Cytoprotective effects of Gymnemic Acid 1 in cellular models of neurodegeneration

Gymnema sylvestre (G. sylvestre) is a traditional medicinal herb known for its anti-diabetic properties, yet its molecular mechanisms remain unknown. Growing evidence suggests a strong link between insulin resistance and neurodegeneration, mediated by impaired pro-survival signaling (e.g., PI3K/Akt), increased oxidative stress, and inflammation. This study investigates the cytoprotective potential of Gymnemic Acid 1 (GA1), a key bioactive compound from G. sylvestre, in cellular models of neurodegeneration. Neurotoxicity was induced in SH-SY5Y cells using either 6-hydroxydopamine (6-OHDA) or streptozotocin (STZ), followed by treatment with increasing concentrations of GA1. GA1 treatment significantly increased cell viability and reduced malondialdehyde (MDA) levels, indicating antioxidant and cytoprotective effects. To explore its mechanism of action, we assessed GA1 activity at the glucagon-like peptide-1 receptor (GLP-1R) using a reporter gene assay. GA1 exhibited agonistic activity at GLP-1R, and its protective effects are lost in the presence of a GLP-1R antagonist, further solidifying the involvement of GLP-1R in GA1's action. Further analysis revealed that GA1 treatment increased phosphorylation of PI3K and Akt proteins compared to toxin-only controls, suggesting activation of the GLP-1R/PI3K/Akt signaling pathway. These findings demonstrate that GA1 confers protection against neurotoxic insults via antioxidant mechanisms and activation of GLP-1R-mediated pro-survival signaling. This study provides mechanistic insight into the neuroprotective potential of G. sylvestre and supports further exploration of GA1 as a candidate for therapeutic development in neurodegenerative diseases.