The effect of rapamycin treatment on cerebral ischemia: A systematic review and meta-analysis of animal model studies

Beard, D. J. and Hadley, G. and Thurley, N. and Howells, D. W. and Sutherland, B. A. and Buchan, A. M.

Int J Stroke (2019) 14: 137–145

DOI: 10.1177/1747493018816503

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 \textless 0.01) improvement in infarct volume and 30.5% (95% CI 17.2%-43.8%, p \textless 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.

Citation

Beard, D. J., Hadley, G., Thurley, N., Howells, D. W., Sutherland, B. A., & Buchan, A. M. (2019). The effect of rapamycin treatment on cerebral ischemia: A systematic review and meta-analysis of animal model studies. Int J Stroke, 14(2), 137–145. https://doi.org/10.1177/1747493018816503 Animals, Disease Models, Animal, Humans, TOR Serine-Threonine Kinases/metabolism, *systematic review, Neuroprotective Agents/*therapeutic use, *meta-analysis, *mTOR, *Experimental stroke, *infarct volume, *rapamycin, Brain Ischemia/*drug therapy, Cerebellum/*pathology, Immunosuppressive Agents/*therapeutic use, Sirolimus/*therapeutic use, Stroke/*drug therapy

Keywords

• Animals
• Disease Models
• Animal
• Humans
• TOR Serine-Threonine Kinases/metabolism
• *systematic review
• Neuroprotective Agents/*therapeutic use
• *meta-analysis
• *mTOR
• *Experimental stroke
• *infarct volume
• *rapamycin
• Brain Ischemia/*drug therapy
• Cerebellum/*pathology
• Immunosuppressive Agents/*therapeutic use
• Sirolimus/*therapeutic use
• Stroke/*drug therapy