PI3 kinase/Akt activation mediates estrogen and IGF-1 nigral DA neuronal neuroprotection against a unilateral rat model of Parkinson's disease
✍ Scribed by Arnulfo Quesada; Becky Y. Lee; Paul E. Micevych
- Publisher
- Wiley (John Wiley & Sons)
- Year
- 2008
- Tongue
- English
- Weight
- 593 KB
- Volume
- 68
- Category
- Article
- ISSN
- 1932-8451
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✦ Synopsis
Abstract
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. © 2008 Wiley Periodicals, Inc. Develop Neurobiol 2008