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- Title
Glucagon-Like Peptide-1 Represents a Promising Treatment Modality for Diabetic Encephalopathy.
- Authors
Kimura, Ryosuke; Okouchi, Masahiro; Mizuno, Tatsuo; Wakami, Kazuko; Yamada, Kazuhiro; Imaeda, Kenro; Okayama, Naotsuka; Kamiya, Yoshinobu; Joh, Takashi
- Abstract
Patients with long-standing diabetes commonly develop cognitive impairment and dementia, defined as diabetic encephalopathy. Enhanced susceptibility of brain neurons to oxidative and carbonyl stress is a contributing factor. Glucagon-like peptide (GLP)-1 is a brain-gut peptide, and recently became an attractive treatment modality for patients with diabetes. GLP-1 readily enters the brain, prevents neuronal cell apoptosis, and improves learning and memory impairment in Alzheimer's disease. Therefore, in the current study, we investigated whether GLP-1 could protect against hyperglycemic- and carbonyl stress- induced neuronal cell apoptosis. Rat pheochromocytoma cell line (PC12), which is used commonly as a neuronal cell model, was exposed to 25 mM glucose and/or 500 µM methylglyoxal (MG) with or without 0.1 nM GLP-1, and cell apoptosis, protein expression and phosphorylation of epidermal growth factor receptor (EGFR)/Akt/mTOR/glutamate-L-cysteine ligase (GCL) were determined. The mechanism of GLP-1-mediated EGFR transactivation was also examined. Hyperglycemia and MG induced PC 12 apoptosis as well as mitochondrial cytochrome c release, caspase-9 and -3 activation, and PARP cleavage. GLP-1 protected against hyperglycemic- and MG- induced PC12 apoptosis, which corresponded to the phosphorylation of EGFR, PI3K, Akt, mTOR, and the upregulation of GCL. Inhibitors of EGFR (14C10), EGFR ligands (anti-HB-EGF-Ab, anti-amphiregulin (AR)-Ab), a metalloproteinase which acts as EGFR ligand shedding (KB-R7785), PI3K (wortmannin, LY294002), Akt (AktI), and mTOR (rapamycin) abrogated the GLP-1 cytoprotective effect. In sum, hyperglycemic and carbonyl stress induces neuronal cell apoptosis through mitochondrial apoptotic signaling. GLP-1 treatment affords neuroprotection by enhancing PI3K/Akt/mTOR/GCL signaling through EGFR transactivation via GLP-1 receptor-mediated EGFR ligand (HB-EGF, AR) shedding, and thus represents a promising treatment modality for diabetic encephalopathy.
- Subjects
GLUCAGON-like peptide 1; BRAIN diseases; DIABETES complications; APOPTOSIS; PHEOCHROMOCYTOMA; LABORATORY rats
- Publication
Diabetes, 2007, Vol 56, pA507
- ISSN
0012-1797
- Publication type
Article