| Abstract No.: | A-B1060 |
| Country: | Canada |
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| Title: | UPREGULATION OF DOPAMINE RECEPTORS D2 INDUCED BY H2O2 AND DOCOSAHEXAENOIC ACID: IMPLICATION FOR SP1. |
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| Authors/Affiliations: | 1 Patrick Berube*; 1 Annie Larouche; 1 Philippe Sarret; 1 Sylvain Grignon;
1 University of Sherbrooke, QC, Canada
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| Content: | Background: The striatum is exposed to high levels of oxidative stress, a fact that is often explained by locally high levels of dopamine and oxidation thereof. Moreover, H2O2 has recently been shown to act as a non conventional neurotransmitter at striatal synapses. Altered expression of Sp1, a redox-sensitive transcription factor involved in the expression of dopamine receptors D2 (DRD2), has been reported in schizophrenia. However, little is known regarding the adaptation of key components of dopaminergic neurotransmission to subacute, non lethal oxidative stress. This prompted us to investigate the effects of H2O2, a canonical oxidant, on the expression levels of DRD2 and Sp1 in retinoic acid (RA) differentiated SH-SY5Y. On the same model, we also tested for the modulatory effect of docosahexaenoic acid (DHA) which has been shown to exert neuroprotective effects against oxidative stress.
Methods: SH-SY5Y were differentiated in the presence of RA (6 days, 10 M), treated with or without DHA (3 days, 25μM) and H2O2 (3h or 24h, 100 M). DRD2 protein levels were assessed by western blotting. We used quantitative real time PCR to measure DRD2 and Sp1 mRNA levels. Oxidative stress was assessed by malonedialdehyde (MDA) quantification. We also tested for nuclear and cytoplasmic levels of transcription factor NFκB p65 by western blotting.
Results: In response to H2O2 treatment, DRD2 protein and mRNA levels were significantly increase by 59% (p=0.012) and 9% (p=0.012) respectively. DHA treatment synergized with H2O2 to upregulate DRD2 mRNA levels by 40% (p=0.024). Under our conditions, Sp1 mRNA is upregulated following H2O2 with or without DHA treatments. Finally, we showed that H2O2 induced nuclear translocation of NFκB p65.
Conclusion: As described in the literature, DHA effects appear to vary according to the cellular redox status, and are unequivocally pro-oxydative under our conditions. Increased striatal DRD2 binding potential has been described in restless legs syndrome, Parkinson’s disease, antipsychotics side effects and schizophrenia, where it might be a vulnerability and prognosis marker. The present results unveiled a potential role of transcription factors Sp1 and NFκB on the control of DRD2 expression level in response to oxidative stress.
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