Combination therapy with liposomal neuroprotectants and tissue plasminogen activator for treatment of ischemic stroke

Abstract

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.

Selective inhibition of brain endothelial Rho-kinase-2 provides optimal protection of an in vitro blood-brain barrier from tissue-type plasminogen activator and plasmin

“…This important finding refines previous observations where nonselective inhibition of ROCK protected the BBB [20, 22, 24], but not isolated BECs [20], from rt-PA. Our study therefore suggests that selective inhibition of ROCK-2 is more suitable for BBB protection during rt-PA treatment and that simultaneous inhibition of both ROCK isoforms is sub-optimal for this purpose.…”

Tissue plasminogen activator-based nanothrombolysis for ischemic stroke

“…Currently, managing both of the primary damage (salvaging the ischemic penumbra) and the secondary neuronal damage stands for comprehensive therapeutics for stroke. Using nanocarriers to co-deliver tPA and neuroprotective agents could not only extend therapeutic time window of tPA 86–89 but also improve long-term neurological outcomes through synergistic mechanisms. tPA and the other drug can be encapsulated into nanocarriers at appropriate drug ratio and released in a controlled manner, thus lead to synergistic efficacy with fewer side effects for stroke treatment 44 .…”

Design, Synthesis and Biological Evaluation of 3-n-Butylphthlide-Edaravone Hybrids as Potential Agents for the Treatment of Cerebral Ischemia

“…The structural basis on which NBP exerts its bioactivities has not yet been elucidated clearly, but some derivatives with substituted groups at position 6 of NBP have been reported to have similar activities as NBP 19,20 (4,5). In particular, the ring-opening prodrug (6) of 6-bromo-3-n-butylphthalide (5) had been approved by CFDA for clinical trials in China in 2016. As for edaravone, it is well recognized that the pyrazolone sub-structure plays an important role in determining its activities through its two tautomeric forms as shown in Figure 1 21,22 .…”

“…The serine protease tissue-type plasminogen activator (t-PA) aimed at restoring cerebral blood flow is the only one approved by FDA for the treatment of RESEARCH ARTICLE acute cerebral ischemia. Although t-PA is powerful, its utilization is limited by a very narrow therapeutic time window of 4.5 h 4,5 . The neuroprotection therapy seems to be a more practical strategy which uses drugs, such as antiplatelet, antithrombotic or antioxidant agents, to prevent neuronal damage or protect the potentially ischemic tissue during cerebral ischemia 6,7 .…”