Abstract
Gender difference in Parkinson’s disease (PD) suggests that female sex steroids may promote dopaminergic neuron survival and protect them from degeneration. The glial cell line-derived neurotrophic factor (GDNF) is believed to be dopaminotrophic; thus it is considered as a potential therapeutic target in PD. Additionally, GDNF is endogenously synthetized in the caudate/putamen of humans and striatum in rodents. A neuroprotective role of estrogens on the nigrostriatal pathway via the stimulation of GDNF has been proposed. Since the GDNF-producing parvalbumin (Parv) interneurons express the estrogen receptor alpha in the mouse striatum, we sought to determine whether ectopic estrogenic compound modulates the GDNF synthesis in mice. Using an ovariectomized-estradiol (E2) replacement regimen, which reliably generates a rise of plasma estradiol, we assessed the effects of different levels of E2 on the activation of striatal neuronal populations, and GDNF production. A strong correlation was found between plasma E2 and the expression of the immediate early gene cFos in the striatum, as well as in other cortical regions. However, moderate and high E2 treatments failed to induce any striatal GDNF mRNA and protein synthesis. High E2 only stimulates cFos induction in a low percentage of striatal Parv neurons whereas the majority of cFos-positive cells are medium spiny neurons. Activation of these projecting neurons by E2 suggests a role of circulating sex steroids in the modulation of striatal neural pathways.
Highlights
Estrogen is an important hormone signal that regulates multiple tissues and functions in the body
We observed the expression of ERα in striatal medium spiny neuron (MSN) by dual staining with dopamine- and cAMP-regulated neuronal phosphoprotein (Darpp32) (Fig 1B), a protein that is expressed in neurons that express DA receptors [30]
To further study the mechanism involved in the estrogen-mediated neuroprotection of the dopaminergic nigrostriatal pathway, we have evaluated the effect of plasma estrogen on glial cell linederived neurotrophic factor (GDNF) production in the striatum using a model of ovariectomized female mice
Summary
Estrogen is an important hormone signal that regulates multiple tissues and functions in the body. The most recent and significant data supporting the neuroprotective role of endogenous GDNF on mesencephalic DA neurons were obtained from Gdnf hypermorphic mice (Gdnf hyper) that express twice the normal GDNF levels in the striatum. Mini-osmotic pumps delivering E2 promoted estrogenic neuroprotection against 6-OHDA-induced nigrostriatal lesion in male rats This neuroprotection effect of E2 was associated to a fair increase of GDNF protein content in both the substantia nigra and the striatum [25]. In an effort to further understand the interaction of E2 with GDNF, and its putative relevance in PD therapy, it is worth investigating the effect of estrogen in different models In this context, we chose to work with a model of ovariectomized (ovx) female mouse, whose depletion of endogenous gonadal estrogen was replaced by 17β-estradiol (E2), the most biologically prevalent and active estrogenic compound. To further understand the action of high circulating E2 in the striatum, we examined the expression pattern of cFos, an indirect marker of neuronal activity, in the main populations of striatal neurons
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