期刊
JOURNAL OF NEUROENDOCRINOLOGY
卷 24, 期 11, 页码 1386-1397出版社
WILEY-BLACKWELL
DOI: 10.1111/j.1365-2826.2012.02348.x
关键词
oestradiol; Parkinson's disease; dopaminergic cells; 6-hydroxydopamine; astrocytes
Parkinsons disease (PD) is characterised by the preferential loss of dopaminergic neurones from the substantia nigra (SN) that leads to the hallmark motor disturbances. Animal and human studies suggest a beneficial effect of oestrogen to the nigrostriatal system, and the regulation of neurotrophic factor expression by oestrogens has been suggested as a possible mechanism contributing to that neuroprotective effect. The present study was designed to investigate whether the neuroprotection exerted by 17 beta-oestradiol on nigrostriatal dopaminergic neurones is mediated through the regulation of glial cell line-derived neurotrophic factor (GDNF) expression. Using an in vivo rat model of PD, we were able to confirm the relevance of 17 beta-oestradiol in defending dopaminergic neurones against 6-hydroxydopamine (6-OHDA) toxicity. 17 beta-oestradiol, released by micro-osmotic pumps, implanted 10 days before intrastriatal 6-OHDA injection, prevented the loss of dopaminergic neurones induced by 6-OHDA. 17 beta-oestradiol treatment also promoted an increase in GDNF protein levels both in the SN and striatum. To explore the relevance of GDNF increases to 17 beta-oestradiol neuroprotection, we analysed, in SN neurone-glia cultures, the effect of GDNF antibody neutralisation and RNA interference-mediated GDNF knockdown. The results showed that both GDNF neutralisation and GDNF silencing abolished the dopaminergic protection provided by 17 beta-oestradiol against 6-OHDA toxicity. Taken together, these results strongly identify GDNF as an important player in 17 beta-oestradiol-mediated dopaminergic neuroprotection.
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