Sexually Dimorphic Response of TRPM2 Inhibition Following Cardiac Arrest-Induced Global Cerebral Ischemia in Mice

• Published in: Journal of molecular neuroscience 2013-09, Vol.51 (1), p.92-98
• Main Authors: Nakayama, S., Vest, R., Traystman, R. J., Herson, P. S.
• Format: Article
• Language: English
• Subjects: Animals; Biomedical and Life Sciences; Biomedicine; Brain Infarction - drug therapy; Brain Infarction - etiology; Brain Ischemia - drug therapy; Brain Ischemia - etiology; CA1 Region, Hippocampal - drug effects; CA1 Region, Hippocampal - pathology; Cardiac arrest; Cardiopulmonary Resuscitation - adverse effects; Cell Biology; Clotrimazole - pharmacology; Clotrimazole - therapeutic use; Female; Heart Arrest - complications; Heart Arrest - therapy; Male; Mice; Mice, Inbred C57BL; Neurochemistry; Neurology; Neurons - drug effects; Neurons - pathology; Neuroprotective Agents - pharmacology; Neuroprotective Agents - therapeutic use; Neurosciences; Proteomics; Sex Factors; TRPM Cation Channels - antagonists & inhibitors
• ISSN: 0895-8696; 1559-1166
• DOI: 10.1007/s12031-013-0005-9

Transient global cerebral ischemia due to cardiac arrest followed by resuscitation (CA/CPR) causes significant neurological damage in vulnerable neuron populations within the brain, such as hippocampal CA1 neurons. In recent years, we have implicated the transient receptor potential M2 (TRPM2) channel as a mediator of ischemic injury to neurons. We previously demonstrated that genetic and pharmacological strategies that reduce TRPM2 function preferentially protect male neurons in vitro and reduce infarct volume following experimental stroke. Due to the narrow therapeutic window for intervention following ischemic stroke, it is important to assess the role of TRPM2 in other models of cerebral ischemia. Therefore, this study utilized a modified mouse model of CA/CPR to mimic more accurately the clinical condition by maintaining body and head temperatures near the physiological range throughout. Here, we report that inhibition of TRPM2 activity with clotrimazole reduces hippocampal CA1 neuronal injury when administered 30 min after resuscitation from cardiac arrest. Consistent with our previous observations, neuroprotection was observed in male mice and no effect on injury was observed in the female. These findings provide further evidence for TRPM2 as a target for protection against cerebral ischemia in the male brain.