For
ischemic stroke treatment, extension of the therapeutic time window (TTW) of
thrombolytic therapy with
tissue plasminogen activator (tPA) and amelioration of secondary
ischemia/reperfusion (I/R) injury are most desirable. Our previous studies have indicated that liposomal delivery of
neuroprotectants into an ischemic region is effective for
stroke treatment. In the present study, for solving the above problems in the clinical setting, the usefulness of combination
therapy with tPA and liposomal
fasudil (
fasudil-Lip) was investigated in
ischemic stroke model rats with photochemically induced
thrombosis, with clots that were dissolved by tPA. Treatment with tPA 3 h after occlusion markedly increased blood-brain barrier permeability and activated
matrix metalloproteinase (MMP)-2 and -9, which are involved in
cerebral hemorrhage. However, an
intravenous administration of
fasudil-Lip before tPA markedly suppressed the increase in permeability and the
MMP activation stemming from tPA. The combination treatment showed significantly larger
neuroprotective effects, even in the case of delayed tPA administration compared with each treatment alone or the tPA/
fasudil-treated group. These findings suggest that treatment with
fasudil-Lip before tPA could decrease the risk of tPA-derived
cerebral hemorrhage and extend the TTW of tPA and that the combination
therapy could be a useful therapeutic option for
ischemic stroke.-Fukuta, T., Asai, T., Yanagida, Y., Namba, M., Koide, H., Shimizu, K., Oku, N. Combination
therapy with liposomal
neuroprotectants and
tissue plasminogen activator for treatment of
ischemic stroke.