity. The excessive nitric oxide levels caused by varied toxicants leads to the formation of reactive nitrogenous species along with ROS leading to mitochondrial dysfunction, oxidative stress, neuroinflammation, and altered NOS expression responsible for worsening of behavioral complications. AREAS COVERED: In this article, we will discuss the plausible role of the nitric oxide pathway in ASD and also discuss the modulation of this pathway by therapeutics, which can be explored in clinics for mitigating nitrosative stress in ASD. Literature was searched utilizing various databases such as Embase, Medline, Web of Science, and Google Scholar from 1966 to 2021. EXPERT OPINION: Nitric oxide pathway is an unexplored domain in the field of ASD and could act as an important therapeutic target in providing relief from behavioral alterations in autistic patients. At present, no major experimental study confirms the role of nitric oxide in autism. However, conclusive preclinical and clinical evidence is needed to evaluate and establish the role of nitric oxide in ASD.

Novel nanotechnological approaches for treatment of skin-aging.

One of the essential organs and protective barricades, the skin, needs to be taken care of early. Skin is affected by several intrinsic and extrinsic factors, and despite their morphological and pathological differences, they have many molecular similarities. As of today, various mechanisms and theories have been recommended for aging, such as cellular anility, reduced proliferative tendency, reduction in length of telomere, mutations in DNA, theory of free radical generation, and many others. In today's society, skin health is often considered an important indicator of health, which has led to an increased demand for anti-aging products. However, numerous conventional cosmetics and phytocompounds (curcumin, Vitamin E, resveratrol) utilized in anti-aging products have inimical physical and chemical attributes, including insufficient chemical stability and inadequate skin penetration bound their effectuality after topical administration. So recently, new novel nanotechnological approaches for preventing skin aging, such as liposomes, niosomes, solid lipid nanoparticles, transferosomes, ethosomes, nanostructured lipid carriers, and carbon nanotubes, are being used. Hence, the field of cosmeceutical nanomaterials is rapidly evolving, and we can look forward to seeing a variety of innovative nanotechnology-based cosmetic products be a game-changer for this multi-million anti-aging cosmetic industry.

Transient Receptor Potential Vanilloid 1 (TRPV1) as a plausible novel therapeutic target for treating neurological complications in ZikaVirus.

Zika virus was declared a national emergency by WHO (World Health Organization) in 2016 when its widespread outbreaks and life-threatening complications were reported, especially in newborns and adults. Numerous studies reported that neuroinflammation is one of the significant root-causes behind its major neurological complications like microcephaly and Guillain-Barré syndrome (GBS). In this hypothesis, we propose Transient Receptor Potential Vanilloid 1 channel (TRPV1) as a major culprit in triggering positive inflammatory loop, ultimately leading to sustained neuroinflammation, one of the key clinical findings in Zika induced microcephalic and GBS patients. Opening of TRPV1 channel also leads to calcium influx and oxidative stress that ultimately results in cellular apoptosis (like Schwann cell in GBS and developing fetal nerve cells in microcephaly), ultimately leading to these complications. Currently, no specific cure exists for these complications. Most of the antiviral candidates are under clinical trials. Though there is no direct research on TRPV1 as a cause of Zika virus's neurological complications, but similarity in mechanisms is undeniable. Thus, exploring pathobiological involvement of TRPV1 channels and various TRPV1 modulators in these complications can possibly prove to be an effective futuristic therapeutic strategy for treatment and management of these life-threatening complications.

Exploring nordihydroguaretic acid (NDGA) as a plausible neurotherapeutic in the experimental paradigm of autism spectrum disorders targeting nitric oxide pathway.

