Exosomes containing miR-451a is involved in the protective effect of cerebral ischemic preconditioning against cerebral ischemia and reperfusion injury

Abstract

Aim: To study the role of exosomes in the protective effect of cerebral ischemic preconditioning (cerebral-IPC) against cerebral I/R injury.

Method: Mouse models of cerebral-IPC and MCAO/R were established as described previously, and their behavioral, pathological, and proteomic changes were analyzed. Neuro-2a subjected to OGD/R were treated with exosomes isolated from the plasma of sham-operated and cerebral-IPC mice. The differentially expressed miRNAs between exosomes derived from sham-operated (S-exosomes) and preconditioned (IPC-exosomes) mice were identified through miRNA array, and their targets were identified through database search. The control and OGD/R cells were treated with the IPC-exosomes, miRNA mimic or target protein inhibitor, and their viability, oxidative, stress and apoptosis rates were measured. The activated pathways were identified by analyzing the levels of relevant proteins.

Results: Cerebral-IPC mitigated the cerebral injury following ischemia and reperfusion, and increased the number of plasma exosomes. IPC-exosomes increased the survival of Neuro-2a cells after OGD/R. The miR-451a targeting Rac1 was upregulated in the IPC-exosomes relative to S-exosomes. The miR-451a mimic and the Rac1 inhibitor NSC23766 reversed OGD/R-mediated activation of Rac1 and its downstream pathways.

Conclusion: Cerebral-IPC ameliorated cerebral I/R injury by inducing the release of exosomes containing miR-451a.

Keywords: cerebral ischemic preconditioning; exosomes; ischemic and reperfusion injury; ischemic stroke.