Q&A: 5 Questions 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 

 

Health effects of rapamycin >>

 

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 

 

Health effects of rapamycin >>