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

TL;DR

This study shows that lithium ions can reduce brain damage and improve recovery after stroke treatment with tPA by protecting the blood-brain barrier.

Contribution

The study reveals a novel role of lithium ions in mitigating tPA-induced hemorrhagic transformation through effects on MMPs and glycolysis.

Findings

tPA disrupted the blood-brain barrier but did not increase lesion volume or neurological deficits.

Poststroke lithium treatment improved neurological outcomes and blood-brain barrier integrity.

Lithium reduced tPA-induced MMP-2/9 activation in endothelial cells under OGD conditions.

Abstract

Thrombolytic therapy with the tissue plasminogen activator (tPA) is a therapeutic option for acute ischemic stroke. However, this approach is subject to several limitations, particularly the increased risk of hemorrhagic transformation (HT). Lithium salts show neuroprotective effects in stroke, but their effects on HT mechanisms are still unknown. In our study, we use the models of photothrombosis (PT)-induced brain ischemia and oxygen-glucose deprivation (OGD) to investigate the effect of Li+ on tPA-induced changes in brain and endothelial cell cultures. We found that tPA did not affect lesion volume or exacerbate neurological deficits but disrupted the blood–brain barrier. We demonstrate that poststroke treatment with Li+ improves neurological status and increases blood–brain barrier integrity after thrombolytic therapy. Under conditions of OGD, tPA treatment increased MMP-2/9 levels in endothelial cells, and preincubation with LiCl abolished this MMP activation. Moreover, we observed the effect of Li+ on glycolysis in tPA-treated endothelial cells, which we hypothesized to have an effect on MMP expression.

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