Role of serum- and glucocorticoid-inducible kinases in stroke.
Increased expression of serum- and glucocorticoid-inducible kinase 1 (SGK1) can be induced by stress and growth factors in mammals, and plays an important role in cancer, diabetes, and hypertension. A recent work suggested that SGK1 activity restores damage in a stroke model. To further investigate the role of SGKs in ischemic brain injury, we examined how SGK inhibitors influence stroke outcome in vivo and neurotoxicity in vitro. Infarct volumes were compared in adult mice with middle cerebral artery occlusion, followed by 24 h reperfusion, in the absence or presence of SGK inhibitors. Neurotoxicity assay, electrophysiological recording, and fluorescence Ca(2+) imaging were carried out using cultured cortical neurons to evaluate the underlying mechanisms. Contrary to our expectation, infarct volume by stroke decreased significantly when SGK inhibitor, gsk650394, or EMD638683, was administrated 30 min before middle cerebral artery occlusion under normal and diabetic conditions. SGK inhibitors reduced neurotoxicity mediated by N-methyl-D-aspartate (NMDA) receptors, a leading factor responsible for cell death in stroke. SGK inhibitors also ameliorated Ca(2+) increase and peak amplitude of NMDA current in cultured neurons. In addition, SGK inhibitor gsk650394 decreased phosphorylation of Nedd4-2 and inhibited voltage-gated sodium currents. These observations suggest that SGK activity exacerbates stroke damage and that SGK inhibitors may be useful candidates for therapeutic intervention. To investigate the role of serum- and glucocorticoid-inducible kinases (SGKs) in ischemic brain injury, we examined how SGK inhibitors influence stroke outcome. Infarct volumes induced by middle cerebral artery occlusion were decreased significantly by SGK inhibitors. The inhibitors also reduced glutamate toxicity, at least partly, by attenuation of NMDA and voltage-gated sodium currents. Thus, SGK inhibition attenuates stroke damage.
Neuroscience Institute, Morehouse School of Medicine, Atlanta, Georgia, USA.|Department of Integrative Anatomy, Nagoya City University Graduate School of Medical Sciences, Nagoya, Japan.
Koichi
K
Inoue
Neuroscience Institute, Morehouse School of Medicine, Atlanta, Georgia, USA.
Tiandong
T
Leng
Neuroscience Institute, Morehouse School of Medicine, Atlanta, Georgia, USA.
Tao
T
Yang
Neuroscience Institute, Morehouse School of Medicine, Atlanta, Georgia, USA.
Zhao
Z
Zeng
Department of Integrative Anatomy, Nagoya City University Graduate School of Medical Sciences, Nagoya, Japan.
Takatoshi
T
Ueki
Neuroscience Institute, Morehouse School of Medicine, Atlanta, Georgia, USA.
Zhi-Gang
ZG
Xiong
D000818:Animals; D001549:Benzamides / Q000494:pharmacology; D005938:Glucocorticoids / Q000494:pharmacology*; D006834:Hydrazines / Q000494:pharmacology; D017874:Immediate-Early Proteins / Q000037:antagonists & inhibitors / Q000097:blood / Q000378:metabolism*; D020244:Infarction, Middle Cerebral Artery / Q000188:drug therapy; D008297:Male; D008810:Mice, Inbred C57BL; D017346:Protein Serine-Threonine Kinases / Q000037:antagonists & inhibitors / Q000378:metabolism*; D051057:Proto-Oncogene Proteins c-akt / Q000378:metabolism; D020521:Stroke / Q000188:drug therapy / Q000378:metabolism*; D044767:Ubiquitin-Protein Ligases / Q000378:metabolism; D000099184:Serum-Glucocorticoid Regulated Kinases
D001549:Benzamides; D005938:Glucocorticoids; D006834:Hydrazines; D017874:Immediate-Early Proteins; D017346:Protein Serine-Threonine Kinases; D051057:Proto-Oncogene Proteins c-akt; D044767:Ubiquitin-Protein Ligases; D000099184:Serum-Glucocorticoid Regulated Kinases; C569030:EMD 638683; C444640:serum-inducible kinase
NMDA; SGK1; glutamate; mouse; sodium channels; stroke