PMID- 36113682 OWN - NLM STAT- MEDLINE DCOM- 20221108 LR - 20221108 IS - 1873-2747 (Electronic) IS - 0361-9230 (Linking) VI - 190 DP - 2022 Nov TI - Homotaurine ameliorates the core ASD symptomatology in VPA rats through GABAergic signaling: Role of GAD67. PG - 122-133 LID - S0361-9230(22)00243-X [pii] LID - 10.1016/j.brainresbull.2022.09.003 [doi] AB - 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-1beta, 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. CI - Copyright (c) 2022 Elsevier Inc. All rights reserved. FAU - Singla, Rubal AU - Singla R AD - Dept. of Pharmacology, Post Graduate Institute of Medical Education & Research (PGIMER), Chandigarh, India. Electronic address: singlarubal1995@gmail.com. FAU - Mishra, Abhishek AU - Mishra A AD - Dept. of Pharmacology, Post Graduate Institute of Medical Education & Research (PGIMER), Chandigarh, India. Electronic address: pharmapgiabhishek@gmail.com. FAU - Joshi, Rupa AU - Joshi R AD - Dept. of Pharmacology, Post Graduate Institute of Medical Education & Research (PGIMER), Chandigarh, India. Electronic address: rupajoshiaiims@gmail.com. FAU - Sarma, Phulen AU - Sarma P AD - Dept. of Pharmacology, Post Graduate Institute of Medical Education & Research (PGIMER), Chandigarh, India. Electronic address: phulen10@gmail.com. FAU - Kumar, Rohit AU - Kumar R AD - Dept. of Pharmacology, Post Graduate Institute of Medical Education & Research (PGIMER), Chandigarh, India. Electronic address: rohit87.aiims@gmail.com. FAU - Kaur, Gurjeet AU - Kaur G AD - Dept. of Pharmacology, Post Graduate Institute of Medical Education & Research (PGIMER), Chandigarh, India. Electronic address: gurjeetkaur268@gmail.com. FAU - Sharma, Amit Raj AU - Sharma AR AD - Dept. of Neurology, Post Graduate Institute of Medical Education & Research (PGIMER), Chandigarh, India. Electronic address: amitrajsharma1992@gmail.com. FAU - Jain, Ashish AU - Jain A AD - Dept. of Pharmacology, Post Graduate Institute of Medical Education & Research (PGIMER), Chandigarh, India. Electronic address: socoolspidey@gmail.com. FAU - Prakash, Ajay AU - Prakash A AD - Dept. of Pharmacology, Post Graduate Institute of Medical Education & Research (PGIMER), Chandigarh, India. Electronic address: ajayprakashpgi@gmail.com. FAU - Bhatia, Alka AU - Bhatia A AD - Dept. of Experimental Medicine and Biotechnology, Post Graduate Institute of Medical Education & Research (PGIMER), Chandigarh, India. Electronic address: bhatia.alka@pgimer.edu.in. FAU - Medhi, Bikash AU - Medhi B AD - Dept. of Pharmacology, Post Graduate Institute of Medical Education & Research (PGIMER), Chandigarh, India. Electronic address: drbikashus@yahoo.com. LA - eng PT - Journal Article PT - Research Support, Non-U.S. Gov't DEP - 20220913 PL - United States TA - Brain Res Bull JT - Brain research bulletin JID - 7605818 RN - 56-12-2 (gamma-Aminobutyric Acid) RN - 5K8EAX0G53 (tramiprosate) RN - 614OI1Z5WI (Valproic Acid) RN - EC 4.1.1.15 (glutamate decarboxylase 1) SB - IM MH - Animals MH - Female MH - Humans MH - Male MH - Rats MH - *Autism Spectrum Disorder/drug therapy MH - Behavior, Animal MH - Disease Models, Animal MH - gamma-Aminobutyric Acid MH - *Prenatal Exposure Delayed Effects MH - Social Behavior MH - Valproic Acid/pharmacology/therapeutic use OTO - NOTNLM OT - Autism spectrum disorder OT - Cerebellum OT - GABA OT - GAD67 OT - Homotaurine OT - VPA EDAT- 2022/09/17 06:00 MHDA- 2022/11/02 06:00 CRDT- 2022/09/16 19:25 PHST- 2022/02/08 00:00 [received] PHST- 2022/08/30 00:00 [revised] PHST- 2022/09/05 00:00 [accepted] PHST- 2022/09/17 06:00 [pubmed] PHST- 2022/11/02 06:00 [medline] PHST- 2022/09/16 19:25 [entrez] AID - S0361-9230(22)00243-X [pii] AID - 10.1016/j.brainresbull.2022.09.003 [doi] PST - ppublish SO - Brain Res Bull. 2022 Nov;190:122-133. doi: 10.1016/j.brainresbull.2022.09.003. Epub 2022 Sep 13.