Evidence for altered insulin signalling in the brains of genetic absence epilepsy rats from Strasbourg.
Animals
Blood Glucose
/ metabolism
Brain Waves
Disease Models, Animal
Epilepsy, Absence
/ genetics
Glycogen Synthase Kinase 3 beta
/ metabolism
Insulin
/ blood
Insulin Receptor Substrate Proteins
/ metabolism
Male
PTEN Phosphohydrolase
/ metabolism
Phosphatidylinositol 3-Kinase
/ metabolism
Phosphorylation
Proto-Oncogene Proteins c-akt
/ metabolism
Rats, Inbred Strains
Receptor, Insulin
/ metabolism
Rhombencephalon
/ metabolism
Signal Transduction
GAERS
GSK3β
PI3K p85
PTEN
absence epilepsy
brain insulin signalling
Journal
Clinical and experimental pharmacology & physiology
ISSN: 1440-1681
Titre abrégé: Clin Exp Pharmacol Physiol
Pays: Australia
ID NLM: 0425076
Informations de publication
Date de publication:
09 2020
09 2020
Historique:
received:
10
04
2019
revised:
12
04
2020
accepted:
13
04
2020
pubmed:
19
4
2020
medline:
18
11
2021
entrez:
19
4
2020
Statut:
ppublish
Résumé
Insulin-mediated signalling in the brain is critical for neuronal functioning. Insulin resistance is implicated in the development of some neurological diseases, although changes associated with absence epilepsy have not been established yet. Therefore, we examined the major components of PI3K/Akt-mediated insulin signalling in cortical, thalamic, and hippocampal tissues collected from Genetic Absence Epilepsy Rats from Strasbourg (GAERS) and Non-Epileptic Control (NEC) rats. Insulin levels were also measured in plasma and cerebrospinal fluid (CSF). For the brain samples, the nuclear fraction (NF) and total homogenate (TH) were isolated and investigated for insulin signalling markers including insulin receptor beta (IRβ), IR substrate-1 and 2 (IRS1 & 2), phosphatase and tensin homologue (PTEN), phosphoinositide 3-kinase phospho-85 alpha (PI3K p85α), phosphatidylinositol 4,5-bisphosphate, phosphatidylinositol (3,4,5)-trisphosphate, protein kinase B (PKB/Akt1/2/3), glucose transporter-1 and 4 (GLUT1 & 4) and glycogen synthase kinase-3β (GSK3β) using western blotting. A significant increase in PTEN and GSK3β levels and decreased PI3K p85α and pAkt1/2/3 levels were observed in NF of GAERS cortical and hippocampal tissues. IRβ, IRS1, GLUT1, and GLUT4 levels were significantly decreased in hippocampal TH of GAERS compared to NEC. A non-significant increase in insulin levels was observed in plasma and CSF of GAERS rats. An insulin sensitivity assay showed decreased p-Akt level in cortical and hippocampal tissues. Together, altered hippocampal insulin signalling was more prominent in NF and TH compared to cortical and thalamic regions in GAERS. Restoring insulin signalling may improve the pathophysiology displayed by GAERS, including the spike-and-wave discharges that relate to absence seizures in patients.
Identifiants
pubmed: 32304254
doi: 10.1111/1440-1681.13326
doi:
Substances chimiques
Blood Glucose
0
Insr protein, rat
0
Insulin
0
Insulin Receptor Substrate Proteins
0
Irs1 protein, rat
0
Irs2 protein, rat
0
Phosphatidylinositol 3-Kinase
EC 2.7.1.137
Receptor, Insulin
EC 2.7.10.1
Glycogen Synthase Kinase 3 beta
EC 2.7.11.1
Gsk3b protein, rat
EC 2.7.11.1
Proto-Oncogene Proteins c-akt
EC 2.7.11.1
PTEN Phosphohydrolase
EC 3.1.3.67
Pten protein, rat
EC 3.1.3.67
Types de publication
Journal Article
Research Support, Non-U.S. Gov't
Langues
eng
Sous-ensembles de citation
IM
Pagination
1530-1536Subventions
Organisme : CIHR
ID : 10677
Pays : Canada
Organisme : CIHR
ID : 227397
Pays : Canada
Informations de copyright
© 2020 John Wiley & Sons Australia, Ltd.
