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- Title
Insulin Confers Neuroprotection Against Hyperglycemic Stress-Induced Apoptosis Through PI3K/Akt/mTOR/Nrf2/GCL/Redox Signaling.
- Authors
Okouchi, Masahiro; Okayama, Naotsuka; Kimura, Ryosuke; Mizuno, Tatsuo; Wakami, Kazuko; Yamada, Kazuhiro; Imaeda, Kenro; Kamiya, Yoshinobu; Joh, Takashi
- Abstract
It is well-known that diabetes exacerbates brain damage after cerebral stroke in patients with diabetes and in experimental diabetic animal models. Increased apoptosis in ischemic and penumbra regions of diabetic brain is a contributing factor in the exacerbation of cerebral infarct volume after ischemic insults. Administration of insulin can reduce neurological disability in cerebral stroke, accompanied by inhibition of neuronal apoptosis. It has been demonstrated that peripheral insulin is transported into the brain through circumventricular organs or blood-brain barrier, and that brain insulin can confer cytoprotection of neuronal cells against oxidative stress. However, the molecular mechanisms underlying the vulnerability of diabetic neuronal cells to chronic oxidative challenge and protective action of brain insulin have not been elucidated. Therefore, in the current study, we investigated the oxidative susceptibility of brain endothelial cells and neurons using human brain endothelial cells (IHEC) and rat pheochromocytoma cells (PC12), both of which are used commonly as neuronal cell models, to chronic hyperglycemic stress and neuroprotective action of insulin. IHEC and PC12 were treated with 25 mM glucose for 7 days with or without 100 nM insulin. Cell apoptosis, cellular redox status, protein expression and phosphorylation of PBK/Akt/mTOR pathway, as well as Nrf2-dependent upregulation of ghitamate-L-cysteine ligase (GCL) were determined. Chronic hyperglycemia exacerbated IHEC and PC12 apoptosis, which corresponded to decreased PI3K/Akt/mTOR/Nrf2/GCL signaling, exaggerated redox imbalance, and enhanced actin/Keap-1 S-glutathionylation. Insulin reversed the impaired PI3K/Akt/mTOR/Nrf2 signaling, and enhanced Nrf2-mediated GCL expression. Consequently, insulin restored redox balance and attenuated apoptosis. Inhibitors of insulin receptor tyrosine kinase, PI3K, Akt and mTOR abrogated insulin-induced Nrf2-mediated GCL expression, redox balance restoration, and IHEC and PC12 survival. In summary, human brain endothelial cells and neurons exhibit vulnerability to hyperglycemic stress which is associated with marked redox shifts and impaired PI3K/Akt/mTOR/Nrf2/GCL signaling. Insulin treatment affords neuroprotection by reversing cellular redox shifts through activating PI3K/Akt/mTOR/Nrf2/GCL signaling.
- Subjects
INSULIN; DIABETES; BRAIN damage; PEOPLE with diabetes; APOPTOSIS; CEREBRAL infarction; OXIDATIVE stress; CELLS
- Publication
Diabetes, 2007, Vol 56, pA169
- ISSN
0012-1797
- Publication type
Article