Daniel J Beard1, Gina Hadley1,2, Neal Thurley3, David W Howells4, Brad A Sutherland4, Alastair M Buchan1,5,6. 1. 1 Acute Stroke Programme, Radcliffe Department of Medicine, University of Oxford, Oxford, UK. 2. 2 Nuffield Department of Clinical Neurosciences, University of Oxford, Oxford, UK. 3. 3 Bodleian Healthcare Libraries, University of Oxford, Oxford, UK. 4. 4 School of Medicine, College of Health and Medicine, University of Tasmania, Hobart, Australia. 5. 5 Medical Sciences Division, University of Oxford, Oxford, UK. 6. 6 Acute Vascular Imaging Centre, University of Oxford, Oxford University Hospitals, Oxford, UK.
Abstract
BACKGROUND: Amplifying endogenous neuroprotective mechanisms is a promising avenue for stroke therapy. One target is mammalian target of rapamycin (mTOR), a serine/threonine kinase regulating cell proliferation, cell survival, protein synthesis, and autophagy. Animal studies investigating the effect of rapamycin on mTOR inhibition following cerebral ischemia have shown conflicting results. AIM: To conduct a systematic review and meta-analysis evaluating the effectiveness of rapamycin in reducing infarct volume in animal models of ischemic stroke. SUMMARY OF REVIEW: Our search identified 328 publications. Seventeen publications met inclusion criteria (52 comparisons: 30 reported infarct size and 22 reported neurobehavioral score). Study quality was modest (median 4 of 9) with no evidence of publication bias. The point estimate for the effect of rapamycin was a 21.6% (95% CI, 7.6%-35.7% p < 0.01) improvement in infarct volume and 30.5% (95% CI 17.2%-43.8%, p < 0.0001) improvement in neuroscores. Effect sizes were greatest in studies using lower doses of rapamycin. CONCLUSION: Low-dose rapamycin treatment may be an effective therapeutic option for stroke. Modest study quality means there is a potential risk of bias. We recommend further high-quality preclinical studies on rapamycin in stroke before progressing to clinical trials.
BACKGROUND: Amplifying endogenous neuroprotective mechanisms is a promising avenue for stroke therapy. One target is mammalian target of rapamycin (mTOR), a serine/threonine kinase regulating cell proliferation, cell survival, protein synthesis, and autophagy. Animal studies investigating the effect of rapamycin on mTOR inhibition following cerebral ischemia have shown conflicting results. AIM: To conduct a systematic review and meta-analysis evaluating the effectiveness of rapamycin in reducing infarct volume in animal models of ischemic stroke. SUMMARY OF REVIEW: Our search identified 328 publications. Seventeen publications met inclusion criteria (52 comparisons: 30 reported infarct size and 22 reported neurobehavioral score). Study quality was modest (median 4 of 9) with no evidence of publication bias. The point estimate for the effect of rapamycin was a 21.6% (95% CI, 7.6%-35.7% p < 0.01) improvement in infarct volume and 30.5% (95% CI 17.2%-43.8%, p < 0.0001) improvement in neuroscores. Effect sizes were greatest in studies using lower doses of rapamycin. CONCLUSION: Low-dose rapamycin treatment may be an effective therapeutic option for stroke. Modest study quality means there is a potential risk of bias. We recommend further high-quality preclinical studies on rapamycin in stroke before progressing to clinical trials.
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