Introduction: Nrf2 is an astrocyte-enriched transcriptional factor that serves as a key regulator of endogenous cellular defense systems against oxidative stress and inflammation. Korean Red Ginseng (Ginseng), one of the most widely used herbal medicines, has exhibited an encouraging protective efficacy against various neurological disorders in preclinical and clinical studies.
Hypothesis: Our study aimed to determine whether Ginseng-pretreatment attenuates sensorimotor deficits and improves long-term recovery after ischemic stroke though the Nrf2 pathway activation by preferentially altering reactive astrogliosis.
Methods: WT and Nrf2-/- mice were pretreated with Ginseng via gavage once daily for 7 days prior to permanent distal middle cerebral artery occlusion (pdMCAO). Neurobehavioral tests were performed to assess sensorimotor deficits and long-term recovery over 28 days, lesion volumes were determined, and immunohistochemical analysis was used to characterize the astrocytic and microglial activation in early stage of ischemic stroke onset (0-3 days). Specific Nrf2 downstream targeted antioxidant genes expressions were assessed by Western Blot.
Results: We first established a novel method that can accurately assess long-term sensorimotor deficits after pdMCAO. Second, we revealed that Ginseng-pretreatment decreased sensorimotor deficits and promoted long-term recovery, reduced ischemic lesion volume (8.03±1.74% vs 12.62±0.81% on day 3), attenuated reactive astrogliosis at a spatiotemporal pattern but not microglia activation, and enhanced the induction of Nrf2-downstream proteins after ischemic injury in WT mice, which was essentially abolished in Nrf2 knockouts. Of interest, Nrf2 deficiency exacerbated the deterioration of ischemic damage.
Conclusion: Ginseng-pretreatment protects against acute ischemic sensorimotor deficits and promotes long-term recovery through Nrf2 activation by preferentially altering the spatiotemporal reactive astrogliosis. These findings indicate that oral consumption of Ginseng in humans may have similar robust efficacy of pre-ischemic intervention that impedes the ischemic cascade and ultimately facilitates functional recovery.