Upregulation of serum and glucocorticoid-regulated kinase 1 exacerbates brain injury and neurological deficits after cardiac arrest

Abstract

Cardiopulmonary arrest (CA) is the leading cause of death and disability in the United States. CA-induced brain injury is influenced by multi-factorial processes, including reduced cerebral blood flow (hypoperfusion) and neuroinflammation, which can lead to neuronal cell death and functional deficits. We have identified serum and glucocorticoid-regulated kinase-1 (SGK1) as a new target in brain ischemia previously described in the heart, liver, and kidneys (i.e. diabetes and hypertension). Our data suggest brain SGK1 mRNA and protein expression (i.e. hippocampus), presented with hypoperfusion (low cerebral blood flow) and neuroinflammation leading to further studies of the potential role of SGK1 in CA-induced brain injury. We used a 6-mins asphyxia cardiac arrest (ACA) rat model to induce global cerebral ischemia. Modulation of SGK1 was implemented via GSK650394, a SGK1 specific inhibitor (1.2 μg/kg, intracerebroventricular injection). Treatment with GSK650394 attenuated cortical hypoperfusion and neuroinflammation (via Iba1 expression) after ACA, whereas neuronal survival was enhanced in the CA1 region of the hippocampus. Learning/memory deficits were observed 3 days after ACA but ameliorated with GSK650394. SGK1 is a major contributor to ACA-induced brain injury and neurological deficits, while inhibition of SGK1 with GSK650394 provided neuroprotection against CA-induced hypoperfusion, neuroinflammation, neuronal cell death, and learning/memory deficits. Our studies could lead to a novel, therapeutic target for alleviating brain injury following cerebral ischemia.

Hepatocyte SGK1 activated by hepatic ischemia-reperfusion promotes the recurrence of liver metastasis via IL-6/STAT3

“…GSK-650394 has been validated in in vitro models to attenuate cerebral ischemia-reperfusion injury. [ 31 – 33 ] Related studies have shown that GSK-650394 exhibits antitumor activity in established breast cancer cell lines in vitro and in vivo [ 56 ]. Application of GSK-650394 to attenuates breast cancer lung metastasis in mice [ 57 ], and we wondered whether GSK-650394 had similar efficacy in CRLM.…”

“…In a mouse model, administration of an SGK1 inhibitor (GSK-650394) reduced cerebral ischemia–reperfusion injury [ 31 , 32 ]. In a rat model of global cerebral ischemia, administration of GSK-650394 was noted to improve the learning and memory deficits caused by cerebral ischemia in rats [ 33 ]. SGK1 plays an important role in tumorigenesis, proliferation, apoptosis, invasion, metastasis and autophagy processes [ 30 ].…”

Rat model of asphyxia-induced cardiac arrest and resuscitation

“…The Y-maze test can evaluate spatial memory quantitatively and objectively. Studies have shown that in the Y-maze test, the spontaneous alternation rate decreased in rats’ post-resuscitation, suggesting cognitive impairment ( Lee et al, 2020 ). Electrical stimulation is needed in Y-maze test, which will cause stress to rats.…”

Hepatocyte SGK1 activated by hepatic ischemia-reperfusion promotes the recurrence of liver metastasis via IL-6/STAT3

“…52 GSK-650394 has been validated in in vitro models to attenuate cerebral ischemia-reperfusion injury. [31][32][33] Related studies have shown that GSK-650394 exhibits antitumor activity in established breast cancer cell lines in vitro and in vivo. 53 Application of GSK-650394 to attenuates breast cancer lung metastasis in mice, 54 and we wondered whether GSK-650394 had similar e cacy in CRLM.…”

“…31,32 In a rat model of global cerebral ischemia, administration of GSK-650394 was noted to improve the learning and memory de cits caused by cerebral ischemia in rats. 33 SGK1 plays an important role in tumorigenesis, proliferation, apoptosis, invasion, metastasis and autophagy processes. 30 In mouse models, activation of neutrophil SGK1 promotes ROS production and NETs formation.…”