Critical Evaluation of Valproic Acid-Induced Rodent Models of Autism: Current and Future Perspectives.

Valproic acid (VPA) induced rodent model of autism is a widely accepted and extensively used rodent model to investigate the pharmacotherapy against autism. But, to date, its validation, suitability, and applicability as a well defining autistic model are still questionable. Previous research efforts highlighted that this model shows various core defining features of autism and related pathways, hence it is very necessary to explore its authenticity as a well-suited model for autism. Therefore, in this review, we summarize the preclinical and neurobiological relevant validated features, involved etiological mechanism, biological markers, treatment responses, drawbacks, current approaches, and future perspectives of VPA-induced model of autism. This review would help in deciphering the validation of the VPA-induced autistic model and its suitability as an experimental model of autism. A thorough investigation of behavioral, molecular, and neurobiological processes in animal models of autism would help in investigating the exact causation and effective treatment for autism.

Neuroprotective efficacy of berberine following developmental exposure to chlorpyrifos in F1 generation of Wistar rats: Apoptosis-autophagy interplay.

Chlorpyrifos (CPF), an organophosphate insecticide commonly used in agriculture and household applications, is considered a developmental neurotoxicant. This study aimed to explain the neuroprotective role of Berberine (BBR) against CPF-induced autophagy dysfunction and apoptotic neurodegeneration in the developing hippocampus. F1 generation of Wistar rats was exposed to CPF (3 mg/kg b.wt.) and co-treated with BBR (10 mg/kg b.wt) in two different exposure regimens, gestational (GD9-12 and GD17-21) and lactational (PND1-20). Our results demonstrated that CPF intoxication instigated cognitive and neurobehavioral impairment, oxidant-antioxidant imbalance, and histomorphological alterations in CA1, CA3, and DG regions of the offsprings. Furthermore, mRNA expression of pro-apoptotic genes (caspase3 and Bax) was upregulated, and that of anti-apoptotic BCl2 was downregulated. In addition, exposure to CPF also activated the autophagy inhibitor (mTOR) transcription and subsequently downregulated the expression of autophagy markers beclin1 and LC3-II. In contrast, gestational and lactational co-treatment of BBR significantly upregulated the enzymatic anti-oxidant bar of the hippocampus and attenuated histological alterations. Moreover, BBR co-treatments reduced apoptotic neurodegeneration in the hippocampal region by regulating the expression of apoptotic genes and upregulated the levels of autophagy, confirmed by ultrastructural studies, decreased gene expression and immunostaining of mTOR and increased, and increased expression gene expression and immunostaining of LC3-II positive cells. Our results confirm that treatment with BBR induces autophagy, which plays a neuroprotective role in CPF-induced developmental neuronal apoptosis in the F1 generation of Wistar rats by regulating the balance between autophagy and apoptosis.

Berberine affords protection against oxidative stress and apoptotic damage in F1 generation of wistar rats following lactational exposure to chlorpyrifos.

Chlorpyrifos (0,0-diethyl 0-(3,5,6-trichloro-2-pyridinyl)-phosphorothioate; (CPF)) is a widely used lipophilic organophosphorus insecticide that primarily manifests into central and peripheral nervous system toxicity. However, it is poorly investigated as a developmental neurotoxicant and thus remains less explored for pharmacological interventions as well. Berberine (BBR) is a benzylisoquinoline alkaloid, primarily found in the plants of Berberidaceae family, and is used for the synthesis of several bioactive derivatives. The goal of this study was to evaluate the CPF-induced neuronal damage through lactational route and analyze the neuroprotective efficacy of berberine (BBR), a potent antioxidant compound in the F1 generation. The environmentally relevant dose of CPF (3 mg/kg b.wt.) was administered via gavage to pregnant dams from postnatal day 1 to day 20 (PND 1-20). BBR (10 mg/kg b.wt.) was administered concurrently with CPF for the same duration as a co-treatment. Levels of reactive oxygen species, lipid peroxidation, membrane bound ATPases (Na+K+ATPase, Ca2+ATPase, and Mg2+ATPase), DNA damage, histomorphological alterations, cellular apoptosis were increased, and activities of glutathione reductase, endogenous antioxidant enzymes (SOD, CAT, GST, and GR) were decreased in cerebellum and cerebrum regions of CPF exposed pups. CPF triggered neuronal apoptosis by upregulating Bax and caspase-3 and downregulating Bcl-2. Co-treatment of BBR significantly attenuated these effects of CPF signifying oxidative stress mediated chlorpyrifos induced neuronal apoptosis. Berberine treatment ameliorated the CPF-induced downregulation of Bcl-2, Bax translocation, and up-regulation of caspase-3 in F1 pups. Therefore, BBR owing to its multiple pharmacological properties can be further explored for its therapeutic potential as an alternative neuroprotective agent against lactational exposure of chlorpyrifos-induced developmental neurotoxicity.