Growth hormone (GH) and GH-releasing peptide-6 increase brain insulin-like growth factor-I expression and activate intracellular signaling pathways involved in neuroprotection.
Beneficial effects of GH on memory, mental alertness, and motivation have been documented. Many actions of GH are mediated through IGF-I; hence, we investigated whether systemic administration of GH or GH-releasing peptide (GHRP)-6 modulates the brain IGF system. Treatment of adult male rats with GHRP-6 or GH for 1 wk significantly increased IGF-I mRNA levels in the hypothalamus, cerebellum, and hippocampus, with no effect in cerebral cortex. Expression of the IGF receptor and IGF-binding protein (IGFBP)-2 were not affected. Phosphorylation of Akt and Bad was stimulated in areas where IGF-I was increased, with no change in MAPK or glycogen synthase kinase-3beta. This suggests that GH and GHRP-6 activate phosphatidylinositol kinase intracellular pathways involved in cell survival in response to growth factors. Indeed, the antiapoptotic protein Bcl-2 was augmented in these same areas, with no change in the proapoptotic protein Bax. IGFBP-5, also reported to be involved in neuron survival processes, was increased mainly in the hypothalamus, suggesting a possible neuroendocrine role. In conclusion, GH and GHRP-6 modulate IGF-I expression in the central nervous system in an anatomically specific manner. This is coincident with activation of intracellular signaling pathways used by IGF-I and increased expression of proteins involved in cell survival or neuroprotection.
Frago
Laura M
LM
Universidad Autónoma, Hospital Universitario Infantil Niño Jesús, Departamento de Endocrinología and Unidad de Investigación, Madrid 28009, Spain.
Pañeda
Covadonga
C
Dickson
Suzanne L
SL
Hewson
Adrian K
AK
Argente
Jesús
J
Chowen
Julie A
JA
D000818:Animals; D001921:Brain / Q000187:drug effects / Q000378:metabolism*; D017871:Calcium-Calmodulin-Dependent Protein Kinases / Q000378:metabolism; D016923:Cell Death; D019610:Cytoprotection / Q000502:physiology; D004789:Enzyme Activation; D038341:Glycogen Synthase Kinases; D013006:Growth Hormone / Q000494:pharmacology*; D018971:Insulin-Like Growth Factor Binding Protein 2 / Q000378:metabolism; D018975:Insulin-Like Growth Factor Binding Protein 5 / Q000378:metabolism; D007334:Insulin-Like Growth Factor I / Q000235:genetics / Q000378:metabolism*; D007425:Intracellular Membranes / Q000502:physiology; D008297:Male; D009842:Oligopeptides / Q000494:pharmacology*; D019869:Phosphatidylinositol 3-Kinases / Q000378:metabolism; D010766:Phosphorylation; D011518:Proto-Oncogene Proteins / Q000378:metabolism; D012333:RNA, Messenger / Q000378:metabolism; D051381:Rats; D017208:Rats, Wistar; D017451:Receptors, Somatomedin / Q000378:metabolism; D015398:Signal Transduction / Q000502:physiology
D018971:Insulin-Like Growth Factor Binding Protein 2; D018975:Insulin-Like Growth Factor Binding Protein 5; D009842:Oligopeptides; D011518:Proto-Oncogene Proteins; D012333:RNA, Messenger; D017451:Receptors, Somatomedin; C041048:growth hormone releasing hexapeptide; D007334:Insulin-Like Growth Factor I; D013006:Growth Hormone; D019869:Phosphatidylinositol 3-Kinases; D038341:Glycogen Synthase Kinases; D017871:Calcium-Calmodulin-Dependent Protein Kinases