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Background and Purpose Remote ischemic conditioning is cardioprotective in myocardial infarction and neuroprotective in mechanical occlusion models of stroke. However, there is no report on its therapeutic potential in a physiologically relevant embolic stroke model (eMCAO) in combination with intravenous (IV) tissue plasminogen activator (tPA). Methods We tested remote ischemic perconditioning therapy (RIPerC) at 2 hours after eMCAO in the mouse with and without IV tPA at 4 hours. We assessed cerebral blood flow (CBF) up to 6 hours, neurologic deficits, injury size and phosphorylation of Akt (Serine473; p-Akt) as a pro-survival signal in the ischemic hemisphere at 48 hours post stroke. Results RIPerC therapy alone improved the CBF and neurologic outcomes. tPA alone at 4 hours did not significantly improve the neurologic outcome even after successful thrombolysis. Individual treatments with RIPerC and IV tPA reduced the infarct size (25.7% and 23.8%, respectively). Combination therapy of RIPerC and tPA resulted in additive effects in further improving the neurologic outcome, and reducing the infarct size (50%). All the therapeutic treatments upregulated p-Akt in the ischemic hemisphere. Conclusions RIPerC is effective alone after eMCAO and has additive effects in combination with IV tPA. RIPerC may be a simple, safe and inexpensive combination therapy with IV tPA.

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