Chrysin Ameliorates Valproic Acid Induced Autism Spectrum Behavioral Phenotypes Through Corticohippocampal Histone Deacetylase and Translational Modulation of SHANK3 Expression in Juvenile Rats.

Autism spectrum disorder (ASD) is a neurodevelopmental disorder marked by repetitive behaviors, social deficits, and comorbid phenotypes, with rising prevalence. Its unclear pathogenesis and symptom heterogeneity hinder therapy development. Chrysin, a flavone from bee products and plants, shows diverse biological effects but limited ASD studies. Therefore, this study examines chrysin's impact on ASD behaviors and comorbidities. Pregnant Wistar rats received 600 mg/kg valproic acid (VPA) on Embryonic day (ED) 12.5 intraperitoneally to induce ASD phenotypes. Neurodevelopmental milestones were evaluated on postnatal day (PND) 3-20. Twenty-seven male offspring were used for the study. The control (n = 9 ), the VPA-exposed offspring were randomly divided into two groups: a VPA + vehicle group (n = 9) and a VPA + chrysin treatment group (n = 9). The animals received distilled water or chrysin (100 mg/kg p.o) from PND21-42. Typical and atypical baseline behaviours were done on PND21 and repeated on PND42. Serum corticosterone, prefrontal cortex (pFC), and hippocampal (HPC) neurotransmitters, Histone deacetylase (HDAC), BDNF, and caspase-3 were evaluated with ELISA, while Shank3, p-AKT, and pS6 were evaluated with immunohistochemistry and Western blot. Data were analysed using One-way or Two-way ANOVA at α < 0.05. The VPA-exposed pups exhibit signs of developmental delay compared to the controls. Chrysin also ameliorated hyperalgesia (2.659 ± 0.2628vs4.257 ± 0.3272), depressive-like behaviour (68.86 ± 3.912vs138.5 ± 9.526), and anxiety (189.6 ± 20.58vs95.10 ± 7.716). Autistic-like, sociability (0.46 ± 0.039vs0.28 ± 0.06), and social novelty (0.77 ± 0.08vs-0.28 ± 0.19) were improved by Chrysin. Chrysin increased the level of serum corticosterone (22.45 ± 1.77vs13.90 ± 0.49) when compared to VPA-only. In the prefrontal cortex and hippocampus, the levels of serotonin, GABA, and dopamine increased, while glutamate levels decreased. The levels of HDAC (1.28 ± 0.12vs2.56 ± 0.10; 1.22 ± 0.11vs1.35 ± 0.18), and Caspase3 (10.33 ± 0.72vs16.79 ± 0.85; 4.50 ± 0.53vs6.45 ± 0.78) were reduced compared to VPA-only, while increasing the levels of BDNF (21.25 ± 0.63vs14.73 ± 0.57; 17.86 ± 1.23vs7.39 ± 0.56). Chrysin increased the expression of SHANK3(1.43 ± 0.1311vs0.6588 ± 0.02533; 0.8895 ± 0.1092 vs. 0.1961 ± 0.1401), p-AKT (0.8923 ± 0.04518vs0.2493 ± 0.03399; 1.011 ± 0.09692vs0.4969 ± 0.08145), and pS6 in the pFC and HPC. Chrysin may have ameliorated valproic acid-induced Autistic-like behaviours by upregulating epigenetic and translational control of scaffolding protein synthesis, and preserving neurotrophic signalling, in male Wistar rats exposed to VPA in utero.