期刊
NEUROBIOLOGY OF DISEASE
卷 153, 期 -, 页码 -出版社
ACADEMIC PRESS INC ELSEVIER SCIENCE
DOI: 10.1016/j.nbd.2021.105317
关键词
Serum and glucocorticoid-regulated kinase 1; KA-induced seizures; Neuroprotection; Epilepsy; Kv7 potassium channels; Apoptosis
资金
- 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)
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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