Introduction: Endogenous defense mechanisms by which the brain protects itself against noxious stimuli and recovers from ischemic damage are key targets of stroke research that may ultimately facilitate functional recovery. Multiple evidences indicate that the transcriptional factor Nrf2 plays a vital role in cellular defense against oxidative stress and inflammation, and consequently, targeting Nrf2 has emerged as a promising therapeutic strategy for disease prevention. Korean Red Ginseng (Ginseng), one of the most widely used herbal medicines in the world, has been suggested as one of the most potent Nrf2 activators, thereby making it efficacious against various acute neurological disorders, including stroke.
Hypothesis: To evaluate whether Ginseng could exert protective effects against hypoxic-ischemic brain damage and whether Nrf2 activation is pivotal to the various neuroprotective effects of Ginseng.
Methods: C57BL/6 WT and Nrf2 knockout mice (10-18 weeks old, n=12-16) were orally administered Ginseng (100mg/kg/d) or vehicle 7d prior to cerebral hypoxic-ischemic damage. At 6 and 24h after stroke, mice were neurologically scored. Brain lesion size and edema formation were measured at 24h. Using immunostaining, we examined which cells appeared to be most preferentially activated in a spatiotemporal pattern by this Nrf2 pathway, in particular, in the early stage of ischemic injury. Based on the results, we are further evaluating the efficacy of inducing the Nrf2 pathway and assess the extended neuroprotective effects of Ginseng at 7d after stroke.
Results: Ginseng treatment significantly reduced cerebral infarct size, neuronal death, edema formation and the resultant functional neurological deficits at 24h after stroke (P<0.001); whereas, Nrf2 ablation remarkably attenuated all benefits. Notably, the above protective effects of Ginseng were significantly attenuated in Nrf2 knockouts (P<0.05). In addition, Ginseng treated mice also exhibited reduced neuronal death and delayed severe reactive astrogliosis at 6 and 12h (P<0.05).
Conclusion: Our findings indicate a neuroprotective effect of Ginseng against hypoxic-ischemic brain damage, and that Nrf2-dependent cytoprotective responses appear to be more prominent in astrocytes.