Journal of chemical neuroanatomy · 2022
TRPM2 mediates CaMKⅡ-Beclin-1 signaling in early cortical injury after induced subarachnoid hemorrhage in mice.
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Tong Lin, Gao Su, Li Wei, Yang Junli, Wang Ping, Li Weiwei
Аннотация
BACKGROUND: Though early brain injury (EBI) is the primary cause of poor outcomes among patients with subarachnoid 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 timepoints. 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 corresponding author.
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 timepoints. 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 corresponding author.