Homotaurine ameliorates the core ASD symptomatology in VPA rats through GABAergic signaling: Role of GAD67.
In: Brain research bulletin, Jg. 190 (2022-11-01), S. 122
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Zugriff:
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-1β, 6, TNF-α) 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.
(Copyright © 2022 Elsevier Inc. All rights reserved.)
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Homotaurine ameliorates the core ASD symptomatology in VPA rats through GABAergic signaling: Role of GAD67.
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Autor/in / Beteiligte Person: | Singla, R ; Mishra, A ; Joshi, R ; Sarma, P ; Kumar, R ; Kaur, G ; Sharma, AR ; Jain, A ; Prakash, A ; Bhatia, A ; Medhi, B |
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Zeitschrift: | Brain research bulletin, Jg. 190 (2022-11-01), S. 122 |
Veröffentlichung: | New York Ny : Elsevier Science ; <i>Original Publication</i>: Phoenix, N. Y. ANKHO International Inc., 2022 |
Medientyp: | academicJournal |
ISSN: | 1873-2747 (electronic) |
DOI: | 10.1016/j.brainresbull.2022.09.003 |
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