Elsevier

Brain Research

Volume 1084, Issue 1, 21 April 2006, Pages 28-37
Brain Research

Research Report
Estrogen down-regulates glial activation in male mice following 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine intoxication

https://doi.org/10.1016/j.brainres.2006.02.029Get rights and content

Abstract

Emerging evidence suggests beneficial effect of estrogen for Parkinson's disease (PD), yet the exact mechanisms implicated remain obscured. Activated glia observed in MPTP mouse model and in PD may participate in the cascade of deleterious events that ultimately leads to dopaminergic nigral neuronal death. In vitro studies demonstrate that estrogen can modify the microglial and astroglial expression of inflammatory mediator, such as cytokines and chemokines implicated in neuroinflammation and neurodegeneration. To determine whether estrogen-elicited neuroprotection in PD is mediated through glia, adult male C57Bl/6 mice were treated with 17β-estradiol (E2) for a total of 11 days. Following 5 days of pretreatment with E2, they were injected with 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) on the sixth day. The brains were collected on day 11. Immunohistochemistry and quantitative study were used to assess the number of tyrosine hydroxylase-immunoreactive (TH-IR) neurons in the substantia nigra pars compacta (SNpc) and that of activated astrocytes and activated microglia in the SNpc and the striatum. Pretreatment with E2 decreased the loss of TH-IR nigral neurons and diminished the deficit of TH-IR striatal fibers triggered by MPTP. The neuroprotective effect of E2 was coincident with an attenuation of a glial response within the nigra and the striatum. These findings suggest that the neuroprotective effects of E2 evidenced in MPTP mouse model might mediate through an inhibition of reactive glia. However, direct neuroprotective effects of E2 upon TH-IR neurons cannot be excluded.

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.

References (84)

  • X. Gao et al.

    Tamoxifen abolishes estrogen's neuroprotective effect upon methamphetamine neurotoxicity of the nigrostriatal dopaminergic system

    Neuroscience

    (2001)
  • J. Garcia-Estrada et al.

    Gonadal hormones down-regulate reactive gliosis and astrocyte proliferation after a penetrating brain injury

    Brain Res.

    (1993)
  • J. Garcia-Estrada et al.

    Dehydroepiandrosterone, pregnenolone and sex steroids down-regulate reactive astroglia in the male rat brain after a penetrating brain injury

    Int. J. Dev. Neurosci.

    (1999)
  • L.M. Garcia-Segura et al.

    Aromatase expression by astrocytes after brain injury: implications for local estrogen formation in brain repair

    Neuroscience

    (1999)
  • Y. He et al.

    Minocycline inhibits microglial activation and protects nigral cells after 6-hydroxydopamine injection into mouse striatum

    Brain Res.

    (2001)
  • E. Hosli et al.

    Colocalization of androgen, estrogen and cholinergic receptors on cultured astrocytes of rat central nervous system

    Int. J. Dev. Neurosci.

    (2001)
  • C. Knott et al.

    Inflammatory regulators in Parkinson's disease: iNOS, lipocortin-1, and cyclooxygenases-1 and -2

    Mol. Cell. Neurosci.

    (2000)
  • M. Kohutnicka et al.

    Microglial and astrocytic involvement in a murine model of Parkinson's disease induced by 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP)

    Immunopharmacology

    (1998)
  • D.L. Lei et al.

    Effects of estrogen and raloxifene on neuroglia number and morphology in the hippocampus of aged female mice

    Neuroscience

    (2003)
  • X. Lu et al.

    Naloxone prevents microglia-induced degeneration of dopaminergic substantia nigra neurons in adult rats

    Neuroscience

    (2000)
  • H.E. Murray et al.

    Dose- and sex-dependent effects of the neurotoxin 6-hydroxydopamine on the nigrostriatal dopaminergic pathway of adult rats: differential actions of estrogen in males and females

    Neuroscience

    (2003)
  • O. Orzylowska et al.

    Prolonged and concomitant induction of astroglial immunoreactivity of interleukin-1beta and interleukin-6 in the rat hippocampus after transient global ischemia

    Neurosci. Lett.

    (1999)
  • H. Sawada et al.

    Estradiol protects dopaminergic neurons in a MPP+Parkinson's disease model

    Neuropharmacology

    (2002)
  • B. Schmidt et al.

    Rat astrocytes express interferon-gamma immunoreactivity in normal optic nerve and after nerve transection

    Brain Res.

    (1990)
  • D. Stanic et al.

    Glial responses associated with dopaminergic striatal reinnervation following lesions of the rat substantia nigra

    Brain Res.

    (2004)
  • L. Zhao et al.

    Estrogen receptor subtypes alpha and beta contribute to neuroprotection and increased Bcl-2 expression in primary hippocampal neurons

    Brain Res.

    (2004)
  • I. Azcoitia et al.

    Localization of estrogen receptor beta-immunoreactivity in astrocytes of the adult rat brain

    Glia

    (1999)
  • A.E. Baker et al.

    Estrogen modulates microglial inflammatory mediator production via interactions with estrogen receptor beta

    Endocrinology

    (2004)
  • R.B. Banati et al.

    Cytotoxicity of microglia

    Glia

    (1993)
  • C. Behl et al.

    Neuroprotective activities of estrogen: an update

    J. Neurocytol.

    (2000)
  • M.D. Benedetti et al.

    Hysterectomy, menopause, and estrogen use preceding Parkinson's disease: an exploratory case-control study

    Mov. Disord.

    (2001)
  • G.I. Botchkina et al.

    Expression of TNF and TNF receptors (p55 and p75) in the rat brain after focal cerebral ischemia

    Mol. Med.

    (1997)
  • A.J. Bruce-Keller et al.

    Antiinflammatory effects of estrogen on microglial activation

    Endocrinology

    (2000)
  • S. Callier et al.

    Neuroprotective properties of 17beta-estradiol, progesterone, and raloxifene in MPTP C57Bl/6 mice

    Synapse

    (2001)
  • K.P. Datla et al.

    Differences in dopaminergic neuroprotective effects of estrogen during estrous cycle

    NeuroReport

    (2003)
  • S.G. Diamond et al.

    An examination of male–female differences in progression and mortality of Parkinson's disease

    Neurology

    (1990)
  • D.E. Dluzen

    Neuroprotective effects of estrogen upon the nigrostriatal dopaminergic system

    J. Neurocytol.

    (2000)
  • D. Dluzen et al.

    Estrogen as neuroprotectant of nigrostriatal dopaminergic system: laboratory and clinical studies

    Endocrine

    (2003)
  • D.E. Dluzen et al.

    Neuroprotective role of estrogen upon methamphetamine and related neurotoxins within the nigrostriatal dopaminergic system

    Ann. N. Y. Acad. Sci.

    (2000)
  • D.E. Dluzen et al.

    Tamoxifen eliminates estrogen's neuroprotective effect upon MPTP-induced neurotoxicity of the nigrostriatal dopaminergic system

    Neurotox. Res.

    (2001)
  • R.C. Dodel et al.

    Sodium salicylate and 17beta-estradiol attenuate nuclear transcription factor NF-kappaB translocation in cultured rat astroglial cultures following exposure to amyloid A beta(1–40) and lipopolysaccharides

    J. Neurochem.

    (1999)
  • K.B.J. Franklin et al.

    The Mouse Brain in the Stereotaxic Coordinates

    (1997)
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