Ischemic stroke is a leading cause of disability worldwide. In
cerebral ischemia there is an enhanced expression of matrix metallo-proteinase-9 (MMP-9), which has been associated with various complications including excitotoxicity, neuronal damage, apoptosis, blood-brain barrier (BBB) opening leading to
cerebral edema, and hemorrhagic transformation. Moreover, the
tissue plasminogen activator (tPA), which is the only US-FDA approved treatment of
ischemic stroke, has a brief 3 to 4 h time window and it has been proposed that detrimental effects of tPA beyond the 3 h since the onset of
stroke are derived from its ability to activate MMP-9 that in turn contributes to the breakdown of BBB. Therefore, the available literature suggests that MMP-9 inhibition can be of therapeutic importance in
ischemic stroke. Hence, combination
therapies of MMP-9 inhibitor along with tPA can be beneficial in
ischemic stroke. In this review we will discuss the current status of various strategies which have shown neuroprotection and extension of thrombolytic window by directly or indirectly inhibiting MMP-9 activity. In the introductory part of the review, we briefly provide an overview on
ischemic stroke, commonly used models of
ischemic stroke and a role of MMP-9 in
ischemia. In next part, the literature is organized as various approaches which have proven
neuroprotective effects through direct or indirect decrease in MMP-9 activity, namely, using biotherapeutics, involving MMP-9 gene inhibition using viral vectors; using endogenous inhibitor of MMP-9, repurposing of old drugs such as
minocycline, new chemical entities like
DP-b99, and finally other approaches like
therapeutic hypothermia.