Red Beet (Beta vulgaris) Extract and Betanin Attenuate Valproic Acid–Induced Autism-Like Neurobehavioral and Molecular Alterations via Modulation of Oxidative Stress, Neuroinflammation, Apoptosis, and Reelin Signaling

Abstract Autism spectrum disorder (ASD) is a complex neurodevelopmental condition linked to social-communication and behavioral impairments, with emerging evidence implicating oxidative stress, neuroinflammation, and disrupted neurotransmission in its pathogenesis. Natural compounds with antioxidant and anti-inflammatory potential are explored as alternative therapeutic agents. This study investigated the neuroprotective effects of Beta vulgaris leaf ethanolic extract and its bioactive compound, betanin, in a rat model of ASD induced by prenatal valproic acid (VPA) exposure. Male neonatal rats, born to dams prenatally exposed to VPA (400 mg/kg b.wt on E12.5), were postnatally (PND 23 to PND 37) treated with either water (VPA/W), extract solvent (VPA/SE), B. vulgaris extract (200 mg/kg b.wt, VPA/EE), or betanin (25 mg/kg b.wt, VPA/BT), and compared to rats from control dams that received the same postnatal treatments (CW, CSE, CEE, and CBT, respectively). Behavioral assessments showed that VPA/EE and VPA/BT significantly improved sociability and social novelty deficits. Biochemical analyses revealed that both treatments enhanced GABA levels, reduced oxidative stress markers (MDA), elevated antioxidant defenses (GSH and CAT), and decreased pro-inflammatory TNF-α. Apoptotic markers (BCL2 and Caspase-3) were normalized, and histopathological brain abnormalities were ameliorated. Also, Reelin gene expression, suppressed by VPA, was significantly upregulated following treatment. While VPA/BT showed greater efficacy in improving sociability and neurotransmitter balance, VPA/EE exhibited broader molecular modulation. These findings concluded that B. vulgaris extract and betanin possess substantial neuroprotective properties via antioxidant, anti-inflammatory, anti-apoptotic, and neuromodulatory pathways. Their potential as adjunctive treatments for ASD warrants further clinical investigation. Graphical abstract