Therapeutic efficacy of Genistein in activation of neuronal AC/cAMP/CREB/PKA and mitochondrial ETC-Complex pathways in experimental model of autism: Evidence from CSF, blood plasma and brain analysis

Autism is a complex neurodevelopmental condition characterized by repetitive behaviors, impaired social communication, and various associated conditions such as depression and anxiety. Its multifactorial etiology includes genetic, environmental, dietary, and gastrointestinal contributions. Pathologically, Autism is linked to mitochondrial dysfunction, oxidative stress, neuroinflammation, and neurotransmitter imbalances involving GABA, glutamate, dopamine, and oxytocin. Propionic acid (PRPA) is a short-chain fatty acid produced by gut bacteria, influencing central nervous system functions. Elevated PRPA levels can exacerbate Autism-related symptoms by disrupting metabolic processes and crossing the blood–brain barrier. Our research investigates the neuroprotective potential of Genistein (GNT), an isoflavone compound with known benefits in neuropsychiatric and neurodegenerative disorders, through modulation of the AC/cAMP/CREB/PKA signaling pathway and mitochondrial ETC complex (I-IV) function. In silico analyses revealed GNT’s high affinity for these targets. Subsequent in vitro and in vivo experiments using a PRPA-induced rat model of autism demonstrated that GNT (40 and 80 mg/kg., orally) significantly improves locomotion, neuromuscular coordination, and cognitive functions in PRPA-treated rodents. Behavioral assessments showed reduced immobility in the forced swim test, enhanced Morris water maze performance, and restored regular locomotor activity. On a molecular level, GNT restored levels of key signaling molecules (AC, cAMP, CREB, PKA) and mitochondrial complexes (I-V), disrupted by PRPA exposure. Additionally, GNT reduced neuroinflammation and apoptosis, normalized neurotransmitter levels, and improved the complete blood count profile. Histopathological analyses confirmed that GNT ameliorated PRPA-induced brain injuries, restored normal brain morphology, reduced demyelination, and promoted neurogenesis. The study supports GNT’s potential in autism treatment by modulating neural pathways, reducing inflammation, and restoring neurotransmitter balance.