Insulin induces dephosphorylation of eukaryotic initiation factor 2alpha and restores protein synthesis in vulnerable hippocampal neurons after transient brain ischemia - PubMed (original) (raw)

Insulin induces dephosphorylation of eukaryotic initiation factor 2alpha and restores protein synthesis in vulnerable hippocampal neurons after transient brain ischemia

J M Sullivan et al. J Cereb Blood Flow Metab. 1999 Sep.

Abstract

Brain reperfusion causes prompt, severe, and prolonged protein synthesis suppression and increased phosphorylation of eukaryotic initiation factor 2alpha [eIF2alpha(P)] in hippocampal CA1 and hilar neurons. The authors hypothesized that eIF2alpha(P) dephosphorylation would lead to recovery of protein synthesis. Here the effects of insulin, which activates phosphatases, were examined by immunostaining for eIF2alpha(P) and autoradiography of in vivo 35S amino acid incorporation. Rats resuscitated from a 10-minute cardiac arrest were given 0, 2, 10 or 20 U/kg of intravenous insulin, underwent reperfusion for 90 minutes, and were perfusion fixed. Thirty minutes before perfusion fixation, control and resuscitated animals received 500 microCi/kg of 35S methionine/cysteine. Alternate 30-microm brain sections were autoradiographed or immunostained for eIF2alpha(P). Controls had abundant protein synthesis and no eIF2alpha(P) in hippocampal neurons. Untreated reperfused neurons in the CA1, hilus, and dentate gyrus had intense staining for eIF2alpha(P) and reduced protein synthesis; there was little improvement with treatment with 2 or 10 U/kg of insulin. However, with 20 U/kg of insulin, these neurons recovered protein synthesis and were free of eIF2alpha(P). These results show that the suppression of protein synthesis in the reperfused brain is reversible; they support a causal association between eIF2alpha(P) and inhibition of protein synthesis, and suggest a mechanism for the neuroprotective effects of insulin.

PubMed Disclaimer

Cited by

Mechanisms underlying insulin deficiency-induced acceleration of β-amyloidosis in a mouse model of Alzheimer's disease.
Devi L, Alldred MJ, Ginsberg SD, Ohno M. Devi L, et al. PLoS One. 2012;7(3):e32792. doi: 10.1371/journal.pone.0032792. Epub 2012 Mar 5. PLoS One. 2012. PMID: 22403710 Free PMC article.
A review of stress-induced hyperglycaemia in the context of acute ischaemic stroke: Definition, underlying mechanisms, and the status of insulin therapy.
Yao M, Hao Y, Wang T, Xie M, Li H, Feng J, Feng L, Ma D. Yao M, et al. Front Neurol. 2023 Mar 21;14:1149671. doi: 10.3389/fneur.2023.1149671. eCollection 2023. Front Neurol. 2023. PMID: 37025208 Free PMC article. Review.
The immunophilin-ligands FK506 and V-10,367 mediate neuroprotection by the heat shock response.
Klettner A, Herdegen T. Klettner A, et al. Br J Pharmacol. 2003 Mar;138(5):1004-12. doi: 10.1038/sj.bjp.0705132. Br J Pharmacol. 2003. PMID: 12642403 Free PMC article.
Insulin action on protein synthesis and its association with eIF5A expression and hypusination.
de Proença ARG, Pereira KD, Meneguello L, Tamborlin L, Luchessi AD. de Proença ARG, et al. Mol Biol Rep. 2019 Feb;46(1):587-596. doi: 10.1007/s11033-018-4512-1. Epub 2018 Dec 5. Mol Biol Rep. 2019. PMID: 30519811
Insulin blocks cytochrome c release in the reperfused brain through PI3-K signaling and by promoting Bax/Bcl-XL binding.
Sanderson TH, Kumar R, Sullivan JM, Krause GS. Sanderson TH, et al. J Neurochem. 2008 Aug;106(3):1248-58. doi: 10.1111/j.1471-4159.2008.05473.x. Epub 2008 Jun 2. J Neurochem. 2008. PMID: 18518905 Free PMC article.

Insulin induces dephosphorylation of eukaryotic initiation factor 2alpha and restores protein synthesis in vulnerable hippocampal neurons after transient brain ischemia - PubMed (original) (raw)