Amplifying endogenous neuroprotective mechanisms is a promising avenue for novel stroke therapy. One such target is mTOR, a serine/threonine kinase that regulates cell growth, cell proliferation, cell motility, cell survival, protein synthesis, autophagy, and transcription. Animal studies investigating the effect of inhibition of mTOR by rapamycin following focal cerebral ischemia have shown conflicting results. We therefore conducted a systematic review and meta-analysis of the efficacy of rapamycin treatment in animal models of focal cerebral ischemia. There were 17 publications that met our inclusion criteria, describing 52 comparisons: 30 comparisons reported infarct size and 22 comparisons reported neurobehavioral score. The overall study quality was modest (median 4 out of 9) with no evidence of publication bias. The point estimate for the effect of rapamycin was a 21.6% (95% CI, 7.6% to 35.7% p < 0.01) improvment in infarct volume and 30.5% (95% CI 17.2% to 43.8%, p < 0.0001) improvement in neuroscores. Infarct and neuroscores were highly correlated. Effect sizes were greatest in studies using lower doses of rapamycin. These findings suggest that low dose rapamycin treatment may be an effective therapeutic option for stroke. As rapamycin is already approved for human use in transplant medicine, with data on dose tolerability, drug interactions and side effects, the lead time to clinical use in stroke could be short. However, because of the modest study quality there is a risk of bias. It would be wise to conduct further high quality preclinical studies on rapamycin in stroke before progress to clinical trial.

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