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Preclinical Characterization of Ginsenoside Rd, a Potential Neuroprotectant for Acute Ischemic Stroke

Author: YeRuiDong
Tutor: ZhaoGang
School: Fourth Military Medical University
Course: Neurology
Keywords: ginsenoside Rd Middle cerebral artery occlusion Neuroprotection Stroke Cerebral ischemia Oxidative stress Mitochondria
CLC: R743.3
Type: PhD thesis
Year: 2012
Downloads: 222
Quote: 0
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Abstract


Ischemic stroke ranks among the leading causes of deathand adult disabilityworldwide. Two major approaches have been developed to treat acuteischemic stroke: recanalizationand neuroprotection. Thrombolysis with tissueplasminogen activator, limited by its narrow therapeutic time window and theconcern of hemorrhagic complication, is still uncommon in use. In the US, only3to5%of patients with ischemic stroke receive tissue plasminogen activator.The goal of neuroprotective strategies is to protect the penumbra brain tissueand attenuate clinical sequelae of stroke. The development of neuroprotectivetherapy for acute ischemic stroke is challenging. Although a large number ofneuroprotective interventions have demonstrated efficacy in preclinical studiesinvolving small animals, clinical studies have so far failed to demonstrate similarefficacy. Part1Ginsenoside Rd in experimental stroke: superior neuroprotectiveefficacy with a wide therapeutic windowBackground and PurposeGinsenoside Rd (Rd), one of the main active ingredients in Panax ginseng, hasbeen demonstrated to protect against ischemic neuronal damage in vitro and invivo. In this study, we aimed to further define the preclinical characteristics ofRd.MethodsTransient and permanent middle cerebral artery occlusion (p/tMCAO) wereused to induce cerebral ischemia in rats. In dose-response study, we comparedthe efficacy of Rd (0.1–50mg/Kg) with two other established neuroprotectants:PBN and edaravone. In therapeutic window study, Rd was administered at0h,2h,4h, or8h after the reperfusion or the onset of artery occlusion. Infarctvolume was measured on post-operative day1,3and7. Neurological deficitswere assessed up to post-operative day42. Furthermore, we tested whetherthe protection of Rd is present in females and aged rats.ResultsRd at the doses of10–50mg/Kg significantly reduced the infarct volume andimproved the neurological outcome for up to6weeks after tMCAO, which wasmore robust than edaravone. Importantly, Rd was effective even whenadministered up to4h after the recirculation of tMCAO or the onset of pMCAO.Furthermore, in female rats or16-month-old rats, the salutary effects of Rdwere also observed.Conclusions Rd yields marked histological and functional improvement after focal cerebralischemia, which occurs within a wide therapeutic window and is reproduciblein different models of stroke (with or without reperfusion) and differentpopulations (male or female, young adult or aged).Part2Ginsenoside Rd attenuates redox imbalance and mitochondiraldysfunction after focal transient cerebral ischemiaBackground and PurposeIn this study, we sought to investigate the potential protective effects andassociated mechanisms of Rd in a rat model of focal cerebral ischemia.MethodsRats administered with Rd (50mg/Kg) or vehicle were subjected to transientmiddle cerebral artery occlusion (MCAO). To evaluate the underlyingmechanisms, in vivo free radical generation was monitored using microdialysis,oxidative DNA damage was identified by8-hydroxy-deoxyguanosineimmunostaining, oxidative protein damage was identified by the assessment ofprotein carbonyl and advanced glycosylation end products, and lipidperoxidation was estimated by determining the malondialdehyde and4-hydroxynonenal formation. To evaluate the mitochondiral protective effectsof Rdafter stroke, brain tissues were assayed for mitochondrial enzymeactivities, mitochondrial membrane potential, production of reactiveoxygenspecies (ROS), energy metabolites, and apoptosis.Results Microdialysis results displayed a prominent inhibitory effect of Rd on thehydroxy radical formation trapped as2,3-and2,5-DHBA. Early accumulation ofDNA, protein and lipid peroxidation products and subsequent inflammatoryinjury were suppressed by Rd treatment. Respiratory chain complex activitiesand mitochondrial membranepotential were also markedly preserved inischemic penumbra. Furthermore, Rd treatment led to a significant metabolicimprovement via increasing pyruvate and reducing lactate concentrations,thereby minimizing mitochondria-mediated apoptosis.ConclusionsOur findings demonstrated that Rd exerts neuroprotective effect in transientfocal ischemia, which may involve an integrated process of the oxidativedamage suppression, mitochondrial protection, energy restoration andsequential inhibition of apoptosis.

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CLC: > Medicine, health > Neurology and psychiatry > Neurology > Cerebrovascular disease > Acute cerebrovascular disease ( stroke)
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