stroke

Daniel Beard, PhD, on Rapamycin Use for Stroke

Stroke kills about 140,000 people in the United States each year and costs the United States nearly $34 billion each year. One potential way to alleviate the stroke burden and reduce the cost of stroke is to amplify endogenous neuroprotective mechanisms as a method of stroke therapy.

A new study—authored by Dr Daniel Beard, Dr Alastair Buchan, and colleagues—examined the potential effectiveness of rapamycin in reducing infarct volume in animal models of ischemic stroke. Dr Beard answered a few of our questions about his study.1

Daniel Beard, PhD, is a postdoctoral scientist in the Acute Stroke Programme, an RF lecturer in medicine, a research associate, and a medical tutor at the University of Oxford in the United Kingdom.

Neurology Consultant: What were your findings from the study, and how might they influence potential treatment options for ischemic stroke?

Daniel Beard: Our lab and others have shown that inhibition of the mammalian target of rapamycin (mTOR) pathway by both endogenous and pharmacological mediators is a potential neuroprotective strategy for stroke. It is fortuitous that there is an existing clinically approved mTOR inhibitor known as rapamycin (sirolimus). This would mean that if it were to be used in the treatment of human stroke, the time to clinic would be dramatically reduced due to a wealth of existing human safety data. However, when we looked into the animal model literature on rapamycin treatment in stroke, we found conflicting results, with a handful of studies showing that rapamycin treatment actually made stroke worse! This provided the impetus for us to conduct our systematic review and meta-analysis. 

We found evidence from 17 studies that rapamycin treatment significantly improved infarct volume by 21% and neurobehavioral score by 30%. However, the quality of the studies was only modest. One of the most interesting findings was that the lowest doses of rapamycin showed the greatest neuroprotective effects. Furthermore, the handful of studies that showed rapamycin made infarct volume worse used the highest doses of rapamycin that were 50 times higher than the clinically approved dose, suggesting that when it comes to the neuroprotective effect of rapamycin, less is more. 

NEURO CON: How did rapamycin effect mTOR inhibition following cerebral ischemia?

DB: The main outcome measures extracted for the meta-analysis were infarct volume and neurobehavioral scores. However, many studies included in our analysis also demonstrated that rapamycin significantly reduced mTOR activation, as expected. 

Many of the studies also investigated the various neuroprotective mechanisms of rapamycin-induced mTOR inhibition. These mechanisms included but are not limited to:

  • Induction of neuronal autophagy (an intracellular recycling system, increasing energy reserves within the cell), 
  • Induction of anti-inflammatory microglia and regulatory T cells in the brain,
  • Reduced blood-brain barrier disruption via brain endothelial cell autophagy,
  • Improved tight junction expression, 
  • Reduced aquaporin 4 expression, and
  • Reduced matrix metalloproteinase expression.  

 

The multimodal nature of rapamycin’s neuroprotective effects make it a very attractive treatment for stroke and are discussed in another review by our group.2 

NEURO CON: What other health effects might rapamycin have?

DB: Rapamycin is a clinically approved immunosuppresant used to prevent rejection following kidney transplantation. Serious side effects of chronic immunosuppression with rapamycin is the development of infection and skin cancers. Other side effects include impaired glucose tolerance. Understandably, this raises concerns for the use of rapamycin in the treatment of stroke, given patient frailty and risk of developing pneumonia. However, what we have learned from our meta-analysis is that one-off administration of low doses (<1 mg/kg) of rapamycin demonstrates the most neuroprotection. 

Studies investigating the potential of rapamycin as an anti-ageing therapy have shown that one-off dosing of 2 mg/kg of rapamycin in rodents produce minimal immunosuppression and glucose intolerance. Therefore, acute administration of low-dose rapamycin may be a viable neuroprotectant in stroke with minimal immunosuppression. However, systemic immunological evaluation after rapamycin administration during experimental stroke is needed to confirm this. 

NEURO CON: What knowledge gaps still exist in the treatment of cerebral ischemia?

