Estrogen interacts with the IGF‐1 system to protect nigrostriatal dopamine and maintain motoric behavior after 6‐hydroxdopamine lesions

Abstract

The most prominent neurochemical hallmark of Parkinson's disease (PD) is the loss of nigrostriatal dopamine (DA). Animal models of PD have concentrated on depleting DA and therapies have focused on maintaining or restoring DA. Within this context estrogen protects against 6-hydroxdopamine (6-OHDA) and 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) lesions of the nigrostriatal DA pathway. Present studies tested the hypothesis that neuroprotective estrogen actions involve activation of the insulin-like growth factor-1 (IGF-1) system. Ovariectomized rats were treated with either a single subcutaneous injection of 17beta-estradiol benzoate or centrally or peripherally IGF-1. All rats were infused unilaterally with 6-OHDA into the medial forebrain bundle (MFB) to lesion the nigrostriatal DA pathway. Tyrosine hydroxylase (TH) immunocytochemistry confirmed that rats injected with 6-OHDA had a massive loss of TH immunoreactivity in both the ipsilateral substantia nigra compacta (60% loss) and the striatum (>95% loss) compared to the contralateral side. Loss of TH immunoreactivity was correlated with loss of asymmetric forelimb movements, a behavioral assay for motor deficits. Pretreatment with estrogen or IGF-1 significantly prevented 6-OHDA-induced loss of substantia nigra compacta neurons (20% loss) and TH immunoreactivity in DA fibers in the striatum (<20% loss) and prevented the loss of asymmetric forelimb use. Blockage of IGF-1 receptors by intracerebroventricular JB-1, an IGF-1 receptor antagonist, attenuated both estrogen and IGF-1 neuroprotection of nigrostriatal DA neurons and motor behavior. These findings suggest that IGF-1 and estrogen acting through the IGF-1 system may be critical for neuroprotective effects of estrogen on nigrostriatal DA neurons in this model of PD.

Interdependence of oestrogen and insulin-like growth factor-I in the brain: potential for analysing neuroprotective mechanisms

“…Pretreatment with oestrogen or IGF-I significantly prevents the loss of substantia nigra compacta neurons and the related motor disturbances. Blockage of IGF-I receptors by intracerebroventricular JB-1 attenuates the neuroprotective effects of both oestrogen and IGF-I (Quesada & Micevych 2004). These findings suggest that the neuroprotective actions of oestradiol and IGF-I after brain injury depend on the coactivation of both oestrogen receptors and IGF-I receptor.…”

Implication of the Phosphatidylinositol-3 Kinase/Protein Kinase B Signaling Pathway in the Neuroprotective Effect of Estradiol in the Striatum of 1-Methyl-4-phenyl-1,2,3,6-tetrahydropyridine Mice

“…Nevertheless, supporting our findings, Dhandapani et al (2005) reported recently that transforming growth factor-␤ mediates the neuroprotective effect of estradiol and involves Akt phosphorylation in cultures of primary rat cortical astrocytes. In addition, estrogen was reported to interact with the IGF-I system to protect nigrostriatal dopamine and maintain motor behavior in 6-hydroxydopaminelesioned rats (Quesada and Micevych, 2004).…”

Neurotrophic and neuroprotective actions of estrogen: Basic mechanisms and clinical implications

“…This preliminary evidence suggests that estrogen protection in the striatum may involve ER-α, but additional studies such as examining estrogen ability to protect the striatum against MPTP-induced damage in ER-knockout mice would help add important corroborating evidence for the role of ER in estrogen action in the striatum. Furthermore, alternative pathways for estrogen neuroprotection must be considered as well, as work by Quesada and Micevych [141] has provided evidence that estrogen interacts with the IGF-1 system to protect nigrostriatal dopaminergic neurons and maintain motor function after 6-hydroxydopamine lesion animals. Finally, it should be added that estrogen has also been shown to reduce the dyskinetic effects produced by MPTP in monkeys, suggesting that estrogen's beneficial effects on the dopaminergic system applies to higher species [142].…”