Journal
NEUROBIOLOGY OF DISEASE
Volume 153, Issue -, Pages -Publisher
ACADEMIC PRESS INC ELSEVIER SCIENCE
DOI: 10.1016/j.nbd.2021.105317
Keywords
Serum and glucocorticoid-regulated kinase 1; KA-induced seizures; Neuroprotection; Epilepsy; Kv7 potassium channels; Apoptosis
Categories
Funding
- Ministerio de Economia y Competitividad-MINECO, Spain [BFU2015-66490-R, RTI2018-098768-B-I00, BFU2015-70067-REDC]
- F.P.I. predoctoral Fellowship [BES-2016-077337]
- European Research Council (ERC) under the European Union''s Horizon 2020 research and innovation programme [648936]
- European Research Council (ERC) [648936] Funding Source: European Research Council (ERC)
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SGK1.1 activation was found to significantly reduce levels of neuronal death and reactive glial activation induced by status epilepticus, synergistically with the regulation of cellular excitability, resulting in a significant reduction of seizure-induced brain damage in relevant areas.
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. For this study, we used 4?5 months old male transgenic C57BL/6 J and FVB/NJ mice expressing near physiological levels of a constitutively active form of the kinase controlled by its endogenous promoter. Here we show that SGK1.1 activation potently reduces levels of neuronal death (assessed using Fluoro-Jade C staining) and reactive glial activation (reported by GFAP and Iba-1 markers) in limbic regions and cortex, 72 h after SE induced by kainate, even in the context of high seizure activity. This neuroprotective effect is not exclusively through M-current activation but is also directly linked to decreased apoptosis levels assessed by TUNEL assays and quantification of Bim and Bcl-xL by western blot of hippocampal protein extracts. 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 in areas relevant to epileptogenesis.
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