PI3 kinase/Akt activation mediates estrogen and IGF-1 nigral DA neuronal neuroprotection against a unilateral rat model of Parkinson's disease.
Recently, using the medial forebrain bundle (MFB) 6-hydroxydopmaine (6-OHDA) lesion rat model of Parkinson's disease (PD), we have demonstrated that blockade of central IGF-1 receptors (IGF-1R) attenuated estrogen neuroprotection of substantia nigra pars compacta (SNpc) DA neurons, but exacerbated 6-OHDA lesions in IGF-1 only treated rats (Quesada and Micevych [2004]: J Neurosci Res 75:107-116). This suggested that the IGF-1 system is a central mechanism through which estrogen acts to protect the nigrostriatal DA system. Moreover, these results also suggest that IGF-1R-induced intracellular signaling pathways are involved in the estrogen mechanism that promotes neuronal survival. In vitro, two convergent intracellular signaling pathways used by estrogen and IGF-1, the mitogen-activated protein kinase (MAPK/ERK), and phosphatidyl-inositol-3-kinase/Akt (PI3K/Akt), have been demonstrated to be neuroprotective. Continuous central infusions of MAPK/ERK and PI3K/Akt inhibitors were used to test the hypothesis that one or both of these signal transduction pathways mediates estrogen and/or IGF-1 neuroprotection of SNpc DA neurons after a unilateral administration of 6-OHDA into the MFB of rats. Motor behavior tests and tyrosine hydroxylase immunoreactivity revealed that the inhibitor of the PI3K/Akt pathway (LY294002) blocked the survival effects of both estrogen and IGF-1, while an inhibitor of the MAPK/ERK signaling (PD98059) was ineffective. Western blot analyses showed that estrogen and IGF-1 treatments increased PI3K/Akt activation in the SN; however, MAPK/ERK activation was decreased in the SN. Indeed, continuous infusions of inhibitors blocked phosphorylation of PI3K/Akt and MAPK/ERK. These findings indicate that estrogen and IGF-1-mediated SNpc DA neuronal protection is dependent on PI3K/Akt signaling, but not on the MAPK/ERK pathway.
Quesada
Arnulfo
A
Department of Neurobiology, Brain Research Institute, David Geffen School of Medicine, UCLA, Los Angeles, California, USA. aquesada@mednet.ucla.edu
Lee
Becky Y
BY
Micevych
Paul E
PE
D000818:Animals; D015153:Blotting, Western; D002452:Cell Count; D004298:Dopamine / Q000502:physiology*; D004789:Enzyme Activation / Q000187:drug effects; D004958:Estradiol / Q000494:pharmacology; D004967:Estrogens / Q000502:physiology*; D005260:Female; D007276:Injections, Intraventricular; D007334:Insulin-Like Growth Factor I / Q000502:physiology*; D009043:Motor Activity / Q000187:drug effects / Q000502:physiology; D009412:Nerve Fibers / Q000201:enzymology; D009474:Neurons / Q000502:physiology*; D051058:Oncogene Protein v-akt / Q000378:metabolism*; D010052:Ovariectomy; D010302:Parkinson Disease, Secondary / Q000139:chemically induced / Q000473:pathology*; D019869:Phosphatidylinositol 3-Kinases / Q000378:metabolism*; D051381:Rats; D020318:Rats, Long-Evans; D015398:Signal Transduction / Q000187:drug effects / Q000502:physiology; D013378:Substantia Nigra / Q000166:cytology / Q000502:physiology*; D014446:Tyrosine 3-Monooxygenase / Q000378:metabolism
D004967:Estrogens; D004958:Estradiol; D007334:Insulin-Like Growth Factor I; D014446:Tyrosine 3-Monooxygenase; D019869:Phosphatidylinositol 3-Kinases; D051058:Oncogene Protein v-akt; D004298:Dopamine