Lithium alleviates blood-brain barrier breakdown after cerebral ischemia and reperfusion by upregulating endothelial Wnt/β-catenin signaling in mice

Feb 1, 2021Neuropharmacology

Lithium helps repair blood vessel barrier damage after brain blood flow loss by boosting cell signaling in mice

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Abstract

Lithium treatment (3 mmol/kg) significantly decreased infarct volume by 34.1 ± 1.8% compared to vehicle controls.

Lithium improved neurological outcomes in mice following ischemic stroke.
Treatment with lithium enhanced blood-brain barrier integrity, evidenced by a 45.7% reduction in Evans blue leakage and a 65.8% decrease in blood IgG extravasation.
Lithium upregulated endothelial Wnt/β-catenin signaling activity in both mice and cell cultures.
Increased protein levels of tight junctions, Claudin-5 and ZO-1, were observed with lithium treatment.
The beneficial effects of lithium on blood-brain barrier integrity were lost in mice lacking the Gpr124 co-receptor, indicating dependence on Wnt/β-catenin signaling.

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Although upregulation of endothelial Wnt/β-catenin signaling may be used to treat blood-brain barrier (BBB) breakdown caused by cerebral ischemia/reperfusion injury, no agents based on this mechanism are available clinically. Lithium, a medication used for treating bipolar mood disorders, upregulates Wnt/β-catenin signaling, but whether lithium alleviates BBB breakdown after ischemic stroke by upregulating endothelial Wnt/β-catenin signaling is unclear. Here, we evaluated the BBB-protective effect of lithium in adult mice with 1-h middle cerebral artery occlusion and 48-h reperfusion (MCAO/R) by determining neurological outcomes, BBB function and related molecular components. Furthermore, we assessed the effect and dependence of lithium on Wnt/β-catenin signaling in brain microvascular endothelial cells in cell culture and in mice with conditional endothelial knockout of Wnt7 co-receptor Gpr124. Our data show that lithium treatment (3 mmol/kg) significantly decreased infarct volume (34.1 ± 1.8% versus 58.3 ± 2.8% in vehicle controls, P < 0.0001) and improved neurological outcomes of mice following MCAO/R. Importantly, lithium significantly increased BBB integrity shown by reduction of Evans blue leakage (by 45.7%, P = 0.0064) and blood IgG extravasation (by 65.8%, P < 0.0001) into infarcted brain tissue. Mechanistically, lithium upregulated the activity of endothelial Wnt/β-catenin signaling in vivo and in vitro, increased the protein levels of tight junctions (Claudin-5 and ZO-1), and reduced MMP-9 expression. Furthermore, the protective effect of lithium on cerebral damage and BBB integrity was abolished in endothelial Gpr124 knockout mice, indicating the protection of lithium on BBB was mainly dependent on the Gpr124-mediated endothelial Wnt/β-catenin signaling. Taken together, our findings indicate that lithium may serve as a therapeutic candidate for treating the BBB breakdown in the early stage of ischemic stroke following reperfusion therapy.

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