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Mmp-9 inhibition: a therapeutic strategy in ischemic stroke
Mayank Chaturvedi1, Leszek Kaczmarek
1Laboratory of Neurobiology, Nencki Institute, Pasteura 3, 02-093, Warsaw, Poland, m.chaturvedi@nencki.gov.pl.
Abstract:
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.
Insights
Matrix metalloproteinase-9 (MMP-9) inhibition shows therapeutic potential for ischemic stroke. Strategies targeting MMP-9 may offer neuroprotection and extend the treatment window for tissue plasminogen activator (tPA).
Area of Science:
- Neuroscience
- Pharmacology
- Biochemistry
Background:
- Ischemic stroke is a major cause of global disability.
- Matrix metalloproteinase-9 (MMP-9) expression is elevated in cerebral ischemia, contributing to neuronal damage, blood-brain barrier (BBB) disruption, and edema.
- The current FDA-approved treatment, tissue plasminogen activator (tPA), has a limited therapeutic window and its detrimental effects may be mediated by MMP-9 activation.
Purpose of the Study:
- To review current strategies for inhibiting matrix metalloproteinase-9 (MMP-9) activity in ischemic stroke.
- To explore therapeutic approaches that offer neuroprotection and potentially extend the thrombolytic window.
- To discuss the combination of MMP-9 inhibitors with tPA for improved ischemic stroke treatment.
Main Methods:
- Literature review of studies investigating MMP-9 inhibition in ischemic stroke models.
- Analysis of various neuroprotective strategies targeting MMP-9, including biotherapeutics and gene inhibition.
- Examination of repurposed drugs (e.g., minocycline), novel chemical entities (e.g., DP-b99), and other interventions like therapeutic hypothermia.
Main Results:
- Various direct and indirect MMP-9 inhibition strategies have demonstrated neuroprotective effects in preclinical models.
- MMP-9 inhibition is associated with reduced neuronal damage, BBB protection, and decreased cerebral edema.
- Therapeutic hypothermia and specific inhibitors show promise in mitigating ischemic stroke complications.
Conclusions:
- Inhibiting MMP-9 activity presents a promising therapeutic avenue for managing ischemic stroke.
- Combination therapies involving MMP-9 inhibitors and tPA could enhance treatment efficacy and broaden the therapeutic time window.
- Further research into these strategies may lead to improved clinical outcomes for stroke patients.