DB: Thousands of neuroprotective agents have shown efficacy in animal models of stroke, but none have shown efficacy in improving stroke outcomes in patients. A burning question for translational stroke researchers is “How effective will old or newly developed neuroprotectants be in the so-called ‘reperfusion era’ of stroke treatment?”

Retrospective analysis of animal neuroprotective studies revealed that there were a number of key differences in how neuroprotective drugs were delivered between animal and human trials. In the majority of animal studies, the drugs were given early after stroke and with reperfusion, while in human trials the drugs were administered late with many patients not receiving reperfusion therapy or receiving therapy and not achieving reperfusion. This most likely limited the delivery of the drug to the brain at risk of infarction. 

Acute ischemic stroke treatment has taken a major leap forward recently with publication of 5 positive randomised controlled trials of mechanical thrombectomy.3 Combining patient selection using advanced imaging with thrombectomy means that more patients are likely to achieve reperfusion, which may be combined with neuroprotective compounds. Our meta-analysis revealed that rapamycin was as efficacious in permanent ischemia as temporary ischemia with reperfusion. However, the majority of studies administered the drug around the onset of ischemia. The efficacy of rapamycin when administered late and during reperfusion still needs to be determined. 

NEURO CON: What is the next step in your research?

DB: Our meta-analysis highlighted that rapamycin may be viable clinical stroke therapy. However, due to the small number of studies, study heterogeneity and modest quality, there is a risk of bias. Therefore, further high-quality studies are needed before rapamycin can be considered as a clinical stroke therapy. 

Preclinical randomized controlled multicenter trials (pRCT) are studies using experimental stroke models but with clinical trial methodology. pRCTs have been proposed as a suitable tool for bridging the gap between experimental stroke research and clinical trials. We are currently applying for funding to conduct a pRCT to test the efficacy of rapamycin administration during experimental ischemic stroke. This will be in collaboration with leading experimental stroke labs from the United Kingdom, Europe, North America, and Australia. 

This will be the third trial of its kind. The first two pRCTs evaluated the efficacy of Interleukin-1 receptor antagonist4 and antiCD-49d antibodies,5 with both studies informing subsequent clinical investigations of these compounds.

Conducting preclinical research in the way that clinical research is randomized and at multiple centers could remove the disparity between therapies that demonstrate promise in animal models yet fail to produce clinically significant effects. Our goal is that a pRCT of rapamycin will give the highest level of preclinical evidence, whether rapamycin should proceed to clinical trials and ultimately improve our ability to predict successful translation of experimental neuroprotectants.

References:

  1. Beard DJ, Hadley G, Thurley N, Howells DW, Sutherland BA, Buchan AM. The effect of rapamycin treatment on cerebral ischemia: a systematic review and meta-analysis of animal model studies [published online November 29,2018]. Int J Stroke. https://doi.org/10.1177/1747493018816503. 
  2. Hadley G, Beard DJ, Couch Y, et al. Rapamycin in ischemic stroke: Old drug, new tricks? J Cereb Blood Flow Metab. 2018:271678X18807309.  https://doi.org/10.1177/0271678X18807309. 
  3. Balami JS, Sutherland BA, Edmunds LD, et al. A systematic review and meta-analysis of randomized controlled trials of endovascular thrombectomy compared with best medical treatment for acute ischemic stroke. Int J Stroke. 2015;10(8):1168-1178. https://doi.org/10.1111/ijs.12618.
  4. Maysami S, Wong R, Pradillo JM, et al. A cross-laboratory preclinical study on the effectiveness of interleukin-1 receptor antagonist in stroke. J Cereb Blood Flow Metab. 2016;36(3):596-605. https://doi.org/10.1177/0271678X15606714. 
  5. Llovera G, Hofmann K, Roth S, et al. Results of a preclinical randomized controlled multicenter trial (pRCT): Anti-CD49d treatment for acute brain ischemia. Sci Transl Med. 2015;7(299):299ra121. doi:10.1126/scitranslmed.aaa9853.