Abstract
Endogenous neuroprotective mechanisms by which the brain protects itself against noxious stimuli and recovers from ischemic damage are key targets of stroke research, ultimately facilitating functional recovery. Transcriptional factor Nrf2, enriched in astrocytes, is a master regulator of endogenous defense systems against oxidative stress and inflammation. Korean Red Ginseng (Ginseng), one most widely used herbal medicine, has exhibited promising potentials in neuroprotection. Our study aimed to determine whether the standardized Ginseng extract pretreatment could attenuate acute sensorimotor deficits and improve long-term functional recovery after ischemic stroke though Nrf2 pathway and whether reactive astrogliosis is associated with such effect. Adult Nrf2−/− and matched wildtype control (WT) mice were pretreated with Ginseng orally for 7 days prior to permanent distal middle cerebral artery occlusion (pdMCAO). Using an optimized method that can accurately assess either severe or mild pdMCAO-induced sensorimotor deficits, neurobehavioral tests were performed over 28 days. The progression of lesion volume and the evolution of astrocytic and microglial activation were determined in the acute stage of ischemic stroke after pdMCAO (0–3 days). Nrf2-downstream target antioxidant genes expression levels was assessed by Western blot. We found that Ginseng pretreatment ameliorated acute sensorimotor deficits and promoted long-term functional recovery, prevented the acute enlargement of lesion volume (36.37 ± 7.45% on day 3), attenuated reactive astroglial progression but not microglia activation, and enhanced the induction of Nrf2-downstream target proteins after ischemic insult in WT mice, an effect which was lost in Nrf2 knockouts. The spatiotemporal pattern of reactive astrogliosis evaluation correlated well with acute ischemic damage progression in an Nrf2-dependent fashion during the acute phase of ischemia. In contrast, Nrf2 deficiency mice exhibited exacerbated ischemic condition compared to WT controls. Together, Ginseng pretreatment protects against acute sensorimotor deficits and promotes its long-term recovery after pdMCAO, at least partly, through Nrf2 activation, highlighting the potential efficacy of oral consumption of Ginseng for stroke preventative intervention in patients who are at great risk of recurrent stroke or transient ischemic attack. The attenuated reactive astrogliosis contributes to the Nrf2 pathway related neuroprotection against acute ischemic outcome and substantially long-term sensorimotor deficits in the context of ischemic stroke under pdMCAO.
Highlights
Ischemic stroke, more often disabling than fatal, is the leading cause of severe and long-term disability in the United States (Mozaffarian et al, 2016)
Considering that the Nrf2 pathway plays a vital role in oxidative stress and inflammation, we propose that Ginseng could act as a protective agent against ischemic stroke insults through this indirect Nrf2 mechanism leading to neuroprotection
We had five goals in this study: (1) to establish a novel method that can accurately evaluate mild sensorimotor deficits in ischemic stroke mouse models; (2) to evaluate the effects of Ginseng pretreatment on acute sensorimotor deficits and anatomical outcomes and functional recovery following permanent distal middle cerebral artery occlusion (pdMCAO) and determine whether these effects are lost in Nrf2−/− mice; (3) to demonstrate the contribution of Nrf2 in the effects of Ginseng pretreatment by examining the induction of Nrf2 downstream target cytoprotective and antioxidative proteins; (4) to assess the contributions of the spatiotemporal reactive astrogliosis and microgliosis in the Ginseng effects in the acute phase of ischemic injury; and (5) to provide the in vivo evidence addressing the functional contribution of Nrf2 and its effects on reactive gliosis after focal permanent stroke
Summary
More often disabling than fatal, is the leading cause of severe and long-term disability in the United States (Mozaffarian et al, 2016). We had five goals in this study: (1) to establish a novel method that can accurately evaluate mild sensorimotor deficits in ischemic stroke mouse models; (2) to evaluate the effects of Ginseng pretreatment on acute sensorimotor deficits and anatomical outcomes and functional recovery following pdMCAO and determine whether these effects are lost in Nrf2−/− mice; (3) to demonstrate the contribution of Nrf in the effects of Ginseng pretreatment by examining the induction of Nrf downstream target cytoprotective and antioxidative proteins; (4) to assess the contributions of the spatiotemporal reactive astrogliosis and microgliosis in the Ginseng effects in the acute phase of ischemic injury; and (5) to provide the in vivo evidence addressing the functional contribution of Nrf and its effects on reactive gliosis after focal permanent stroke
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