Homotaurine ameliorates the core ASD symptomatology in VPA rats through GABAergic signaling: Role of GAD67

Dysregulated GABAergic signaling is reported in Autism Spectrum disorder (ASD). In the present study, we evaluated a GABA structural mimicker homotaurine (HT) via in-silico docking and investigated the therapeutic efficacy of this drug to ameliorate ASD symptoms in the valproic acid (VPA) rat model of ASD. For the in-vivo study, animals were divided into two groups [Normal control (NC, 0.9 % saline; i.p) and disease control (VPA 600 mg/kg; i.p)] on gestational day (GD) 12.5. Male pups from VPA-exposed mothers were further divided into five groups (n = 6 in each group): disease control (DC, no-further treatment), standard treatment (risperidone (RES) 2.5 mg/kg; i.p, consecutively from PND 23-43), HT (10, 25 and 50 mg/kg; i.p, consecutively from PND 23-43). In in-silico studies, the binding pattern of homotaurine to GABA-A receptor was found similar to GABA with Tyr205, Glu155, Tyr157, Arg6, and Thr 130 as shared residues. In the in-vivo phase, the early developmental parameters (from PND 7-23) and behavioral parameters (from PND 43-54) were assessed. The offsprings of the VPA exposed group exhibited significant (p < 0.05) developmental delays, behavioral deficits [decreased sociability and social novelty (three-chamber sociability test), spatial memory (Morris water maze), increased stereotypy (self-grooming)], increased oxidative stress (decreased GSH, SOD, Catalase, and increased MDA), increased pro-inflammatory (IL-1 beta, 6, TNF-alpha) and decreased anti-inflammatory (IL-10) cytokines, Purkinje cell loss in the cerebellum and pyknosis in PFC (H/E, Nissil staining) and decreased GAD67 expression in the cerebellum (RT-PCR & immunohistochemistry). Compared to the DC, HT treatment (50 mg/kg) was able to ameliorate the aberrant core behavioral deficits, decreased oxidative stress, decreased pro-inflammatory and increased anti-inflammatory cytokine profile with preservation of the Purkinje cell density in the cerebellum, decreased pyknosis in the prefrontal cortex and normalized the expression of GAD67. Thus, HT can be a useful therapeutic agent in ASD and requires further clinical evaluation.

Automated summary

In this study, the therapeutic efficacy of the GABA mimic homotaurine (HT) in ameliorating ASD symptoms was evaluated in an ASD rat model. The results showed that HT treatment improved core behavioral deficits, decreased oxidative stress and pro-inflammatory cytokines, increased anti-inflammatory cytokines, preserved cell density, and normalized gene expression. This suggests that HT may be a potential therapeutic agent for ASD.