Insulin activates the PI3K-Akt survival pathway in vulnerable neurons following global brain ischemia

Autor: Gary S. Krause, Jonathon M. Sullivan, Rita Kumar, Andrea B. Page, Thomas H. Sanderson, Alina C. Murariu-Dobrin
Rok vydání: 2009
Předmět:
Male
medicine.medical_specialty
Cell Survival
medicine.medical_treatment
Neuroprotection
Brain Ischemia
Brain ischemia
Wortmannin
Phosphatidylinositol 3-Kinases
chemistry.chemical_compound
Proto-Oncogene Proteins
Internal medicine
medicine
Animals
Insulin
Rats
Long-Evans
Phosphorylation
CA1 Region
Hippocampal
Protein kinase B
PI3K/AKT/mTOR pathway
Neurons
Memory Disorders
Bcl-2-Like Protein 11
Dose-Response Relationship
Drug
business.industry
Forkhead Box Protein O3
Membrane Proteins
Forkhead Transcription Factors
General Medicine
medicine.disease
Rats
Cortex (botany)
Disease Models
Animal
Dose–response relationship
Neuroprotective Agents
Endocrinology
Neurology
chemistry
Reperfusion Injury
bcl-Associated Death Protein
Neurology (clinical)
Apoptosis Regulatory Proteins
business
Proto-Oncogene Proteins c-akt
Signal Transduction
Zdroj: Neurological Research. 31:947-958
ISSN: 1743-1328
0161-6412
DOI: 10.1179/174313209x382449
Popis: Insulin is neuroprotective following transient global brain ischemia; however, the mechanisms by which insulin exerts its salutary effects remain unclear.We assessed insulin's effect on the PI3K-Akt survival system and consequent modulation of the pro-apoptotic proteins Bim, Bad and FoxO3a.We utilized rats subjected to 10 minutes of global brain ischemia, with or without insulin administered at the onset of reperfusion.In sham-operated animals, minimal pAkt immunofluorescence was detected in the CA1. Moreover, at 30 minute reperfusion, there was no change in pAkt in CA1 neurons. Single bolus high-dose insulin treatment resulted in an early increase in pAkt after 30 minutes, preservation of CA1 neurons to 14 days of reperfusion and preservation of spatial learning ability. Insulin treatment increased cytoplasmic and nuclear staining for pAkt in both CA1 and cortex. Insulin-induced Akt phosphorylation was suppressed by the PI3K inhibitor wortmannin. Neither reperfusion nor insulin induced any change in the phosphorylation or subcellular localization of FoxO3a, Bim or Bad. A single bolus of high-dose insulin reduced CA1 neuronal cell death and thus represents a potential therapeutic intervention for global brain ischemia.These results reveal that proximal elements of a known cell-survival pathway are triggered by high-dose insulin during early reperfusion. Insulin induces robust PI3K-dependent phosphorylation of Akt by 30 minute reperfusion and results in improvement of hippocampal structure and function. However, the Akt substrates FoxO3a, Bim and Bad do not undergo corresponding changes in phosphorylation or subcellular localization in this model of global brain ischemia. The downstream components of insulin-induced Akt survival signaling after transient global brain ischemia remain to be identified.
Databáze: OpenAIRE
Externí odkaz: