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Tetramethylpyrazine nitrone, a multifunctional neuroprotective agent for ischemic stroke therapy.

ABSTRACT: TBN, a novel tetramethylpyrazine derivative armed with a powerful free radical-scavenging nitrone moiety, has been reported to reduce cerebral infarction in rats through multi-functional mechanisms of action. Here we study the therapeutic effects of TBN on non-human primate model of stroke. Thirty male Cynomolgus macaques were subjected to stroke with 4 hours ischemia and then reperfusion. TBN were injected intravenously at 3 or 6 hours after the onset of ischemia. Cerebral infarction was examined by magnetic resonance imaging at 1 and 4 weeks post ischemia. Neurological severity scores were evaluated during 4 weeks observation. At the end of experiment, protein markers associated with the stroke injury and TBN treatment were screened by quantitative proteomics. We found that TBN readily penetrated the blood brain barrier and reached effective therapeutic concentration after intravenous administration. It significantly reduced brain infarction and modestly preserved the neurological function of stroke-affected arm. TBN suppressed over-expression of neuroinflammatory marker vimentin and decreased the numbers of GFAP-positive cells, while reversed down-regulation of myelination-associated protein 2', 3'-cyclic-nucleotide 3'-phosphodiesterase and increased the numbers of NeuN-positive cells in the ipsilateral peri-infarct area. TBN may serve as a promising new clinical candidate for the treatment of ischemic stroke.

SUBMITTER: Zhang Z

PROVIDER: S-EPMC5107909 | biostudies-literature | 2016 Nov

REPOSITORIES: biostudies-literature

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Tetramethylpyrazine nitrone, a multifunctional neuroprotective agent for ischemic stroke therapy.

Zhang Zaijun Z Zhang Gaoxiao G Sun Yewei Y Szeto Samuel S W SS Law Henry C H HC Quan Quan Q Li Guohui G Yu Pei P Sho Eiketsu E Siu Michael K W MK Lee Simon M Y SM Chu Ivan K IK Wang Yuqiang Y

Scientific reports 20161114

TBN, a novel tetramethylpyrazine derivative armed with a powerful free radical-scavenging nitrone moiety, has been reported to reduce cerebral infarction in rats through multi-functional mechanisms of action. Here we study the therapeutic effects of TBN on non-human primate model of stroke. Thirty male Cynomolgus macaques were subjected to stroke with 4 hours ischemia and then reperfusion. TBN were injected intravenously at 3 or 6 hours after the onset of ischemia. Cerebral infarction was examin ...[more]

PMID: 27841332

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Project description:BackgroundVinpocetine as a neuroprotective agent is effective in acute ischemic stroke in some randomized controlled trials (RCTs). Since the last systematic review has been published in 2008, which didn't find conclusive evidence favoring its use, two more RCTs have also been completed.MethodsRelevant electronic databases were searched with a suitable combination of Medical Subject Headings terms to detect publications describing RCTs exploring the safety and efficacy of vinpocetine in patients with acute ischemic stroke. The risk of bias was determined by using the Cochrane Collaboration's tool for assessing the risk of bias in RCTs after full-text review and relevant data extraction. Higgins and Thompson's I2 method was used to assess heterogeneity in studies. The presence of publication bias was assessed by Egger's test. We used a random effect model when I2 was more than 50% and a fixed-effect model for other parameters.ResultsFour placebo-controlled RCTs enrolling a total of 601 and 236 patients in vinpocetine and placebo groups, respectively, were included. The number of patients with death or significant disability was lower in the vinpocetine group than that in the placebo group at both 1 and 3 months (relative risk 0.80, 95% confidence interval [CI] 0.65-0.99 and relative risk 0.67, CI 0.48-0.92, p = 0.04 and 0.02, respectively). The degree of disability in participants at 1 month and 3 months was also lower in vinpocetine group than that in the placebo group (standardized mean difference (SMD) 0.49, 95% CI 0.03-0.95 and SMD 1.22, CI 0.23-2.24, p = 0.001 and 0.04, respectively). Change in mini-mental state examination score compared with baseline at trial enrolment was also better in the vinpocetine group than in the placebo group (pooled weighted mean difference 0.92, 95% CI 0.02-1.82, p = 0.04).ConclusionsVinpocetine has some promising efficacy in patients with ischemic stroke when used in the acute stage in reducing the disability, but presently there is not enough evidence to suggest that it also reduces case fatality. More double-blind, placebo-controlled RCTs of adequate sample size are needed before making recommendations for the routine administration of vinpocetine for all patients with acute ischemic stroke.

Dataset Information

Tetramethylpyrazine nitrone, a multifunctional neuroprotective agent for ischemic stroke therapy.

Publications

Tetramethylpyrazine nitrone, a multifunctional neuroprotective agent for ischemic stroke therapy.

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