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Abstract
Reperfusion therapy is currently the gold standard treatment for acute ischemic stroke. However, reperfusion injuries such as oedema and haemorrhagic transformation largely limit the use of this potent treatment to a narrow time window. Recently, transient receptor potential melastatin 4 (TRPM4) channel has emerged as a potential target for vascular protection in stroke management. Non-specificity and side effects are major concerns for current TRPM4 blockers. The present study was undertaken to develop a novel TRPM4 blocker for stroke management. We report the generation of a TRPM4-specific antibody M4P which binds to a region close to the channel pore. M4P could inhibit TRPM4 current and downregulate TRPM4 surface expression, therefore prevent hypoxia-induced cell swelling. In the rat model of 3-h stroke reperfusion, application of M4P at 2 h after occlusion ameliorated reperfusion injury by improving blood–brain barrier integrity, and enhanced functional recovery. Our results demonstrate that TRPM4 blockade could attenuate reperfusion injury in stroke recanalization. When applied together with reperfusion treatments, TRPM4 blocking antibody has the potential to extend the therapeutic time window for acute ischemic stroke.
Highlights
We describe the production of a transient receptor potential melastatin 4 (TRPM4)-specific blocking antibody M4P and demonstrate that M4P could improve stroke outcome in stroke reperfusion model
For a–d, TRPM4-transfected HEK 293 cells were incubated with 20.8 μg/ml IgG or M4P for 30 min before patchclamping
We further examined whether M4P could block TRPM4 channel under hypoxic conditions
Summary
TRPM4 has emerged as a therapeutic target for many brain disorders such as stroke, spinal cord injury, and head injury
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