Drug repurposing for immune modulation in acute ischemic stroke

• The immune system plays a dual role in the evolution of ischemic brain damage.
• Promoting immune polarization towards protective phenotypes provides neuroprotection.
• Repurposing immunomodulatory drugs represents a promising strategy for stroke therapy.

Innate immune cells play a dualistic role in the evolution of ischemic brain damage, with classic phenotypes promoting injury, and alternatively activated M2 microglia/macrophages or N2 neutrophils providing tissue remodelling and repair. Recently, a number of drugs commonly used for other indications (i.e., azithromycin, minocycline, bexarotene, rosiglitazone, metformin) was reported to provide neuroprotection in preclinical stroke models by promoting immune polarization towards non-inflammatory, protective phenotypes. Repurposing drugs with a well-established safety profile should allow a reduction in the risk of clinical trial failure that has dominated the unsuccessful development of neuroprotective drugs in stroke during the last decades. The clinical validation of the proof of concept, followed by the assessment of safety and efficacy of immune-polarizing repurposed drugs will definitively offer new opportunities for the acute treatment of ischemic stroke.