TRPM2 mediates CaMKⅡ-Beclin-1 signaling in early cortical injury after induced subarachnoid hemorrhage in mice

Background: Though early brain injury (EBI) is the primary cause of poor outcomes among patients with sub-arachnoid hemorrhage (SAH), its exact molecular mechanisms remain unclear. Improved the understanding of how transient receptor potential melastatin-related 2 (TRPM2) is involved in SAH-induced EBI will help develop novel interventions. Methods: Wild type (WT) male C57BL/6J mice were subjected to SAH for 12 h, 24 h or 48 h, after which neurological scores and pathological changes in the hippocampus (CA3, DG, and CA1) and temporal base cortex were observed. Expressions of TRPM2, Ca2+/calmodulin (CaM)-dependent protein kinase II (CaMKII), and Beclin-1 in hippocampus (CA3, DG, and CA1) and temporal base cortex were compared across post-SAH time-points. TRPM2-deficient (TRPM2(-/-)) male C57BL/6 J mice and a CaMKII inhibitor (KN-93) were used to analyze the effects oTRPM2 on the CaMKII-Beclin-1 signaling post SAH. Results: Neurological and temporal base cortex deterioration were more severe with increased time post-SAH induction, whereas hippocampal damage was not observed. Post-SAH, TRPM2-CaMKII-Beclin-1 cascade was activated in the temporal base cortex, but not the hippocampus. Using TRPM2(-/-) mice and KN-93 administration, SAH-induced EBI was improved, and CaMKII and Beclin-1 expressions in the temporal base cortex were significantly decreased compared with WT mice. TRPM2(-/-) mice also showed better neurological improvement compared with KN-93 treated mice. Conclusion: TRPM2 mediates CaMKII-Beclin-1 signaling that aggravates SAH-induced EBI in the temporal base cortex. TRPM2 may be an alternative therapy target in EBI after SAH. Data availability: The datasets generated and/or analysed during the current study are available from the cor-responding author