Investigation of the protective effect of 6-gingerol against cisplatin-induced neurotoxicity in DRG neurons

Peripheral neuropathy leads to reversible or irreversible damage to peripheral nerves (sensory, motor, and autonomic) at varying degrees and remains a major neurological issue that significantly reduces patients' quality of life, even in survivors. One of the main limitations in the clinical use of cisplatin, a widely used chemotherapeutic agent, is its tendency to cause peripheral neuropathy. Therefore, neuroprotective agents that can prevent or minimize this side effect without compromising cisplatin's anticancer efficacy are urgently needed to improve patient outcomes. 6-Gingerol (G), a bioactive compound derived from Zingiber officinale (ginger), possesses anticancer, antioxidant, and anti-inflammatory properties. In this study, neurotoxicity was induced in mouse dorsal root ganglion (DRG) neuron cultures using cisplatin (5 μg/ml). Experimental groups included: Control (C), Cisplatin only (S), and Cisplatin combined with 6-gingerol at three different concentrations (10 μM, 50 μM, and 100 μM), forming groups G10, G50, and G100, respectively. The neuroprotective effects of 6-gingerol were evaluated at the cellular level using live-cell imaging for neuronal survival and neurite outgrowth. Immunocytochemical analyses were performed using confocal microscopy with neurofilament (neuronal marker) and anti-Sox10 (Schwann cell marker). At 24, 48, and 72 hours, neurite lengths in G10 and G50 groups significantly exceeded those of the control group (p<0.001). Regarding cell survival at 72 hours, G10 and G50 showed similar profiles and were comparable to the control group, whereas S and G100 groups displayed reduced viability (p<0.001). Neurofilament expression was statistically similar among groups C, G10, G50, and G100, while it was significantly lower in group S compared to C, G10, G50 (p<0.001), and G100 (p=0.017). Anti-Sox10 intensity was highest in groups S and G100 (p<0.001), indicating possible Schwann cell stress or proliferation in response to damage. The most effective protective dose was observed in the G10 group (p<0.001). These findings suggest that 6-gingerol may serve as a promising neuroprotective agent for preventing or mitigating cisplatin-induced peripheral neuropathy.