Korean Red Ginseng Attenuates Reactive Gliosis And Confers Sustained Neuroprotection Against Cerebral Hypoxic-Ischemic Damage In An Nrf2-Dependent Manner

Introduction: The transcriptional factor Nrf2, a master regulator of oxidative stress and inflammation that contribute to cerebral ischemia pathogenesis, plays a vital role in inducing the endogenous neuroprotective process. The standardized Korean red ginseng (Ginseng) extracts, derived from the root of Panax ginseng C.A. Meyer, have exhibited an encouraging protective efficacy with antioxidant and anti-inflammatory properties. Hypothesis: We hypothesized that the putative protection of Ginseng, a potent Nrf2 inducer, was through an Nrf2-dependent mechanism involving the attenuation of reactive gliosis in the hypoxic-ischemic (HI) stroke. Methods: Adult Nrf2 knockout and wildtype mice were orally pretreated with Ginseng for 7 days prior to HI surgery. The histological and neurobehavioral outcomes, as well as the structural and functional alternation of reactive gliosis were examined before and at 6h, 24h, 7d after HI. The Nr2 and its downstream markers were also monitored. Results: The expression levels of Nrf2 and its target markers were distinctly elevated in the ischemic brain region. Ginseng pretreatment elicited robust neuroprotection against the deterioration of acute cerebral ischemia damage in an Nrf2-dependent manner over 7 days, revealed by the reductions of neurological deficits score (P≤0.05, n=7-10), infarct volume and brain edema (P≤0.05, n=5-7), as well as the enhanced expression levels of Nrf2 target antioxidant proteins and anti-inflammation mediators (P≤0.05, n=4) compared to WT controls. In both ischemic striatum and cortex, the dynamic pattern of attenuated reactive gliosis in astrocytes and microglia, including affected astrocytic dysfunction in glutamate metabolism and cell osmotic water permeability, correlated well with the Nrf2-dependent neuroprotection by Ginseng. Furthermore, such neuroprotective benefits extended to the late phase of ischemic brain damage after HI, as evidenced by the improvements in neurobehavioral outcomes, infarct volume and brain edema. Conclusion: Overall, pretreatment with Ginseng attenuates reactive gliosis and confers long-lasting neuroprotective efficacy against ischemic brain damage through an Nrf2-dependent mechanism.