Objective: To evaluate the neuroprotective potential of wogonin in modulating excitatory–inhibitory neurotransmission via GABA_A receptor and gephyrin signaling in rat models of Parkinson’s disease (PD).

Background: Imbalance between excitatory and inhibitory neurotransmission is a key contributor to PD pathology, driving excitotoxicity, synaptic dysfunction, and progressive neuronal loss. Disruption of GABA_A receptor–mediated inhibitory signaling and altered gephyrin-dependent synaptic anchoring further exacerbate neuronal vulnerability. Wogonin, a naturally occurring flavonoid with reported antioxidant, anti-inflammatory, and neuromodulatory properties, has not been systematically evaluated for its ability to modulate GABAergic signaling and the stability of inhibitory synapses in PD models.

Method: Network pharmacology, molecular docking, and molecular dynamics simulations were used to identify wogonin-associated targets and pathways related to excitotoxicity and synaptic signaling. In-vitro studies were performed in rotenone-exposed SH-SY5Y cells to assess neuronal viability, mitochondrial dysfunction, apoptosis, and expression of GABA_A receptor and gephyrin using immunocytochemistry and western blotting. In-vivo validation employed a rotenone-induced rat model. Study included four groups (n=8), normal control, rotenone group, Wogonin groups, and Standard group. Behavioral assessments conducted weekly. On day 22, rats were sacrificed and brains isolated for biochemical, molecular, and histopathological analyses.

Results: Computational analyses identified inhibitory synaptic signaling pathways as key targets of wogonin, with stable binding to the GABA_A receptor. Rotenone exposure induced mitochondrial dysfunction, neuronal loss, and downregulation of GABA_A receptor and gephyrin expression. Wogonin treatment significantly improved neuronal viability, reduced apoptosis, restored inhibitory synaptic markers (in vitro), ameliorated behavioral deficits, modulated molecular markers, and preserved neuronal architecture in vivo.

Conclusion: Wogonin confers neuroprotection by restoring GABA_A receptor-gephyrin-mediated inhibitory neurotransmission and counteracting excitotoxic neuronal injury, highlighting its potential as a plant-derived candidate for excitatory–inhibitory imbalance-driven PD.

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MDS Abstracts - https://www.mdsabstracts.org/abstract/modulation-of-excitatory-inhibitory-neurotransmission-via-targeting-gabaa-gephyrin-signaling-integrated-in-silico-in-vitro-and-in-vivo-evidence-in-parkinsons-disease-models/