The present study investigates the neuro-protective ability of nordihydroguaretic acid (NDGA) in the experimental paradigm of autism spectrum disorders (ASD) and further decipher the nitric oxide pathway's role in its proposed action. An intracerebroventricular infusion of 4 µl of 1 M PPA was given in the lateral ventricle's anterior region to induce autism-like phenotype in male rats. Oral administration of NDGA (5, 10 & 15 mg/kg) was initiated from the 3rd day lasting till the 28th day. L-NAME (50 mg/kg) and L-Arginine (800 mg/kg) were also given individually and combined to explore NDGA's ability to act via the nitric oxide pathway. Behavior tests for sociability, stereotypy, anxiety, depression, novelty, repetitive and perseverative behavior were carried out between the 14th and 28th day. On the 29th day, animals were sacrificed, and mitochondrial complexes and oxidative stress parameters were evaluated. We also estimated the levels of neuroinflammatory and apoptotic markers such as TNF-α, IL-6, NF-κB, IFN-γ, HSP-70, and caspase-3. To assess the involvement of the nitric oxide pathway, levels of iNOS and homocysteine were estimated. Treatment with NDGA significantly restored behavioral, biochemical, neurological, and molecular deficits. Hence, NDGA can be used as a neurotherapeutic agent in ASD. Targeting nitric oxide pathway mediated oxidative & nitrosative stress responsible for behavioral, biochemical, and molecular alterations via modulating nitric oxide pathway. The evaluation of iNOS and homocysteine levels conclusively establishes the nitric oxide pathway's role in causing behavioral, biochemical & molecular deficits and NDGA's beneficial effect in restoring these alterations.

Effects of catechin on a rodent model of autism spectrum disorder: implications for the role of nitric oxide in neuroinflammatory pathway.

AIM: The present research work aims at deciphering the involvement of nitric oxide pathway and its modulation by ( ±)catechin hydrate in experimental paradigm of autism spectrum disorders (ASD). METHOD: An intracerebroventricular infusion of 4 µl of 1 M propanoic acid was given in the anterior region of the lateral ventricle to induce autism-like phenotype in male rats. Oral administration of ( ±)catechin hydrate (25, 50, and 100 mg/kg) was initiated from the 3rd day lasting till the 28th day. L-NAME (50 mg/kg) and L-arginine (800 mg/kg) were also given individually as well as in combination to explore the ability of ( ±)catechin hydrate to act via nitric oxide pathway. Behavior test for sociability, stereotypy, anxiety, depression, and novelty, repetitive, and perseverative behavior was carried out between the 14th and 28th day. On the 29th day, animals were sacrificed, and levels of mitochondrial complexes and oxidative stress parameters were evaluated. We also estimated the levels of neuroinflammatory and apoptotic markers such as TNF-α, IL-6, NF-κB, IFN-γ, HSP-70, and caspase-3. To evaluate the involvement of nitric oxide pathway, the levels of iNOS and homocysteine were estimated. RESULTS: Treatment with ( ±)catechin hydrate significantly ameliorated behavioral, biochemical, neurological, and molecular deficits. Hence, ( ±)catechin hydrate has potential to be used as neurotherapeutic agent in ASD targeting nitric oxide pathway-mediated oxidative and nitrosative stress responsible for behavioral, biochemical, and molecular alterations via modulating nitric oxide pathway. CONCLUSION: The evaluation of the levels of iNOS and homocysteine conclusively establishes the role of nitric oxide pathway in causing behavioral, biochemical, and molecular deficits and the beneficial effect of ( ±)catechin hydrate in restoring these alterations.

TLR4 as a therapeutic target for respiratory and neurological complications of SARS-CoV-2.

Introduction: The COVID-19 pandemic remains aglobal challenge. While there are mRNA agents on the horizon as apotential prevention, adefinitive drug therapy is an unmet medical need. The hyperinflammatory response, known as the 'cytokine storm', is chiefly responsible for complications and deaths. The binding of spike-glycoprotein of SARS-CoV-2 to TLR4 receptors has been documented in several studies and has been found to play arole in hyperinflammation; hence, there is an interest in TLR4 as apotential drug target.Areas covered: This review discusses the neurological and respiratory complications of SARS-CoV-2 infection and progresses to examine the role of the 'cytokine storm' and the involvement of TLR4 receptors in these complications. The possibility of using TLR4 modulators to curb the complications are considered and finally, ashort perspective on future potential drug treatments is offered. Various databases were searched including Pub-Med, Google Scholar, and Medline. The search mainly included research articles, meta-analysis, retrospective studies, reports, and systematic reviews.Expert opinion: TLR4 modulators are being investigated in clinical trials for COVID-19. Challenges in terms of structural diversity of the agents, their natural origin, and efficacy demand extensive research.

IDO-1 inhibition protects against neuroinflammation, oxidative stress and mitochondrial dysfunction in 6-OHDA induced murine model of Parkinson's disease.

