Insulin-like growth factor-1 prevents Abeta[25-35]/(H2O2)- induced apoptosis in lymphocytes by reciprocal NF-kappaB activation and p53 inhibition via PI3K-dependent pathway.
The role of insulin-like growth factor (IGF-1) as neural survival factor for the treatment of Alzheimer's disease has recently gained attention. The present study shows that IGF-1 protects lymphocytes from (10, 30 microM) Abeta[(25-35)] and (25, 50, 100 microM) H(2)O(2)-induced apoptosis through NF-kappaB activation and p53 down regulation involving the phosphoinositide 3-kinase (PI-3K)-dependent pathway as demonstrated by using either (25 microM) LY294002 (PI-3K inhibitor), (10 nM) ammonium pyrrolidinedithiocarbamate (PDTC; NF-kappaB inhibitor), 50 nM pifithrin-alpha (PFT; p53 inhibitor) or by using immunocytochemistry detection of NF-kappaB and p53 transcription factors activation. Importantly, IGF-1, PDTC and PFT were able to protect and rescue lymphocytes pre-exposed to 10 muM Abeta[(25-35)], even when the three compounds were added up-to 12 h post- Abeta[(25-35)] exposure. Altogether these results suggest that survival/rescue of lymphocytes from Abeta[(25-35)] toxicity is determined by p53 inactivation via IGF-1/ PI-3K pathway.
Jimenez Del Rio
Marlene
M
Internal Medicine, Neuroscience Research Program, School of Medicine, University of Antioquia, UdeA, Medellin, Colombia. mdelrio@quimbaya.udea.edu.co
Velez-Pardo
Carlos
C
D000328:Adult; D016229:Amyloid beta-Peptides / Q000494:pharmacology / Q000502:physiology*; D017209:Apoptosis; D052160:Benzothiazoles; D002867:Chromones / Q000494:pharmacology; D006801:Humans; D006861:Hydrogen Peroxide / Q000378:metabolism* / Q000494:pharmacology; D066298:In Vitro Techniques; D007334:Insulin-Like Growth Factor I / Q000502:physiology*; D008214:Lymphocytes / Q000187:drug effects / Q000502:physiology*; D008297:Male; D051336:Mitochondrial Membranes / Q000502:physiology; D009025:Morpholines / Q000494:pharmacology; D016328:NF-kappa B / Q000037:antagonists & inhibitors / Q000378:metabolism*; D010446:Peptide Fragments / Q000494:pharmacology / Q000502:physiology*; D019869:Phosphatidylinositol 3-Kinases / Q000378:metabolism*; D000081082:Phosphoinositide-3 Kinase Inhibitors; D011392:Proline / Q000031:analogs & derivatives / Q000494:pharmacology; D013844:Thiazoles / Q000494:pharmacology; D013859:Thiocarbamates / Q000494:pharmacology; D014050:Toluene / Q000031:analogs & derivatives / Q000494:pharmacology; D016159:Tumor Suppressor Protein p53 / Q000037:antagonists & inhibitors* / Q000378:metabolism; D015854:Up-Regulation
D016229:Amyloid beta-Peptides; D052160:Benzothiazoles; D002867:Chromones; D006861:Hydrogen Peroxide; D007334:Insulin-Like Growth Factor I; D009025:Morpholines; D016328:NF-kappa B; D010446:Peptide Fragments; D019869:Phosphatidylinositol 3-Kinases; D000081082:Phosphoinositide-3 Kinase Inhibitors; D011392:Proline; D013844:Thiazoles; D013859:Thiocarbamates; D014050:Toluene; D016159:Tumor Suppressor Protein p53; C074636:amyloid beta-protein (25-35); C066229:prolinedithiocarbamate; C085911:2-(4-morpholinyl)-8-phenyl-4H-1-benzopyran-4-one; C121565:pifithrin