Neuroprotective potential of Garcinia extracts against diabetic peripheral neuropathy: GC-MS profiling, network...

Diabetic peripheral neuropathy (DPN) remains refractory to current single-target pharmacotherapies, warranting multi-target interventions. This study investigated the neuroprotective potential of methanolic fruit extracts from Garcinia pedunculata (MEGP) and Garcinia lanceifolia (MEGL) using integrated chemoinformatics-systems pharmacology-cell biology approaches. GC-MS profiling identified 11 (MEGP) and 20 (MEGL) bioactive compounds. Target prediction revealed 2359 compound-associated proteins, with 270 significantly overlapping with DPN-associated genes (p < 0.001). Network analysis identified TNF and AKT1 as key hubs, with GO/KEGG enrichment highlighting critical pathways including PI3K-Akt, MAPK, JAK-STAT, and Wnt/β-catenin involved in neuronal survival and inflammation. Molecular docking demonstrated notable binding affinities: 12-hydroxy-14-methyl-oxa-cyclotetradec-6-en-2-one with AKT1 (ΔG = - 7.1 kcal/mol) and benzofuran acetic acid derivative with TNF (ΔG = - 6.5 kcal/mol). In vitro validation using high glucose-stressed SH-SY5Y cells (1000 µg/mL, 1 h) showed significant cytoprotection with MEGP (50 µg/mL) and MEGL (100 µg/mL) pre-treatment, restoring cell viability to 75-78% (p < 0.001), reducing ROS levels by ~ 60%, and decreasing apoptotic cell counts by 30-40%. MEGP demonstrated superior neuroprotective efficacy across all assays. These findings reveal that MEGP and MEGL exert multi-targeted neuroprotective effects through TNF and AKT1-centered signaling networks, highlighting their polypharmacological potential for DPN therapy and emphasizing conservation needs for these bioactive-rich endangered species.

The online version contains supplementary material available at 10.1007/s13205-025-04580-3.