Parkinson's disease (PD), a common neurodegenerative motor disorder characterized by striatal dopaminergic neuronal loss and localized neuroinflammation in the midbrain region. Activation of microglia is associated with various inflammatory mediators and Kynurenine pathway (KP) being one of the major regulator of immune response, is involved in the neuroinflammatory and neurotoxic cascade in PD. In the current study, 1-Methyltryptophan (1-MT), an Indolamine-2,3-dioxygenase-1 (IDO-1) inhibitor was tested at different doses (2.5 mg/kg, 5 mg/kg and 10 mg/kg) for its effect on behavioral parameters, oxidative stress, neuroinflammation, apoptosis, mitochondrial dysfunction, neurotransmitter levels, biochemical and behavioral alterations in unilateral 6-OHDA (3 µg/µL) murine model of PD. The results showed improved locomotion in open field test and motor coordination in rota-rod, reduced oxidative stress, neuroinflammatory markers (TNF-α, IFN-γ, IL-6), mitochondrial dysfunction and neuronal apoptosis (caspase-3). Also, restoration of neurotransmitter levels (dopamine and homovanillic acid) in the striatum and increased striatal BDNF levels were observed. Overall findings suggest that 1-MT could be a potential candidate for further studies to explore its possibility as an alternative in the pharmacotherapy of PD.

Divulging the Intricacies of Crosstalk Between NF-Kb and Nrf2-Keap1 Pathway in Neurological Complications of COVID-19.

The severity of COVID-19 infection is surging day by day. With the cases increasing daily, it is becoming more and more essential to understand the pathogenic mechanisms underlying the severity of the disease. It is now well known that the infection manifests itself primarily as respiratory, but the involvement of the other organ systems has now been documented in many studies. SARS-CoV-2 can invade the nervous system by a multitude of proposed mechanisms that have been discussed in this review. NF-κB and Nrf2 are transcription factors that regulate genes responsible for inflammatory and anti-oxidant response respectively. Specific focus in this review has been given to NF-κB and Nrf2 pathways that are involved in the cytokine storm and oxidative stress that are the hallmarks of COVID-19. As the immune injury is an important mechanism of neuro-invasion and neuroinflammation, there is the possible involvement of these two pathways in the neurological complications. The crosstalk mechanisms of these signaling pathways have also been discussed. Immuno-modulators both synthetic and natural are promising candidates in catering to the pathologies targeted in the aforementioned pathways.

The Nrf2 pathway in psychiatric disorders: pathophysiological role and potential targeting.

Introduction: All psychiatric disorders exhibit excitotoxicity, mitochondrial dysfunction, inflammation, oxidative stress, and neural damage as their common characteristic. The endogenous nuclear factor erythroid 2-related factor 2 (Nrf2) signaling pathway is implicated in the defense mechanism against oxidative stress and has a significant role in psychiatric disorders.Areas covered: We explore the role of Nrf2 pathway and its modulators in psychiatric disorders. The literature was searched utilizing various databases such as Embase, Medline, Web of Science, Pub-Med, and Google Scholar from 2010 to 2020. The search included research articles, clinical reports, systematic reviews, and meta-analyses.Expert opinion: Environmental factors and genetic predisposition can be a trigger for the development of psychiatric disorders. Nrf2 downregulates certain inflammatory pathways and upregulates various antioxidant enzymes to maintain a balance. However, its intricate balance with NF-Kß (Nuclear factor kappa light chain enhancer of activated B cells) and its crosstalk with the transcription factor Nrf2 is critical in severe oxidative stress. Several Nrf2 modulators are now in clinical trials and can help reduce oxidative stress and neuroinflammation. There are immense potential opportunities for these modulators to become a novel therapeutic option.

Novel Nanotechnological Approaches for Targeting Dorsal Root Ganglion (DRG) in Mitigating Diabetic Neuropathic Pain (DNP).

