Isaridin E Attenuates Ischemic Brain Injury in Mice by Concurrently Reducing Platelet Hyperactivity and Microglial Neuroinflammation Associated with LRP1.

Isaridin E (ISE), a marine-derived fungal cyclodepsipeptide, possesses antiplatelet activity in vitro and antithrombotic efficacy in a FeCl3-induced carotid artery thrombosis mouse model without prolonging bleeding time. In this study, we investigated the antiplatelet and neuroprotective effects of prophylactic and therapeutic administration of ISE in a transient middle cerebral artery occlusion (tMCAO) mouse model. We found that both prophylactic administration (50 and 100 mg/kg) and therapeutic administration (50 mg/kg) of ISE significantly reduced cerebral infarct volume, alleviated neurological deficits, and attenuated neuronal injury. Furthermore, therapeutic administration of ISE suppressed platelet hyperactivity, as evidenced by reduced P-selectin expression, downregulated platelet secretion-related proteins (SNAP23, VAMP8), and decreased plasma levels of platelet-derived pro-inflammatory cytokines (IL-1β, PF4, and CCL5). Moreover, ISE attenuated microglial inflammatory activation in the peri-infarct region in vivo. Mechanistically, in vitro studies revealed that this effect may be mediated through the LRP1/IκB/NF-κB signaling pathway. In conclusion, these results suggest that ISE protects mice against ischemic stroke by concurrently suppressing platelet hyperactivity and LRP1-associated microglial neuroinflammation.