Estrogen, neuroinflammation and neuroprotection in Parkinson’s disease : key role of neuron-glia crosstalk

Abstract

Post-menopausal estrogen deficiency is recognized as playing 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 (DA) system, such as Parkinson’s disease (PD), a chronic progressive degenerative disorder characterized by the selective degeneration of mesencephalic dopaminergic (DA) neurons in the substantia nigra pars compacta (SNpc). The mechanism(s) responsible for DA neuron degeneration in PD are still unknown, but oxidative stress and neuroinflammation are believed to play a pivotal role in nigrostriatal DA neuron demise. In addition, a complex interplay between genetic and environmental factors is believed to modulate the vulnerability of nigral DA neurons. Estrogen (E2) neuroprotective effects have been widely reported in a number of neuronal cell systems including nigrostriatal DA neurons, via both genomic and non-genomic effects. Besides other mechanisms, E2 modulation of astrocyte and microglia function in a 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) mouse model of PD has recently emerged. Here we highlight E2 as a multifunctional hormone targeting the nigrostriatal DA system during health and disease with a particular focus on gender and E2 modulation of innate and adaptive immune responses as key factors involved in neuronal vulnerability. Special emphasis is given to the cardinal role of glia-neuron crosstalk directing neuroprotection vs neurodegneration and the role of E2 in switching astrocyte and microglia pro-inflammatory phenotype into a neuroprotective and anti-inflammatory state. Specifically, astrocyte and microglia response to the neurotoxin MPTP, and in particular the expression of pro-inflammatory mediators, vary according to estrogenic status with direct consequences for DA neuron survival, recovery and repair. The herein described estrogenic activation of glial anti-inflammatory and “protective” functions may provide a means to reduce the detrimental effects of neuroinflammation, while promoting cytokine activation of astroglial “pro-regenerative” functions. This mechanism might represent a compensatory/adaptive response to reduce neuronal vulnerability and/or to stimulate the repair process. 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.