ABSTRACT NUMBER: ESOC2026A86 BLOCKING TRPM4 WITH THERAPEUTIC HUMANIZED ANTIBODY M4H ATTENUATES NEUROINFLAMMATION AND STROKE REPERFUSION INJURY

Abstract Background and aims TRPM4 channel has emerged as a potential drug target for stroke. We have developed a humanized antibody M4H to block human TRPM4 channel specifically. The aim of this study is to examine the therapeutic potential of M4H in stroke reperfusion injury. Methods A transgenic rat model (hTRPM4 rat) carrying human TRPM4 sequence was generated. Middle cerebral arteries of the hTRPM4 rats were occluded for 3 hours followed by filament removal. One hour before recanalization, M4H was administered intravenously at 1 mg/kg. TTC staining was performed to calculate infarct volume and cerebral edema. Vascular morephology and neuroinflammation were examined by immunostaining. Evans blue extravasation was quantified to study blood-brain barrier (BBB) leakage. Functional recovery was evaluated by Rotarod test and neurological score. Results The results showed that M4H treatment could reduce infarct volume by 41.3% and cerebral edema by 31.3%. Evans blue leakage revealed that M4H significantly reduced dye infiltration area from 13.7% in control group to 6.2% in M4H group. Immunohistochemistry results showed that vascular integrity was improved by M4H. Staining of GFPA, Iba1 and MPO demonstrated that neuroinflammation was attenuated following M4H treatment. Accordingly, neurological score and Rotarod tests identified significant improvement of functional recovery in hTRPM4 rats receiving M4H. Conclusions M4H has demonstrated strong therapeutic potential in attenuating stroke reperfusion injury with improved BBB integrity and reduced neuroinflammation. If M4H is used in together with current reperfusion therapies, management of stroke reperfusion can be greatly improved with much less adverse effects associated with vascular injury. Conflict of interest Ping Liao. nothing to disclose