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Dipyridamole decreases inflammatory metalloproteinase-9 expression and release by human monocytes
Marika Massaro1, Egeria Scoditti, Maria Annunziata Carluccio
1C.N.R. Institute of Clinical Physiology, Pisa and Lecce, Italy.
Abstract:
Matrix metalloproteinase (MMP)-9 plays an important role in stroke by accelerating matrix degradation, disrupting the blood-brain barrier and increasing infarct size. Dipyridamole is an antiplatelet agent with recognised benefits in ischaemic stroke prevention. In addition to its antiplatelet properties, recent studies have reported that dipyridamole also features anti-inflammatory and anti-oxidant properties. We therefore investigated whether dipyridamole can ameliorate the proinflammatory profile of human monocytes, a source of MMP-9 in stroke, in terms of regulation of MMP-9 activity and expression, and explored underlying mechanisms. Human peripheral blood mononuclear cells (PBMC) and U937 cells were treated with increasing concentrations of dipyridamole (up to 10 µg/ml) for 60 minutes before stimulation with tumour necrosis factor (TNF)-α or phorbol myristate acetate (PMA). Exposure of PBMC and U937 to dipyridamole reduced TNF-α- and PMA-induced MMP-9 activity and protein release as well as MMP-9 mRNA, without significantly affecting the release of TIMP-1. This inhibitory effect was independent of dipyridamole-induced cyclic adenosine monophosphate (cAMP) and cyclic guanosine monophosphate (cGMP) increase. Correspondingly, dipyridamole also significantly inhibited TNF-α-induced nuclear factor (NF)-κB activation and nuclear translocation of the p65 NF-κB subunit through a mechanism involving the inhibition of IkBα degradation and p38 MAPK activation. In conclusion, dipyridamole, at therapeutically achievable concentrations, reduces the expression and release of MMP-9 through a mechanism involving p38 MAPK and NF-κB inhibition. These results indicate that dipyridamole exerts anti-inflammatory properties in human monocytes that may favourably contribute to its actions in the secondary prevention of stroke, independent of its antiplatelet properties.
Insights
Dipyridamole reduces matrix metalloproteinase-9 (MMP-9) expression and release in human monocytes, offering potential anti-inflammatory benefits for stroke prevention beyond its antiplatelet effects.
Area of Science:
- Neuroscience
- Immunology
- Pharmacology
Background:
- Matrix metalloproteinase-9 (MMP-9) exacerbates stroke damage by degrading tissue and compromising the blood-brain barrier.
- Dipyridamole, an antiplatelet drug, also exhibits anti-inflammatory and antioxidant properties.
- Human monocytes are a significant source of MMP-9 in stroke pathogenesis.
Purpose of the Study:
- To investigate dipyridamole's effect on the pro-inflammatory profile of human monocytes, specifically MMP-9 expression and activity.
- To explore the underlying molecular mechanisms of dipyridamole's action on MMP-9 regulation.
- To determine if dipyridamole's anti-inflammatory effects are relevant at therapeutically achievable concentrations.
Main Methods:
- Human peripheral blood mononuclear cells (PBMC) and U937 cells were treated with dipyridamole.
- Cells were stimulated with tumor necrosis factor-alpha (TNF-α) or phorbol myristate acetate (PMA) to induce inflammation.
- MMP-9 activity, protein release, mRNA levels, and signaling pathways (NF-κB, p38 MAPK) were analyzed.
Main Results:
- Dipyridamole significantly reduced TNF-α- and PMA-induced MMP-9 activity, protein release, and mRNA expression in both PBMC and U937 cells.
- The inhibitory effect on MMP-9 was independent of cyclic adenosine monophosphate (cAMP) and cyclic guanosine monophosphate (cGMP) signaling.
- Dipyridamole inhibited TNF-α-induced nuclear factor-kappa B (NF-κB) activation and p38 mitogen-activated protein kinase (MAPK) activation by preventing IκBα degradation.
Conclusions:
- Dipyridamole effectively reduces MMP-9 expression and release in human monocytes via inhibition of p38 MAPK and NF-κB signaling pathways.
- These anti-inflammatory actions of dipyridamole in monocytes may contribute to its therapeutic benefits in secondary stroke prevention.
- The findings highlight dipyridamole's potential as an anti-inflammatory agent in stroke, independent of its established antiplatelet activity.
