Tissue Plasminogen Activator Neurotoxicity is Neutralized by Recombinant ADAMTS 13

Area of Science:

• Neuroscience
• Pharmacology
• Vascular Biology

Background:

• Tissue plasminogen activator (tPA) is a critical treatment for ischemic stroke.
• However, tPA exhibits significant neurotoxicity, limiting its therapeutic application.
• Developing strategies to mitigate tPA-induced neurotoxicity is crucial for improving stroke patient outcomes.

Purpose of the Study:

• To investigate the neuroprotective potential of recombinant ADAMTS 13 (rADAMTS 13) in reducing tPA-induced neurotoxicity.
• To elucidate the underlying molecular mechanisms by which rADAMTS 13 exerts its neuroprotective effects.

Main Methods:

• A mouse model of ischemic stroke was utilized.
• Mice were treated with a combination of rADAMTS 13 and tPA, or with tPA or vehicle alone.
• Neuroprotection was assessed by measuring infarct volume, neurological deficits, fibrin deposition, and cell death.
• Molecular mechanisms involving N-methyl-D-aspartate (NMDA) receptors, NR2B subunit, and ERK1/2 signaling were investigated.

Main Results:

• Combination therapy with rADAMTS 13 and tPA significantly reduced infarct volume and neurological deficits compared to tPA alone.
• Neuroprotection was associated with reduced fibrin deposits and less severe cell death in the ischemic brain.
• rADAMTS 13 inhibited tPA's interaction with the NMDA receptor NR2B, preventing downstream signaling.
• The effects of rADAMTS 13 were mimicked by NMDA receptor antagonists and abolished by NMDA.

Conclusions:

• Combination therapy of rADAMTS 13 and tPA offers a novel therapeutic strategy for ischemic stroke.
• rADAMTS 13 effectively diminishes the neurotoxic effects of exogenous tPA.
• This approach holds promise for enhancing the safety and efficacy of tPA treatment in stroke patients.