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bioRxiv · 10.1101/2020.04.03.024067

Neuronal kinase SGK1.1 protects against brain damage after status epilepticus

Martin-Batista, E.·Maglio, L. E.·Armas-Capote, N.·Hernandez, G.·Alvarez de la Rosa, D.·Giraldez, T.
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Abstract

Epilepsy is a neurological condition associated to significant brain damage produced by status epilepticus (SE) including neurodegeneration, gliosis and ectopic neurogenesis. Reduction of these processes constitutes a useful strategy to improve recovery and ameliorate negative outcomes after an initial insult. SGK1.1, the neuronal isoform of the serum and glucocorticoids-regulated kinase 1 (SGK1), has been shown to increase M-current density in neurons, leading to reduced excitability and protection against seizures. We now show that SGK1.1 activation potently reduces levels of neuronal death and gliosis after SE induced by kainate, even in the context of high seizure activity. This neuroprotective effect is not exclusively a secondary effect of M-current activation but is also directly linked to decreased apoptosis levels through regulation of Bim and Bcl-xL cellular levels. Our results demonstrate that this newly described antiapoptotic role of SGK1.1 activation acts synergistically with the regulation of cellular excitability, resulting in a significant reduction of SE-induced brain damage. The protective role of SGK1.1 occurs without altering basal neurogenesis in brain areas relevant to epileptogenesis. SIGNIFICANCE STATEMENTApproaches to control neuronal death and inflammation are of increasing interest in managing epilepsy, one of the most important idiopathic brain diseases. We have previously shown that activation of SGK1.1 reduces neuronal excitability by increasing M-current levels, significantly reducing seizure severity. We now describe a potent neuroprotective role of SGK1.1, which dramatically reduces neuronal death and gliosis after status epilepticus. This effect is partially dependent on M-current activation and includes an additional anti-apoptotic role of SGK1.1. Our data strongly support the relevance of this kinase as a potential target for epilepsy treatment.

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Martin-Batista, E., Maglio, L. E., Armas-Capote, N., Hernandez, G., Alvarez de la Rosa, D., Giraldez, T.. 2020-04-05. Neuronal kinase SGK1.1 protects against brain damage after status epilepticus. https://doi.org/10.1101/2020.04.03.024067

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