Diabetic neuropathy is the most entrenched complication of diabetes. Usually, it affects the distal foot and toes, which then gradually approaches the lower part of the legs. Diabetic foot ulcer (DFU) could be one of the worst complications of diabetes mellitus. Long-term diabetes leads to hyperglycemia, which is the utmost contributor to neuropathic pain. Hyperglycemia causing an upregulation of voltage-gated sodium channels in the dorsal root ganglion (DRG) was often observed in models of neuropathic pain. DRG opening frequency increases intracellular sodium ion levels, which further causes increased calcium channel opening and stimulates other pathways leading to diabetic peripheral neuropathy (DPN). Currently, pain due to diabetic neuropathy is managed via antidepressants, opioids, gamma-aminobutyric acid (GABA) analogs, and topical agents such as capsaicin. Despite the availability of various treatment strategies, the percentage of patients achieving adequate pain relief remains low. Many factors contribute to this condition, such as lack of specificity and adverse effects such as light-headedness, languidness, and multiple daily doses. Therefore, nanotechnology outperforms in every aspect, providing several benefits compared to traditional therapy such as site-specific and targeted drug delivery. Nanotechnology is the branch of science that deals with the development of nanoscale materials and products, even smaller than 100 nm. Carriers can improve their efficacy with reduced side effects by incorporating drugs into the novel delivery systems. Thus, the utilization of nanotechnological approaches such as nanoparticles, polymeric nanoparticles, inorganic nanoparticles, lipid nanoparticles, gene therapy (siRNA and miRNA), and extracellular vesicles can extensively contribute to relieving neuropathic pain.

Pharmacological insight into potential therapeutic agents for the deadly Covid-19 pandemic.

Coronaviruses are pleomorphic, enveloped, or spherical viruses, which have a size ranging from 80 to 120 nm. These viruses act on receptors that cause the triggering of fusion. Coronaviruses were first described after cultivation from patients with common colds by Tyrell and Bynoe in 1966. There are various subtypes of coronavirus, 7 out of these can cause infection in human beings. The Alpha subtype is responsible for mild infection showing symptoms or infection without any prevailing symptoms. On the other hand, the beta subtype is responsible for very serious diseases leading to fatality. The lineage of this novel SARS-CoV-2 falls under the beta lineage of the beta coronavirus which has been observed to have a relation to the MERS and SARS coronavirus. In the Huanan market selling seafood, the transition of this novel virus in humans from animals has occurred. It has the potential to be the cause of widespread fatality amongst the people of the globe. On August 16, 2020, the World Health Organisation had reported 2,1294,845 cases which are confirmed to date out of which 413,372 deaths have occurred. Currently, no targeted antiviral vaccines or drugs to fight against COVID-19 infection have been approved for use in humans. This pandemic is fast emerging and drug repurposing is the only ray of hope which can ensure quick availability. Vaccine development is progressing each day with various platforms such as DNA, Live Attenuated Virus, Non-Replicating Viral Vector, Protein Subunit, and RNA, being utilized for the development. COVID-19 attacks the immune system of the host & this can result in a cytokine storm. As a result, various herbal agents both acting as antivirals and immunomodulatory can also be used. Convalescent Plasma Therapy and Mesenchymal Stem Cell therapy are also being explored as a plausible therapeutic. There remains a considerable unmet need for therapeutics to be addressed. The development and availability of accessible and efficient therapy are essential for the treatment of patients. This review discusses the epidemiology, pathogenesis, the tale of origin, and transmission of COVID-19 or Sars-Cov2 virus and gives evidence of potential therapeutic agents that can be explored to cast away this pandemic.

Effect of ethanolic extract of Solanum virginianum Linn. on neuropathic pain using chronic constriction injury rat model and molecular docking studies.

The present research work was designed to examine the neuroprotective effect of ethanolic extract of Solanum virginianum Linn. (SV) in chronic construction injury (CCI) of sciatic nerve-induced neuropathic pain in rats. The extract was initially standardized by high-performance thin-layer chromatography using solasodine as a biomarker and was then subjected to assess the degree of mechanical allodynia, thermal allodynia, mechanical hyperalgesia, thermal hyperalgesia and biochemical evaluations. Administration of SV (100 and 200 mg/kg; p.o.) and pregabalin (10 mg/kg; p.o.) as a reference standard significantly debilitated hyperalgesia and allodynia and notably restored the altered antioxidant level and pro-inflammatory cytokine (IL-1ß and TNF-α) expression in a dose-dependent manner. Further, to appraise the mechanistic approach of solasodine, docking simulation studies were done on the 3D structure of the voltage-gated N-type calcium channel (Cav 2.2), R-type calcium channel (Cav 2.3) and sodium channel (Nav 1.7), and the results revealed that solasodine properly positioned into Phe 19, Leu 32, Met 51 and Met 71 (FLMM pocket) of Cav 2.2 and Cav 2.3 and being a competitor of Ca2+/N-lobe it may inactivate these calcium channels but did not bind into the desired binding pocket of Nav 1.7. Thus, the study confirmed the role of solasodine as a major biomarker for the observed neuroprotective nature of Solanum virginianum.

