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 multifactorial 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-min 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 icv). Accordingly, 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. In conclusion, 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.NEW & NOTEWORTHY Upregulation of SGK1 exacerbates brain injury during cerebral ischemia. Inhibition of SGK1 affords neuroprotection against cardiac arrest-induced hypoperfusion, neuroinflammation, neuronal cell death, and neurological deficits.

• Authors: Reggie Hui-Chao Lee, Mychal S Grames, Celeste Yin-Chieh Wu, Chih-Feng Lien, Alexandre Couto E Silva, HarLee E Possoit, Garrett A Clemons, Cristiane T Citadin, Jake T Neumann, Donatella Pastore, Davide Lauro, David Della-Morte, Hung Wen Lin
• Journal: American journal of physiology. Heart and circulatory physiology (Am J Physiol Heart Circ Physiol) Vol. 319 Issue 5 Pg. H1044-H1050 (11 01 2020) ISSN: 1522-1539 [Electronic] United States
• PMID: 32946263 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)

Chemical References

• Benzoates
• Bridged Bicyclo Compounds, Heterocyclic
• Immediate-Early Proteins
• Neuroprotective Agents
• Protein Kinase Inhibitors
• 2-cyclopentyl-4-(5-phenyl-1H-pyrrolo(2,3-b)pyridin-3-yl)-benzoic acid
• Protein Serine-Threonine Kinases
• serum-glucocorticoid regulated kinase

Topics

• Animals
• Benzoates (pharmacology)
• Brain Injuries (drug therapy, etiology, metabolism)
• Bridged Bicyclo Compounds, Heterocyclic (pharmacology)
• Cerebrovascular Circulation
• Heart Arrest (complications)
• Hippocampus (drug effects, metabolism)
• Immediate-Early Proteins (antagonists & inhibitors, genetics, metabolism)
• Male
• Memory
• Neuroprotective Agents (pharmacology, therapeutic use)
• Protein Kinase Inhibitors (pharmacology)
• Protein Serine-Threonine Kinases (antagonists & inhibitors, genetics, metabolism)
• Rats
• Rats, Sprague-Dawley
• Up-Regulation