SK2 channels are neuroprotective for ischemia-induced neuronal cell death

• Published in: Journal of cerebral blood flow and metabolism Vol. 31; no. 12; pp. 2302 - 2312
• Main Authors: Allen, Duane, Nakayama, Shin, Kuroiwa, Masayuki, Nakano, Takaaki, Palmateer, Julie, Kosaka, Yasuharu, Ballesteros, Carmen, Watanabe, Masahiko, Bond, Chris T, Luján, Rafael, Maylie, James, Adelman, John P, Herson, Paco S
• Format: Journal Article
• Language: English
• Published: London, England SAGE Publications 01.12.2011; Nature Publishing Group; Sage Publications Ltd
• Subjects: Animals; Behavior, Animal - physiology; Benzimidazoles - pharmacology; Biological and medical sciences; Brain Ischemia - pathology; Brain Ischemia - psychology; CA1 Region, Hippocampal - pathology; Cardiopulmonary Resuscitation; Cell Death; Heart Arrest - complications; Heart Arrest - pathology; Immunohistochemistry; In Vitro Techniques; Male; Medical sciences; Mice; Mice, Inbred C57BL; Mice, Transgenic; Microscopy, Immunoelectron; Motor Activity - physiology; Neurology; Neurons - pathology; Neurons - physiology; Neuropharmacology; Neuroprotective agent; Original; Patch-Clamp Techniques; Pharmacology. Drug treatments; Pyramidal Cells - pathology; Recognition (Psychology) - physiology; Small-Conductance Calcium-Activated Potassium Channels - genetics; Small-Conductance Calcium-Activated Potassium Channels - physiology; Synapses - physiology; Synapses - ultrastructure; Vascular diseases and vascular malformations of the nervous system; global ischemia; electrophysiology; hippocampus; excitotoxicity; cardiac arrest; potassium channels; Cardiocirculatory arrest; Nervous system diseases; Toxicity; Electrophysiology; Cardiovascular disease; Inorganic element; Cerebral disorder; Ischemia; Cell death; Excitotoxicity; Central nervous system disease; Potassium; Hippocampus; Cerebrovascular disease
• ISSN: 0271-678X; 1559-7016
• DOI: 10.1038/jcbfm.2011.90

In mouse hippocampal CA1 pyramidal neurons, the activity of synaptic small-conductance Ca2+-activated K+ channels type 2 (SK2 channels) provides a negative feedback on N-methyl-d-aspartate receptors (NMDARs), reestablishing Mg2+ block that reduces Ca2+ influx. The well-established role of NMDARs in ischemia-induced excitotoxicity led us to test the neuroprotective effect of modulating SK2 channel activity following cerebral ischemia induced by cardiac arrest and cardiopulmonary resuscitation (CA/CPR). Administration of the SK channel positive modulator, 1-ethyl-benzimidazolinone (1-EBIO), significantly reduced CA1 neuron cell death and improved CA/CPR-induced cognitive outcome. Electrophysiological recordings showed that CA/CPR-induced ischemia caused delayed and sustained reduction of synaptic SK channel activity, and immunoelectron microscopy showed that this is associated with internalization of synaptic SK2 channels, which was prevented by 1-EBIO treatment. These results suggest that increasing SK2 channel activity, or preventing ischemia-induced loss of synaptic SK2 channels, are promising and novel approaches to neuroprotection following cerebral ischemia.