Ginsenoside Rh1 Modulates GABAergic Inhibitory Homeostasis and Mitochondrial Quality Control During Lead (Pb)-Associated Neuronal Dysfunction

Abstract

Disruption of neuronal excitation–inhibition balance and mitochondrial quality control may contribute importantly to lead (Pb)-induced neurotoxicity, but nutritional modulators targeting these processes remain poorly characterized. This study investigated the protective effects and underlying mechanisms of ginsenoside Rh1, a ginseng-derived bioactive compound, in Pb-exposed mice and Pb-treated HT22 hippocampal cells. Chronic Pb exposure caused spatial recognition deficits, reduced exploratory activity, anxiety-like behaviors, and marked neuronal injury, accompanied by Pb accumulation in blood and brain tissues, elevated IL-1β, TNF-α, and IL-6 levels, oxidative stress, reduced Gama-aminobutyric acid (GABA) content, and dysregulated NKCC1/KCC2 expression. In HT22 cells, Pb increased intracellular ROS generation and disrupted mitophagy-related signaling, as indicated by alterations in PINK1, Parkin, LC3, P62, and GABARAP. Rh1 treatment alleviated Pb-induced behavioral abnormalities and neuronal pathology, reduced Pb burden, suppressed neuroinflammatory responses, enhanced antioxidant defenses, improved Pb-associated alterations in GABAergic regulation, and modulated mitochondrial quality-control signaling in vivo and in vitro. These findings suggest that Rh1 may represent a promising nutritional intervention strategy for mitigating Pb-associated neurotoxicity.