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Effects of metformin in experimental stroke.

ABSTRACT: Adenosine 5'-monophosphate-activated protein kinase (AMPK) is an important sensor of energy balance. Stroke-induced AMPK activation is deleterious because both pharmacological inhibition and genetic deletion of AMPK are neuroprotective. Metformin is a known AMPK activator but reduces stroke incidence in clinical populations. We investigated the effect of acute and chronic metformin treatment on infarct volume and AMPK activation in experimental stroke.Male mice were subjected to middle cerebral artery occlusion after acute (3 days) or chronic (3 weeks) administration of metformin. Infarct volumes, AMPK activation, lactate accumulation, and behavioral outcomes were assessed. The roles of neuronal nitric oxide synthase and AMPK were examined using mice with targeted deletion of AMPK or neuronal nitric oxide synthase.Acute metformin exacerbated stroke damage, enhanced AMPK activation, and led to metabolic dysfunction. This effect was lost in AMPK and neuronal nitric oxide synthase knockout mice. In contrast, chronic metformin given prestroke was neuroprotective, improved stroke-induced lactate generation, and ameliorated stroke-induced activation of AMPK. Similarly, the neuroprotective effect of chronic prestroke metformin was lost in neuronal nitric oxide synthase knockout mice.AMPK is an important potential target for stroke treatment and prevention. These studies show that the timing, duration, and amount of AMPK activation are key factors in determining the ultimate downstream effects of AMPK on the ischemic brain.

SUBMITTER: Li J

PROVIDER: S-EPMC2994809 | biostudies-literature | 2010 Nov

REPOSITORIES: biostudies-literature

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Effects of metformin in experimental stroke.

Li Jun J Benashski Sharon E SE Venna Venugopal Reddy VR McCullough Louise D LD

Stroke 20100916 11

<h4>Background and purpose</h4>Adenosine 5'-monophosphate-activated protein kinase (AMPK) is an important sensor of energy balance. Stroke-induced AMPK activation is deleterious because both pharmacological inhibition and genetic deletion of AMPK are neuroprotective. Metformin is a known AMPK activator but reduces stroke incidence in clinical populations. We investigated the effect of acute and chronic metformin treatment on infarct volume and AMPK activation in experimental stroke.<h4>Methods</ ...[more]

PMID: 20847317

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Project description:Metformin improves cardiovascular prognosis in patients with diabetes mellitus, compared to alternative glucose-lowering drugs, despite similar glycemic control. Direct cardiovascular protective properties have therefore been proposed, and studied in preclinical models of myocardial infarction. We now aim to critically assess the quality and outcome of these studies. We present a systematic review, quality assessment and meta-analysis of the effect of metformin in animal studies of experimental myocardial infarction. Through a comprehensive search in Pubmed and EMBASE, we identified 27 studies, 11 reporting on ex vivo experiments and 18 reporting on in vivo experiments. The primary endpoint infarct size as percentage of area at risk was significantly reduced by metformin in vivo (MD -18.11[-24.09,-12.14]) and ex vivo (MD -18.70[-25.39, -12.02]). Metformin improved the secondary endpoints left ventricular ejection fraction (LVEF) and left ventricular end systolic diameter. A borderline significant effect on mortality was observed, and there was no overall effect on cardiac hypertrophy. Subgroup analyses could be performed for comorbidity and timing of treatment (infarct size and mortality) and species and duration of ischemia (LVEF), but none of these variables accounted for significant amounts of heterogeneity. Reporting of possible sources of bias was extremely poor, including randomization (reported in 63%), blinding (33%), and sample size calculation (0%). As a result, risk of bias (assessed using SYRCLE's risk of bias tool) was unclear in the vast majority of studies. We conclude that metformin limits infarct-size and improves cardiac function in animal models of myocardial infarction, but our confidence in the evidence is lowered by the unclear risk of bias and residual unexplained heterogeneity. We recommend an adequately powered, high quality confirmatory animal study to precede a randomized controlled trial of acute administration of metformin in patients undergoing reperfusion for acute myocardial infarction.

Project description:The effect of oestrogen replacement therapy (ERT) on stroke incidence and severity has been extensively debated. Clinical trials of ERT have demonstrated an increased risk of stroke in treated women, although the study participants were well past menopause when therapy was initiated. It has been suggested that detrimental effects of ERT may be unmasked after prolonged periods of hypoestrogenicity. To date, very few studies have examined the effect of ERT in aged animals, although the timing of replacement may be critical to the neuroprotective effects of ERT. We hypothesised that chronic ERT initiated in late middle age would decrease infarct size in the brain after an induced stroke, whereas acute ERT would have no beneficial effects in aged females. To test this hypothesis, two paradigms of ERT were administered to aged mice of both sexes aiming to determine the effects on stroke outcome and to explore the possible mechanisms by which ERT interacts with age. Female mice that received chronic ERT from 17-20?months of age showed improved stroke outcomes after experimental stroke, whereas females that had acute ERT initiated at 20?months of age did not. Chronic ERT females exhibited diminished levels of nuclear factor kappa B (NF-?B) translocation compared to acute ERT females after stroke. Acute ERT females demonstrated both an increase in nuclear NF-?B and enhanced expression of pro-inflammatory cytokines. In addition, a sexual dimorphic effect of ERT was seen because males benefited from ERT, regardless of the timing of initiation. Aged males had significantly reduced expression of pro-inflammatory markers after stroke compared to age-matched females, suggesting a pro-inflammatory milieu emerges with age in females. These results are consistent with the emerging clinical literature suggesting that ERT should be initiated at the time of menopause to achieve beneficial effects. The present study demonstrates the importance of using appropriate animal models in preclinical studies.

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Effects of metformin in experimental stroke.

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Effects of metformin in experimental stroke.

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