The Role of Matrix Metalloproteinases in Hemorrhagic Transformation in the Treatment of Stroke with Tissue Plasminogen Activator

Abstract

Ischemic stroke is a leading cause of disability and mortality worldwide. The only approved treatment for ischemic stroke is thrombolytic therapy with tissue plasminogen activator (tPA), though this approach often leads to a severe complication: hemorrhagic transformation (HT). The pathophysiology of HT in response to tPA is complex and not fully understood. However, numerous scientific findings suggest that the enzymatic activity and expression of matrix metalloproteinases (MMPs) in brain tissue play a crucial role. In this review article, we summarize the current knowledge of the functioning of various MMPs at different stages of ischemic stroke development and their association with HT. We also discuss the mechanisms that underlie the effect of tPA on MMPs as the main cause of the adverse effects of thrombolytic therapy. Finally, we describe recent research that aimed to develop new strategies to modulate MMP activity to improve the efficacy of thrombolytic therapy. The ultimate goal is to provide more targeted and personalized treatment options for patients with ischemic stroke to minimize complications and improve clinical outcomes.

Effects of Lithium Ions on tPA-Induced Hemorrhagic Transformation under Stroke

“…We investigated the possible influence of lithium on MMP activity since it is known that MMPs, especially MMP-9 and MMP-2, play a crucial role in hemorrhagic transformation [ 35 , 37 , 38 ]. The proteolytic activity of these enzymes contributes to the destruction of the BBB [ 39 ], and the effect of tPA on MMPs is apparently one of the main reasons for the increased risk of hemorrhagic transformation during thrombolytic therapy [ 10 ]. Our findings indicate that tPA exposure elevates MMP-2 and MMP-9 levels in EA.hy926 cells, a response that can be mitigated through prior incubation with LiCl ( Figure 5 A,B).…”

“…One of the mechanisms of injury associated with thrombolytic therapy with tPA involves matrix metalloproteinases (MMPs) [ 10 ]. MMPs are known to be upregulated in response to acute central nervous system injury, including ischemia and trauma [ 11 , 12 ].…”

“…MMPs are known to be upregulated in response to acute central nervous system injury, including ischemia and trauma [ 11 , 12 ]. Treatment with tPA in acute ischemic stroke has been reported to result in significantly increased levels of pro-MMP-9 and activated MMP-9 [ 4 , 10 , 11 ]. These proteolytic enzymes, which belong to the extracellular protease family, are capable of degrading various components of the extracellular matrix.…”

“…Therefore, it is still appropriate to modify thrombolytic tPA therapy and deepen our understanding of the mechanisms underlying its adverse effects in order to minimize them. One of the mechanisms of injury associated with thrombolytic therapy with tPA involves matrix metalloproteinases (MMPs) [10]. MMPs are known to be upregulated in response to acute central nervous system injury, including ischemia and trauma [11,12].…”