Références
Blazquez E, Velazquez E, Hurtado-Carneiro V, Ruiz-Albusac JM. Insulin in the brain: its pathophysiological implications for States related with central insulin resistance, type 2 diabetes and Alzheimer's disease. Front Endocrinol (Lausanne). 2014;5:161.
Karelina K, Sarac B, Freeman LM, Gaier KR, Weil ZM. Traumatic brain injury and obesity induce persistent central insulin resistance. Eur J Neurosci. 2016;43:1034-1043.
Kim B, Feldman EL. Insulin resistance in the nervous system. Trends Endocrinol Metab. 2012;23:133-141.
Lee EB, Warmann G, Dhir R, Ahima RS. Metabolic dysfunction associated with adiponectin deficiency enhances kainic acid-induced seizure severity. J Neurosci. 2011;31:14361-14366.
Schauwecker PE. The effects of glycemic control on seizures and seizure-induced excitotoxic cell death. BMC Neurosci. 2012;13:94.
Cheong E, Shin HS. T-type Ca(2)(+) channels in absence epilepsy. Biochim Biophys Acta. 2013;1828:1560-1571.
Lakaye B, Thomas E, Minet A, Grisar T. The genetic absence epilepsy rat from Strasbourg (GAERS), a rat model of absence epilepsy: computer modeling and differential gene expression. Epilepsia. 2002;43(suppl 5):123-129.
Arcaro J, Ma J, Chu LK, et al. The hippocampus participates in a pharmacological rat model of absence seizures. Epilepsy Res. 2016;120:79-90.
Holmes GL. Cognitive impairment in epilepsy: the role of network abnormalities. Epileptic Disord. 2015;17:101-116.
Kobylarek D, Iwanowski P, Lewandowski Z, et al. Advances in the potential biomarkers of epilepsy. Front Neurol. 2019;10:685.
Steriade M. Sleep, epilepsy and thalamic reticular inhibitory neurons. Trends Neurosci. 2005;28:317-324.
Dufour F, Koning E, Nehlig A. Basal levels of metabolic activity are elevated in Genetic Absence Epilepsy Rats from Strasbourg (GAERS): measurement of regional activity of cytochrome oxidase and lactate dehydrogenase by histochemistry. Exp Neurol. 2003;182:346-352.
Verrotti A, Basciani F, De Simone M, et al. Insulin resistance in epileptic girls who gain weight after therapy with valproic acid. J Child Neurol. 2002;17:265-268.
Daniels ZS, Nick TG, Liu C, Cassedy A, Glauser TA. Obesity is a common comorbidity for pediatric patients with untreated, newly diagnosed epilepsy. Neurology. 2009;73:658-664.
Farrell JS, Greba Q, Snutch TP, Howland JG, Teskey GC. Fast oxygen dynamics as a potential biomarker for epilepsy. Sci Rep. 2018;8:17935.
Henbid MT, Marks WN, Collins MJ, et al. Sociability impairments in genetic absence epilepsy rats from strasbourg: reversal by the T-type calcium channel antagonist Z944. Exp Neurol. 2017;296:16-22.
Marescaux C, Vergnes M. Genetic Absence Epilepsy in Rats from Strasbourg (GAERS). Ital J Neurol Sci. 1995;16:113-118.
Snead 3rd OC, Depaulis A, Vergnes M, Marescaux C. Absence epilepsy: advances in experimental animal models. Adv Neurol. 1999;79:253-278.
Brailowsky S, Montiel T, Boehrer A, Marescaux C, Vergnes M. Susceptibility to focal and generalized seizures in Wistar rats with genetic absence-like epilepsy. Neuroscience. 1999;93:1173-1177.
