Rapamycin Treatment Reduces Brain Pericyte Constriction in Ischemic Stroke
Daniel J Beard1,2, Lachlan S Brown3, Gary P Morris3
1Acute Stroke Programme, Radcliffe Department of Medicine, University of Oxford, Oxford, UK. daniel.j.beard@newcastle.edu.au.
Abstract:
The contraction and subsequent death of brain pericytes may play a role in microvascular no-reflow following the reopening of an occluded artery during ischemic stroke. Mammalian target of rapamycin (mTOR) inhibition has been shown to reduce motility/contractility of various cancer cell lines and reduce neuronal cell death in stroke. However, the effects of mTOR inhibition on brain pericyte contraction and death during ischemia have not yet been investigated. Cultured pericytes exposed to simulated ischemia for 12 h in vitro contracted after less than 1 h, which was about 7 h prior to cell death. Rapamycin significantly reduced the rate of pericyte contraction during ischemia; however, it did not have a significant effect on pericyte viability at any time point. Rapamycin appeared to reduce pericyte contraction through a mechanism that is independent of changes in intracellular calcium. Using a mouse model of middle cerebral artery occlusion, we showed that rapamycin significantly increased the diameter of capillaries underneath pericytes and increased the number of open capillaries 30 min following recanalisation. Our findings suggest that rapamycin may be a useful adjuvant therapeutic to reduce pericyte contraction and improve cerebral reperfusion post-stroke.
Insights
Rapamycin, a target of rapamycin (mTOR) inhibitor, reduces brain pericyte contraction during stroke. This improves capillary blood flow after artery reopening, suggesting its therapeutic potential for stroke recovery.
Area of Science:
- Neuroscience
- Vascular Biology
- Pharmacology
Background:
- Brain pericyte contraction and death contribute to microvascular no-reflow after ischemic stroke.
- Mammalian target of rapamycin (mTOR) inhibition reduces cancer cell motility and neuronal death in stroke.
- The effect of mTOR inhibition on brain pericytes during ischemia is unknown.
Purpose of the Study:
- To investigate the impact of mTOR inhibition on brain pericyte contraction and viability during ischemia.
- To evaluate the therapeutic potential of rapamycin in a mouse model of ischemic stroke.
Main Methods:
- In vitro study of cultured pericytes under simulated ischemia.
- Assessment of pericyte contraction and viability with and without rapamycin.
- In vivo study using a mouse model of middle cerebral artery occlusion and recanalization.
Main Results:
- Pericytes contracted within 1 hour and died after 7 hours of simulated ischemia.
- Rapamycin significantly reduced pericyte contraction rate but did not affect viability.
- Rapamycin increased capillary diameter and the number of open capillaries post-stroke in mice.
Conclusions:
- mTOR inhibition by rapamycin mitigates pericyte contraction during ischemia via a calcium-independent pathway.
- Rapamycin enhances cerebral reperfusion by improving capillary patency after stroke.
- Rapamycin shows promise as an adjuvant therapy to improve outcomes post-ischemic stroke.
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