title: Ginsenoside Rd Is Efficacious Against Acute Ischemic Stroke by Suppressing Microglial Proteasome-Mediated Inflammation.
abstract: A great deal of attention has been paid to neuroprotective therapies for cerebral ischemic stroke. Our two recent clinical trials showed that ginsenoside Rd (Rd), a kind of monomeric compound extracted from Chinese herbs, Panax ginseng and Panax notoginseng, was safe and efficacious for the treatment of ischemic stroke. In this study, we conducted a pooled analysis of the data from 199 patients with acute ischemic stroke in the first trial and 390 in the second to reanalyze the efficacy and safety of Rd. Moreover, animal stroke models were carried out to explore the possible molecular mechanisms underlying Rd neuroprotection. The pooled analysis showed that compared with placebo group, Rd could improve patients' disability as assessed by modified Rankin Scale (mRS) score on day 90 post-stroke and reduce neurologic deficits on day 15 or day 90 post-stroke as assessed by NIH Stroke Scale (NIHSS) and Barthel Index (BI) scores. For neuroprotective mechanisms, administration of Rd 4 h after stroke could inhibit ischemia-induced microglial activation, decrease the expression levels of various proinflammatory cytokines, and suppress nuclear factor of kappa light polypeptide gene enhancer in B cells inhibitor, alpha (IκBα) phosphorylation and nuclear factor kappa-light-chain-enhancer of activated B cells (NF-κB) nuclear translocation. An in vitro proteasome activity assay revealed a significant inhibitory effect of Rd on proteasome activity in microglia. Interestingly, Rd was showed to have less side effects than glucocorticoid. Therefore, our study demonstrated that Rd could safely improve the outcome of patients with ischemic stroke, and this therapeutic effect may result from its capability of suppressing microglial proteasome activity and sequential inflammation.
authors.affiliation: Department of Neurology, Xijing Hospital, The Fourth Military Medical University, 15 Changle-xi Road, Xi'an, 710032, China.
authors.forename: Guangyun
authors.initials: G
authors.lastname: Zhang
authors.affiliation: Department of Neurology, Xijing Hospital, The Fourth Military Medical University, 15 Changle-xi Road, Xi'an, 710032, China.
authors.forename: Feng
authors.initials: F
authors.lastname: Xia
authors.affiliation: Department of Neurology, Xijing Hospital, The Fourth Military Medical University, 15 Changle-xi Road, Xi'an, 710032, China.|Medical Center of Neurology, The First Affiliated Hospital, Chinese PLA General Hospital, Beijing, China.
authors.forename: Yunxia
authors.initials: Y
authors.lastname: Zhang
authors.affiliation: Department of Neurology, Xijing Hospital, The Fourth Military Medical University, 15 Changle-xi Road, Xi'an, 710032, China.
authors.forename: Xiao
authors.initials: X
authors.lastname: Zhang
authors.affiliation: Department of Pediatrics, Xijing Hospital, The Fourth Military Medical University, Xi'an, Shaanxi, China.
authors.forename: Yuhong
authors.initials: Y
authors.lastname: Cao
authors.affiliation: Department of Statistics, The Fourth Military Medical University, Xi'an, Shaanxi, China.
authors.forename: Ling
authors.initials: L
authors.lastname: Wang
authors.affiliation: Department of Neurology, Xijing Hospital, The Fourth Military Medical University, 15 Changle-xi Road, Xi'an, 710032, China. liuxued@fmmu.edu.cn.
authors.forename: Xuedong
authors.initials: X
authors.lastname: Liu
authors.affiliation: Department of Neurology, Xijing Hospital, The Fourth Military Medical University, 15 Changle-xi Road, Xi'an, 710032, China. zhaogang@fmmu.edu.cn.
authors.forename: Gang
authors.initials: G
authors.lastname: Zhao
authors.affiliation: Department of Neurology, Xijing Hospital, The Fourth Military Medical University, 15 Changle-xi Road, Xi'an, 710032, China. biomidas@fmmu.edu.cn.
authors.forename: Ming
authors.initials: M
authors.lastname: Shi
mesh_terms: D000818:Animals; D000831:Animals, Newborn; D002545:Brain Ischemia / Q000150:complications / Q000188:drug therapy* / Q000473:pathology; D002467:Cell Nucleus / Q000187:drug effects / Q000378:metabolism; D016207:Cytokines / Q000378:metabolism; D003907:Dexamethasone / Q000494:pharmacology; D036145:Ginsenosides / Q000009:adverse effects / Q000494:pharmacology / Q000627:therapeutic use*; D006801:Humans; D020244:Infarction, Middle Cerebral Artery / Q000150:complications / Q000473:pathology; D007249:Inflammation / Q000473:pathology*; D008297:Male; D008810:Mice, Inbred C57BL; D017628:Microglia / Q000187:drug effects / Q000473:pathology*; D000072000:NF-KappaB Inhibitor alpha / Q000378:metabolism; D016328:NF-kappa B / Q000378:metabolism; D010766:Phosphorylation / Q000187:drug effects; D046988:Proteasome Endopeptidase Complex / Q000378:metabolism*; D017207:Rats, Sprague-Dawley; D020521:Stroke / Q000150:complications / Q000188:drug therapy* / Q000473:pathology*; D016896:Treatment Outcome
chemical_list: D016207:Cytokines; D036145:Ginsenosides; D016328:NF-kappa B; D000072000:NF-KappaB Inhibitor alpha; D003907:Dexamethasone; D046988:Proteasome Endopeptidase Complex; C049863:ginsenoside Rd
keywords: Ginsenoside Rd; Inflammation; Ischemic stroke; Microglia; Pooled analysis; Proteasome