Contribution of GDNF to the Estrogen-mediated Neuroprotection
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1
Universidade da Beira Interior, Centro de Investigacao em Ciencias da Saude, Portugal
Parkinson’s disease (PD) is characterized by the degeneration of dopaminergic (DA) neurons in the substantia nigra (SN) and estrogens have shown to promote the survival of these cells. Several studies demonstrated that glial cell line-derived neurotrophic factor (GDNF) represents a potential therapeutic tool for rescuing DA neurons in PD. The present study was designed to investigate whether the neuroprotection exerted by 17-ß- estradiol (E2) on nigrostriatal DA neurons is mediated by the regulation of GDNF expression and to undisclosed the mechanisms involved in the protective effects of E2-upregulation GDNF.
Using rat postnatal SN cell cultures as a model we observe that E2 increased the expression of GDNF in a concentration- dependent manner. In order to understand which cells were responsible for this increase in GDNF, we have tested the effect of E2 in cultures of astrocytes or neurons separately. The results have shown that in individual cultures the up-regulation of GDNF does not occurs, suggesting that both, astrocytes and neurons, are required to stimulate GDNF expression. We also proved that E2 protects DA neurons from injury induced by the complex I inhibitor, 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridene. To clarify the relevance of GDNF increases in neuroprotection provided by E2, we are now performing studies using siRNA- mediated GDNF knockdown.
In in vivo studies we were able to confirm the importance of E2 in the protection of DA neurons against the toxin 6-hydroxydopamine (6-OHDA). The toxin, injected stereotaxically into the striatum of male Wistar rats, induced a significant loss of nigral DA cells. E2, released by micro-osmotic pumps, implanted 10 days before the 6-OHDA induced lesion, prevented the reduction in DA neurons. In addition, 8 days after pumps implant, the levels of GDNF protein were increased in the SN and in the striatum of E2 pre-treated animals. Currently, we are evaluating which mechanism could be involved in these in vivo protective effects of E2. For that we are assessing the levels of apoptose; oxidative stress and microglia activation state. Preliminary results have shown that the levels of oxidative stress are decreased in animals pre-treated with E2 and treated with 6- OHDA when compared with animals treated only with 6-OHDA. Altogether these results strongly suggest that beside its well known antioxidant role, the protective effects of E2 also involve an up-regulation of GDNF expression.
Conference:
11th Meeting of the Portuguese Society for Neuroscience, Braga, Portugal, 4 Jun - 6 Jun, 2009.
Presentation Type:
Poster Presentation
Topic:
Neurodegenerative Disorders
Citation:
Campos
FL,
Batista
C,
Cristovao
A,
Fonseca
CP and
Baltazar
G
(2009). Contribution of GDNF to the Estrogen-mediated Neuroprotection.
Front. Neurosci.
Conference Abstract:
11th Meeting of the Portuguese Society for Neuroscience.
doi: 10.3389/conf.neuro.01.2009.11.060
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Received:
07 Aug 2009;
Published Online:
07 Aug 2009.
*
Correspondence:
Filipa L Campos, Universidade da Beira Interior, Centro de Investigacao em Ciencias da Saude, Covilhã, Portugal, filipalcampos@gmail.com