Tissue plasminogen activator (t-PA) is the only FDA-approved drug for
acute ischemic stroke treatment, but its clinical use is limited due to the narrow
therapeutic time window and severe adverse effects, including hemorrhagic
transformation (HT) and neurotoxicity. One of the potential resolutions is to use
adjunct therapies to reduce the side effects and extend t-PA's therapeutic time window.
However, therapies modulating single target seem not to be satisfied, and a multitarget
strategy is warranted to resolve such complex disease. Recently, large amount
of efforts have been made to explore the active compounds from herbal supplements
to treat ischemic stroke. Some natural compounds revealed both neuro- and bloodbrain-
barrier (BBB)-protective effects by concurrently targeting multiple cellular
signaling pathways in cerebral ischemia-reperfusion injury. Thus, those compounds
are potential to be one-drug-multi-target agents as combined therapy with t-PA for ischemic stroke.
In this review article, we summarize current progress about molecular targets involving in t-PA-mediated
HT and neurotoxicity in ischemic brain injury. Based on these targets, we select 23 promising compounds
from currently available literature with the bioactivities simultaneously targeting several important molecular
targets. We propose that those compounds merit further investigation as combined therapy with t-PA.
Finally, we discuss the potential drawbacks of the natural compounds' studies and raise several important
issues to be addressed in the future for the development of natural compound as an adjunct therapy.