PI3 kinase/Akt activation mediates estrogen and IGF-1 nigral DA neuronal neuroprotection against a unilateral rat model of Parkinson's disease

Authors

  • Arnulfo Quesada,

    Corresponding author
    1. Laboratory of Neuroendocrinology, Department of Neurobiology, Brain Research Institute, David Geffen School of Medicine UCLA, Los Angeles, California
    • Laboratory of Neuroendocrinology, Department of Neurobiology, Brain Research Institute, David Geffen School of Medicine UCLA, Los Angeles, California
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  • Becky Y. Lee,

    1. Laboratory of Neuroendocrinology, Department of Neurobiology, Brain Research Institute, David Geffen School of Medicine UCLA, Los Angeles, California
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    • This manuscript is dedicated to the loving memory of Becky Y. Lee B.S., MPH who was instrumental in this work

  • Paul E. Micevych

    1. Laboratory of Neuroendocrinology, Department of Neurobiology, Brain Research Institute, David Geffen School of Medicine UCLA, Los Angeles, California
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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

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