Neuroprotective effect of estradiol in a Parkinson?s disease model on female rats: motor dysfunctions, brain derived neurotrophic factor (BDNF) and 𝜶-synuclein expression and striatal dopamine release

HERRERA MACARENA; GIULIANI FERNANDO; YUNES ROBERTO; CABRERA RICARDO

Ribeirao Preto

Jornada; XXI Curso de Verano en genética; 2016

Departamento de Posgraduación en Genética-USP

Neuroprotective effect of estradiol in a Parkinson?s disease model on female rats: motor dysfunctions, BDNF and α-synuclein expression and striatal dopamine release.Macarena Herrera1*; Fernando Giuliani1; Roberto Yunes1; Ricardo Cabrera1. 1. Instituto de Investigaciones Biomédicas-Universidad de Mendoza-Instituto de Medicina y Biología Experimental de Cuyo-CCT Mendoza-CONICET. Argentina.*macarenalherrera@hotmail.comBACKGROUND: Parkinson?s disease (PD) is the second most common neurodegenerative disorder, with a prevalence that is higher in men than women. This has raised the hypothesis that female hormones could have neuroprotective properties. Their actions might be evidenced as improvements in the motor symptoms as well as changes in the expression of neurotrophic factors, in the neuronal activity of the affected brain areas and in the expression of protein aggregates α-syn (Lewis Body inclusions). OBJECTIVES: To determine in an experimental model of the neuropathology (hemiparkinsonian rats) if estradiol (E) treatment could: 1) improve the motor dysfunctions; 2) induce changes in the striatal mRNA expression of BDNF and α-syn; and 3) modify the striatal dopamine release. METHODS: We used ovariectomized adult rats that were unilaterally injected in right corpus striatum with either the neurotoxic 6-hydroxydopamine (HP rats), or vehicle (sham rats) as controls. Five days after lesion they were treated with a subcutaneous daily treatment of either 0.1µg/kg estradiol (HP-E group) or vehicle (HP-group and sham-group) for 10 consecutive days. To assess the objective 1, eight weeks after lesion we assayed for each rat stepping, curling and apomorphine-induced turning behavior tests. After that, we killed them by decapitation and dissected out the corpus striata. A subset of each tissue was assigned to mRNA extraction and ulterior RTqPCR of BDNF and RTPCR of α-syn (objective 2). The other subset was separated to superfusion assays with [3H]-dopamine to study the ex vivo K+-evoked release of this neurotransmitter (objective 3). All data were compared by 1-way ANOVA (p<0.05 considered as statistically significant). RESULTS: 1) The contralateral turning behavior (turns towards the left) was increased in rats of the HP group regarding sham group (p<0.01). This effect was reverted in the HP-E group (p<0.05). In turn, there was a reduction in the number of steps and an increase in the deviation of the corporal axis in rats of the HP group regarding sham group (p<0.01 in both, stepping and curling behavior tests). These effects were reverted in HP-E group (p<0.01 in both tests). 2) There was a reduction in the mRNA expression of BDNF in the right striata of rats belonging to the HP group regarding sham group (p<0.01). The treatment with E induced an increase in the mRNA expression of this factor (p<0.05). The gene expression of α-syn in right SN showed higher expression levels in the Hp group compared to the SHAM group (p<0,05).This overexpression decreased in HP-E group (p<0,05). 3) The K+-evoked dopamine release was decreased in the right striata of HP rats regarding sham rats (p<0.05). This effect was reverted in HP-E rats (p<0.05). CONCLUSIONS: Our results suggest that estradiol could be an important neuroprotective molecule against neurodegeneration. Its effect on BDNF expression and dopamine release could explain in part the improvement in the motor symptoms that we observed in this animal model of PD. 6-OHDA unilateral injection triggers the expression of α-syn in ovx rats. However, this neurotoxicity was attenuated with E2 treatment. Taken together, our findings motivates us to further studies under this experimental model.FINANCIAL SUPPORT: This work was supported by the University of Mendoza (Res133/07) and CONICET (PIP112201100100126/11).