Estrogen, neuroinflammation and neuroprotection in Parkinson’s disease: Glia dictates resistance versus vulnerability to neurodegeneration

doi:10.1016/j.neuroscience.2005.07.060

Neuroscience

Volume 138, Issue 3, 27 March 2006, Pages 869-878

https://doi.org/10.1016/j.neuroscience.2005.07.060 Get rights and content

Abstract

Post-menopausal estrogen deficiency is recognized to play a pivotal role in the pathogenesis of a number of age-related diseases in women, such as osteoporosis, coronary heart disease and Alzheimer’s disease. There are also sexual differences in the progression of diseases associated with the nigrostriatal dopaminergic system, such as Parkinson’s disease, a chronic progressive degenerative disorder characterized by the selective degeneration of mesencephalic dopaminergic neurons in the substancia nigra pars compacta. The mechanism(s) responsible for dopaminergic neuron degeneration in Parkinson’s disease are still unknown, but oxidative stress and neuroinflammation are believed to play a key role in nigrostriatal dopaminergic neuron demise. Estrogen neuroprotective effects have been widely reported in a number of neuronal cell systems including the nigrostriatal dopaminergic neurons, via both genomic and non-genomic effects, however, little is known on estrogen modulation of astrocyte and microglia function in 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine model of Parkinson’s disease. We here highlight estrogen modulation of glial neuroinflammatory reaction in the protection of mesencephalic dopaminergic neurons and emphasize the cardinal role of glia-neuron crosstalk in directing neuroprotection vs neurodegeneration. In particular, the specific role of astroglia and its pro-/anti-inflammatory mechanisms in estrogen neuroprotection are presented. This study shows that astrocyte and microglia response to 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine injury vary according to the estrogenic status with direct consequences for dopaminergic neuron survival, recovery and repair. These findings provide a new insight into the protective action of estrogen that may possibly contribute to the development of novel therapeutic treatment strategies for Parkinson’s disease.

Section snippets

The Mr. Hyde’s face of glia

Evidence from both experimental and postmortem studies accumulated over the past two decades has clearly suggested that a sustained inflammatory reaction is present in acute CNS injury as well as in chronic neurodegenerative states. In the context of innate inflammatory mechanisms, glia is recognized to play active roles in most degenerative CNS pathologies and reactive gliosis recognized as universal hallmark of both acute or chronic damage to the CNS (Marchetti et al 2005b, Marchetti and

Conclusion

In summary, from the overall findings, it seems tempting to speculate that a causal relationship may exist between the exacerbation of glia reactivity of E₂-deprived females and increased vulnerability of nigral DA neurons to MPTP, possibly implicating E₂-induced switch of pro-inflammatory astroglial “Mr. Hyde” into a “Dr. Jekyll” phenotype, as determining factor in DA neuron protection. Given the crucial role of glia–neuron interactions in neuronal growth, survival, differentiation and synapse

Acknowledgments

The authors wish to thank the Italian Ministry of Health (Strategic Research Project contract no. 189), Italian Ministry of Research (MURST), OASI (IRCCS) Institution for Research and Care on Mental Retardation and Brain Aging Troina (EN) Italy.

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View all citing articles on Scopus

¹: M. C. Morale and P. A. Serra share the first authorship.

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Estrogen, neuroinflammation and neuroprotection in Parkinson’s disease: Glia dictates resistance versus vulnerability to neurodegeneration

Abstract

Section snippets

The Mr. Hyde’s face of glia

Conclusion

Acknowledgments

Prog Brain Res

Neuroscience

Neuropharmacology

J Neuroimmunol

Trends Pharmacol Sci

Brain Res Rev

Neuroscience

Neurobiol Aging

Brain Res Rev

Brain Res Rev

Parkinsonism Relat Disord

Bioch Pharm

Domest Anim Endocrinol

Neuropharmacology

Trends Neurosci

J Biol Chem

J Steroid Biochem Mol Biol

Psychoneuroendocrinology

Brain Res Rev

Inflammatory neurodegeneration mediated by nitric oxide from activated glia-inhibiting neuronal respiration, causing glutamate release and excitotoxicity

J Neurosci

Oxidative stress in Alzheimer’s diseaseimplications for prevention and therapy

Subcell Biochem

Antiinflammatory effects of estrogen on microglial activation

Endocrinology

Stereospecific prevention by 17-beta estradiol of MPTP-induced dopamine depletion

Synapse

Nonsteroidal anti-inflammatory drugs and the risk of Parkinson’s disease

Arch Neurol

Idiopathic and 1-methyl-4phenyl-1,2,3,6-tetrahydropyridine (MPTP)-induced Parkinsonism

Developmental and genetic influences upon gender differences in methamphetamine-induced nigrostriatal dopaminergic neurotoxicity

Ann N Y Acad Sci

MWI Estrogen as a neuroprotectant of nigrostriatal dopaminergic system

Endocrine

Sodium salicylate and 17 beta estradiol attenuate nuclear transcription factor NF-kB translocation in cultured rat astroglia cultures following exposure to amyloid beta (1–40) and lipopolysaccharide

J Neurochem

Glutathione metabolism in brainMetabolic interaction between astrocytes and neurons in the defense against reactive oxygen species

Eur J Biochem

Inflammation is detrimental for neurogenesis in adult brain

Proc Natl Acad Sci U S A

Reactive astrocytes protect tissue and preserve function after spinal cord injury

J Neurosci

Basic fibroblast growth factor (bFGF) acts on both neurons and glia to mediate the neurotrophic effects of astrocytes on LHRH neurons in culture

Synapse

Role of astroglia in estrogen regulation of synaptic plasticity and brain repair

J Neurobiol

Bilirubin protects astrocytes from its own toxicity inducing up-regulation and translocation of multidrug resistance-associated protein 1 (Mrp 1)

Proc Natl Acad Sci U S A

17beta Estradiol inhibits inflammatory gene expression by controlling NF-kappaB intracellular localization

Mol Cell Biol