Powell KL, Cain SM, Ng C, et al. A Cav3.2 T-type calcium channel point mutation has splice-variant-specific effects on function and segregates with seizure expression in a polygenic rat model of absence epilepsy. J Neurosci. 2009;29:371-380.
Danober L, Vergnes M, Depaulis A, Marescaux C. Nucleus basalis lesions suppress spike and wave discharges in rats with spontaneous absence-epilepsy. Neuroscience. 1994;59:531-539.
Sekar S, Omran E, Gopalakrishnan V, et al. Elevated sterol regulatory elementary binding protein 1 and GluA2 levels in the hippocampal nuclear fraction of genetic absence epilepsy rats from Strasbourg. Epilepsy Res. 2017;136:1-4.
Balbaa M, Abdulmalek SA, Khalil S. Oxidative stress and expression of insulin signaling proteins in the brain of diabetic rats: role of Nigella sativa oil and antidiabetic drugs. PLoS ONE. 2017;12:e0172429.
Bathina S, Das UN. Dysregulation of PI3K-Akt-mTOR pathway in brain of streptozotocin-induced type 2 diabetes mellitus in Wistar rats. Lipids Health Dis. 2018;17:168.
Lee CC, Huang CC, Hsu KS. Insulin promotes dendritic spine and synapse formation by the PI3K/Akt/mTOR and Rac1 signaling pathways. Neuropharmacology. 2011;61:867-879.
Ari C, Murdun C, Koutnik AP, et al. Exogenous ketones lower blood glucose level in rested and exercised rodent models. Nutrients. 2019;11(10):2330.
Nehlig A, Vergnes M, Boyet S, Marescaux C. Local cerebral glucose utilization in adult and immature GAERS. Epilepsy Res. 1998;32:206-212.
Nehlig A, Vergnes M, Boyet S, Marescaux C. Metabolic activity is increased in discrete brain regions before the occurrence of spike-and-wave discharges in weanling rats with genetic absence epilepsy. Brain Res Dev Brain Res. 1998;108:69-75.
Reid CA, Kim TH, Berkovic SF, Petrou S. Low blood glucose precipitates spike-and-wave activity in genetically predisposed animals. Epilepsia. 2011;52:115-120.
Ross DL, Swaiman KF, Torres F, Hansen J. Early biochemical and EEG correlates of the ketogenic diet in children with atypical absence epilepsy. Pediatr Neurol. 1985;1:104-108.
Zhang S, Taghibiglou C, Girling K, et al. Critical role of increased PTEN nuclear translocation in excitotoxic and ischemic neuronal injuries. J Neurosci. 2013;33:7997-8008.
Jacobs KM, Bhave SR, Ferraro DJ, et al. GSK-3beta: a bifunctional role in cell death pathways. Int J Cell Biol. 2012;2012:930710.
Papp P, Kovacs Z, Szocsics P, Juhasz G, Magloczky Z. Alterations in hippocampal and cortical densities of functionally different interneurons in rat models of absence epilepsy. Epilepsy Res. 2018;145:40-50.
Ebeling P, Koistinen HA, Koivisto VA. Insulin-independent glucose transport regulates insulin sensitivity. FEBS Lett. 1998;436:301-303.
Sirvanci S, Meshul CK, Onat F, San T. Immunocytochemical analysis of glutamate and GABA in hippocampus of genetic absence epilepsy rats (GAERS). Brain Res. 2003;988:180-188.
Taghibiglou C, Martin HG, Lai TW, et al. Role of NMDA receptor-dependent activation of SREBP1 in excitotoxic and ischemic neuronal injuries. Nat Med. 2009;15:1399-1406.
Nirogi R, Kandikere V, Mudigonada K, et al. A simple and rapid method to collect the cerebrospinal fluid of rats and its application for the assessment of drug penetration into the central nervous system. J Neurosci Methods. 2009;178:116-119.
Mielke JG, Taghibiglou C, Liu L, et al. A biochemical and functional characterization of diet-induced brain insulin resistance. J Neurochem. 2005;93:1568-1578.