Neuropsychopathology of Autism Spectrum Disorder: Complex Interplay of Genetic, Epigenetic, and Environmental Factors.

Autism spectrum disorder (ASD) is a complex heterogeneous consortium of pervasive development disorders (PDD) which ranges from atypical autism, autism, and Asperger syndrome affecting brain in the developmental stage. This debilitating neurodevelopmental disorder results in both core as well as associated symptoms. Core symptoms observed in autistic patients are lack of social interaction, pervasive, stereotyped, and restricted behavior while the associated symptoms include irritability, anxiety, aggression, and several comorbid disorders.ASD is a polygenic disorder and is multifactorial in origin. Copy number variations (CNVs) of several genes that regulate the synaptogenesis and signaling pathways are one of the major factors responsible for the pathogenesis of autism. The complex integration of various CNVs cause mutations in the genes which code for molecules involved in cell adhesion, voltage-gated ion-channels, scaffolding proteins as well as signaling pathways (PTEN and mTOR pathways). These mutated genes are responsible for affecting synaptic transmission by causing plasticity dysfunction responsible, in turn, for the expression of ASD.Epigenetic modifications affecting DNA transcription and various pre-natal and post-natal exposure to a variety of environmental factors are also precipitating factors for the occurrence of ASD. All of these together cause dysregulation of glutamatergic signaling as well as imbalance in excitatory: inhibitory pathways resulting in glial cell activation and release of inflammatory mediators responsible for the aberrant social behavior which is observed in autistic patients.In this chapter we review and provide insight into the intricate integration of various genetic, epigenetic, and environmental factors which play a major role in the pathogenesis of this disorder and the mechanistic approach behind this integration.

Dietary Phytochemicals as Neurotherapeutics for Autism Spectrum Disorder: Plausible Mechanism and Evidence.

Autism spectrum disorder (ASD) is a complex neurodevelopmental disorder with symptoms ranging from lack of social interaction and communication deficits to rigid, repetitive, and stereotypic behavior. It has also been associated with comorbidities such as anxiety, aggression, epilepsy, deficit in sensory processing, as well as ADHD (attention deficit hyperactivity disorder). Apart from several behavioral and cognitive complications arising as a result of central nervous system dysfunction, there are various physiological comorbidities such as immune system deregulation, neuroinflammation, oxidative stress, mitochondrial dysfunction, and gastrointestinal complications which can worsen existing behavioral complications. There are no available treatments for these physiological comorbidities. The prevalence of gastrointestinal complications in ASD ranges from 9% to 70% and it correlates with behaviors consistent with the autistic endophenotype indicating that these are one of the major comorbidities associated with ASD. A strong connection of gut-brain cross talk occurs as a result of gut dysbiosis responsible for excessive production of short-chain fatty acids such as propanoic acid (PPA) by abnormal gut flora in ASD patients. This worsens behavioral, neurochemical, and mitochondrial dysfunction occurring in ASD. These physiological comorbidities are responsible for the generation of free radical species that cause immune system dysfunction leading to synthesis of various pro-inflammatory cytokines and chemokines. This in turn causes activation of microglia. Dietary phytochemicals are thought to be safer and useful as an alternative neurotherapeutic moiety. These compounds provide neuroprotection by modulating signaling pathways such as Nrf2, NF-κB, MAPK pathway or Sirtuin-FoxO pathway. There has been recent evidence in scientific literature regarding the modulation of gut-brain cross talk responsible for behavioral, biochemical, and mitochondrial dysfunction as well as cellular and behavioral sensory alterations by dietary phytochemicals such as curcumin, resveratrol, naringenin, and sulforaphane. These dietary phytochemicals can be formulated in novel brain-targeted delivery systems which overcome their limitation of low oral bioavailability and short half-life leading to prolonged action. Till date, not much work has been done on the development of brain-targeted neurotherapeutics for ASD. In this chapter we discuss plausible mechanisms and evidence from our own and other scientific research for the utilization of curcumin, resveratrol, naringenin, and sulforaphane as neurotherapeutics for ASD.