Effect of ovarian steroids in an hemiparkinsonism modelo on female rats: differencial gene expresión of α-synuclein and 3α-HSOR

HERRERA MACARENA; GIULIANI FERNANDO; MULLE BERNEDO MARIA BELEN; YUNES ROBERTO; CABRERA RICARDO

Mendoza

Workshop; International Workshop in Neuroendocrinology (IWNE 2015); 2015

International Neuroendocrine Federation- Universidad de Mendoza

One of the key factors into the molecular pathogenesis of Parkinson´s disease is the progressive loss of dopaminergic (DA) neurons in the nigrostriatal pathway and the role of protein aggregates, such as Lewy Body inclusions. The major component of these inclusions is the protein α-synuclein (α-syn), with high expression levels in this pathology. On the other hand, it seems to be a major incidence of the disease in men than in women so it is proposed that neuroactive steroids, neuroesteroidogenic enzymes and neurosteroids are potencial inducers of neuronal regeneration and neuroprotection against experimental neuropathologies. OBJECTIVES: Evaluate the differential gene expression of the protein α-syn and of the neuroesteroidogenic enzyme 3alpha-hydroxysteroid dehydrogenase (3α-HSOR) in female normal rats and ovariectomized (OVX) rats under the subchronic treatment with estrogen (E2) and progesterone (P4) in a model of unilateral injection of the neurotoxin 6-OHDA. METHODS: Female Sprague Dawley rats were divided into 6 experimental groups: G1) SHAM (rat without lesion), G2) HP (hemiparkinsonian rat), G3) OVX-SHAM (ovx rat without lesion), G4) OVX-HP (ovx hemiparkinsonian rat), G5) OVX-HP-E (ovx hemiparkinsonian rat with E2 therapy 0,1mg/kg/day for 10 consecutive days), G6) OVX-HP-P (ovx hemiparkinsonian rat with P4 therapy 4mg/kg/day for 10 consecutive days). At 8 weeks post-lesion with 6-OHDA the animals were sacrificed and their striatum and substantia nigra (SN) dried and submitted to PCR. RESULTS: The gene expression of α-syn in right SN showed no significant changes in G2 respect to G1, higher expression levels in G4 compared to G3 (p<0,05) and a significant increase in G4 compared with G3 (p<0,05). This overexpression remained in G6 but decreased in G5 (p<0,05). Moreover, in right striatum there was a significant decrease in the gene expression of 3α-HSOR in G2 compared to G1 (p<0,05). This overexpression increased further in G4 compared to G3 (p<0,001). P4 treatment (G6) and, in a lesser extent, E2 (G5) significantly increased the expression levels over the G4 (p<0,001 and p<0,05, respectively). CONCLUSIONS: The deleterious effects of the neurotoxin 6-OHDA at molecular levels of 3α-HSOR were attenuated in groups treated with ovarian steroids, especially P4. 6-OHDA unilateral injection triggers the expression of α-syn in ovx rats. However, this neurotoxicity was attenuated with P4 treatment and, particularly, E2 treatment. Taken together, our findings demonstrate that E2 and P4 act as neuroprotective molecules in striatal activity of female hemiparkinsonian rats, which 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)