Rapamycin in ischemic stroke: Old drug, new tricks?

Abstract

The significant morbidity that accompanies stroke makes it one of the world's most devastating neurological disorders. Currently, proven effective therapies have been limited to thrombolysis and thrombectomy. The window for the administration of these therapies is narrow, hampered by the necessity of rapidly imaging patients. A therapy that could extend this window by protecting neurons may improve outcome. Endogenous neuroprotection has been shown to be, in part, due to changes in mTOR signalling pathways and the instigation of productive autophagy. Inducing this effect pharmacologically could improve clinical outcomes. One such therapy already in use in transplant medicine is the mTOR inhibitor rapamycin. Recent evidence suggests that rapamycin is neuroprotective, not only via neuronal autophagy but also through its broader effects on other cells of the neurovascular unit. This review highlights the potential use of rapamycin as a multimodal therapy, acting on the blood-brain barrier, cerebral blood flow and inflammation, as well as directly on neurons. There is significant potential in applying this old drug in new ways to improve functional outcomes for patients after stroke.

Keywords: Ischemic stroke; cerebral blood flow; inflammation; mTOR; rapamycin.

Figure 1.

The role of mTOR in neuronal survival following ischemia. (a) Under normal conditions, the adequate provision of nutrients and oxygen activates mTOR to stimulate anabolic processes such as protein synthesis while suppressing catabolic processes such as autophagy. (b) During stroke the reduction in provision of nutrients reduces mTOR activation, limiting protein synthesis and inducing autophagy. (c) Treatment of neurons with rapamycin can further reduce mTOR activation and increase the induction of autophagy. If autophagy induction is optimal this may lead to cell component recycling and cell survival (right-hand box). If autophagy is excessive, this may lead to apoptosis and cell death (left-hand box). mTORC1: mammalian target of rapamycin complex 1; S6K: S6kinase; S6rp: S6 ribosomal protein; 4EBP: eukaryotic translation initiation factor 4E binding protein; eIF4e: eukaryotic initiation factor 4e.

Figure 2.

Suggested neurovascular effects of rapamycin. Astrocyte: Stroke/hypoxia causes conversion of astrocytes from cytotropic to cytotoxic driven by mTOR and retraction of astrocytes from the BBB driven by Rho-GTP. Rapamycin treatment stops transition from cytotropic to cytotoxic phenotype in cell culture. Rapamycin can potentially reduce the retraction of astrocytic endfeet and improve BBB permeability by inhibiting RhoA-GTP (hypothetical). Pericyte: Stroke/hypoxia causes pericyte constriction and MMP-9 release (animal and cell culture). Rapamycin may reduce constriction by RhoA-GTP (hypothetical). Rapamycin can reduce MMP-9 expression following stroke (shown in animal models). Endothelial cells: Stroke/hypoxia can cause reduced CBF, endothelial cell death and tight junction breakdown. Excess calcium entry into the endothelial cell leads to cytoskeletal re-arrangements by myosin light chain phosporylation and stress fibre formation leading to BBB opening. Rapamycin can increase eNOS activity and improves CBF in Alzheimer's Disease (AD) mouse models. Rapamycin increases autophagy leading to enhanced cell viability and tight junction expression (based on cell culture and animal studies). Rapamycin can reduce Rho-A mediated cytoskeletal rearrangements by inhibiting mTOR s6K (hypothetical).

Figure 3.

Rapamycin (Sirolimus) and rapalogues (a). Chemical structure of Sirlolimus. (b) Chemical structure of temsirolimus. Substitution of the C40 hydroxyl group is shown in blue.