Co-administration of liposomal fasudil and tissue plasminogen activator ameliorated ischemic brain damage in occlusion model rats prepared by photochemically induced thrombosis

Abstract

Delivery of neuroprotectants with liposomes has been shown to be effective for the treatment of ischemic stroke. We have recently revealed that intravenous administration of liposomal fasudil (Fasudil-Lip), a Rho-kinase inhibitor, prior to thrombolysis with tissue plasminogen activator (t-PA) can extend the narrow therapeutic time window (TTW) of t-PA. In the present study, we examined the influence of t-PA treatment on liposomal accumulation into the ischemic region and cerebroprotective effect of combined treatment with Fasudil-Lip and t-PA performed at the same timing after the onset of ischemia in middle cerebral artery occlusion (MCAO) prepared by photochemically induced thrombosis. The t-PA administration into MCAO rats 3 h after occlusion brought about significantly higher accumulation of intravenously injected PEGylated liposomes in wide area of ischemic region. Confocal images showed that extravasation of the liposomes from cerebral vessels into brain parenchyma was markedly facilitated by the t-PA treatment which increased blood flow in cerebral vessels. Importantly, co-administration of Fasudil-Lip and t-PA after 3 h occlusion, beyond the TTW of t-PA in MCAO rats, significantly suppressed brain cell damage compared with t-PA treatment alone. These findings suggest that co-administration of Fasudil-Lip and t-PA should lead to prolong t-PA's TTW and become a useful therapeutic option for ischemic stroke.