Research ReportEstrogen down-regulates glial activation in male mice following 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine intoxication
Introduction
Parkinson's disease (PD) is a neurodegenerative disease commonly characterized by the progressive loss of dopaminergic neurons in the substantia nigra pars compacta (SNpc) and their projections in the striatum (McGeer et al., 1988a, McGeer et al., 1988b). Epidemiological studies have shown a greater prevalence of PD in men compared to women (Diamond et al., 1990, Kurtzke and Goldberg, 1988). Furthermore, estrogen improves motor disability in parkinsonian postmenopausal women with motor fluctuations (Tsang et al., 2000) and reduces the risk of PD in postmenopausal women (Benedetti et al., 2001). Altogether, these data indicate a beneficial effect of this ovarian hormone in the progression of PD. The evidence of a neuroprotective role of estrogen in PD is provided by studies in PD animal models. These studies have reported that estrogen decreases the striatal dopamine depletion in MPTP-intoxicated mice (Callier et al., 2001, Dluzen et al., 1996, Dluzen et al., 2001, Grandbois et al., 2000, Ramirez et al., 2003) and in 6-hydroxydopamine (6-OHDA)-lesioned rats (Datla et al., 2003, Dluzen, 1997, Murray et al., 2003). Besides, in vitro studies have revealed that estrogen can protect against 1-methyl-4-phenylpyridinium (MPP+) induced dopaminergic neuronal death (Sawada et al., 2002). Nevertheless, the effect of E2 on protecting against loss of tyrosine hydroxylase-immunoreactive (TH-IR) neurons in the SNpc of PD animal model remains controversial (Ferraz et al., 2003, Murray et al., 2003, Quesada and Micevych, 2004).
Although data suggest that estrogen confers benefits in PD, the mechanisms by which the hormone exerts its neuroprotection remains poorly understood. Glial reaction observed in PD and in PD animal model may contribute to the degeneration of dopaminergic neurons (Kohutnicka et al., 1998, Liberatore et al., 1999, McGeer et al., 1988a, McGeer et al., 1988b, Wu et al., 2002). Indeed, activated astrocytes and microglia express broad array of neurotoxic molecules, including pro-inflammatory cytokines, pro-inflammatory prostaglandins, reactive oxygen species and reactive nitrogen species (Knott et al., 2000, Liberatore et al., 1999, Norenberg, 1996, Qin et al., 2002). Previous studies have reported that glia have estrogen receptors and are targets for estrogen actions (Azcoitia et al., 1999, Bruce-Keller et al., 2000, Garcia-Ovejero et al., 2002, Hosli et al., 2001, Langub and Watson, 1992, Lei et al., 2003, Mor et al., 1999, Platania et al., 2003, Santagati et al., 1994, Vegeto et al., 2001). Additionally, glia have been implicated in the regenerative and neuroprotective effects of estrogen (Garcia-Estrada et al., 1999, Garcia-Segura et al., 1999a, Garcia-Segura et al., 1999b, Jones et al., 1999, Rozovsky et al., 2002, Sortino et al., 2004).
In view of the wide-ranging effect of estrogen on glia, it is of interest whether neuroprotection of estrogen in PD animal model is mediated through glia. The present study investigated the effect of 17β-estradiol (E2) on glial reaction in the SNpc and the striatum of adult male mice following acute MPTP intoxication. Further, we also examined if E2 was able to protect against MPTP-induced loss of TH-IR nigral neurons and their projections to the striatum.
Section snippets
Estrogen attenuates MPTP-mediated loss of TH-IR neurons in the SNpc and TH-IR fibers in the striatum
In MPTP-treated animals, only 34% of the TH-IR nigral neurons survived MPTP injection (P < 0.05 vs. control animals). In contrast, about 1.7 times as many TH-IR nigral neurons in MPTP/E2-treated animals survived MPTP intoxication (P < 0.05 vs. MPTP-treated animals) (Fig. 1, Fig. 2). Correspondingly, MPTP-induced loss of the TH-IR fibers in the striatum was abated with E2 pretreatment (Figs. 2D–F).
Estrogen decreases MPTP-mediated glial activation in the SNpc and the striatum
In the SNpc of control animals, GFAP-IR astrocytes and GSI-B4+ve microglia were observed in small
Discussion
The present study shows that, in addition to providing some protection against MPTP-induced deficit of dopaminergic neurons in the SNpc and loss of dopaminergic fibers in the striatum, E2 also diminishes the response of GFAP-IR astrocytes and GSI-B4+ve microglia in the SNpc and the striatum of MPTP-treated mice. These data suggest that E2 may provide neuroprotection by acting on dopaminergic neurons directly or through inhibition of astroglial and microglial reactions.
Previous studies have
Animals
Fifteen male C57Bl/6 mice at the age of 14 weeks were obtained from National Laboratory Animal Center, Thailand. They were housed two to three per cage with a 12-h light–dark cycle at a room temperature of 23 °C and had access to food and water ad libitum. All experiments were performed according with the European Communities Council Directive of 24 November 1986 (86/609/EEC), using protocols approved by the Committee of Animal Used for Research of the Faculty of Medicine, Srinakharinwirot
Acknowledgments
We wish to thank Professor Glenda Halliday for her invaluable comments on the manuscript. This study was supported by the Thailand Research Fund, Thailand, grant number MRG4680177.
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