The role of heme oxygenase on the protecti̇ve effect of docosahexaenoi̇c aci̇d i̇n an experi̇mental model of parki̇nson's di̇sease

Parkinson's disease (PD) is characterized by degeneration of the dopaminergic neurons in substantia nigra (SN). Its major clinical symptoms are tremor, rijidity, bradykinesia and postural instability. Docosahexaenoic acid (DHA) is an essential fatty acid for neural functions that resides within the neural membrane. A decline in fatty acid concentration is observed in case of neurodegenerative diseases such as PD. The present study is designed to investigate the role of heme oxygenase enzyme in protective effect of DHA administration in experimental Parkinson model elicited by 1-Methly-4-phenyl-1,2,3,6- tetrahydropyridine (MPTP). Three-month old male C57BL/6 mice were randomly divided into 4 groups as: Control (C), DHA-treated (D), MPTP-induced PD (P) and DHA-treated PD (DP). DHA dissolved in corn oil was administered daily (36 mg∙kg-1∙day-1) by oral gavage to D and DP groups for 30 days. On the 23rd day of the DHA administration, the neurotoxin MPTP was intraperitoneally injected at a dose of 4x20mg∙kg-1 at 2-hr intervals. Motor activities of mice were evaluated by locomotor cage and rotarod test on the 7th day of the utilization of Parkinson model. SN tissues were obtained for biochemical and immunohistochemical analyses. The loss of the cells in SN was detected by the immunohistochemical analysis of the tyrosine hydroxylase (TH)-immunopositive cells. The intensities of the Bcl-2, Bax, HO-2, Nrf-2 proteins were determined by immunohistochemistry, while HO-1 ve HO-2 protein levels were assayed by western blot. As an indicator of motor coordination and balance, the rotarod test at 40 rpm showed that MPTP-treated animals exhibited shorter time on the rotating rod mill which was significantly increased by DHA treatment in DP group. The total locomotor activity, ambulatory movement and total distance were decreased in P group; whereas, they were improved upon DHA treatment. The results of the pole test indicating the intensity of the bradykinesia showed that the return time and the total down time were increased in P group, while DHA treatment significantly shortened both parameters.Compared to the control, increased caspase 3 activity was found in P group. The increased activity of caspase 3 was attenuated but not significantly decreased in DP group. The number of TH-positive cells in SN was significantly reduced in P group; whereas, the reduction was found to be 50% in cells DP group. The Bcl-2 and Bax expressions were increased in P and DP group. The upregulated expressions of Nrf2 was observed in P group; whereas, its expression was down-regulated in DP group. The increased HO-1 and HO-2 protein levels were detected in P group compared with DP. The results of the present study indicate the protective effect of DHA administration on dopaminergic neurons in MPTP-induced experimental Parkinson model. Furthermore, the pathways of HO-1 and HO-2 are partly involved in this protective mechanism. In apoptotic pathway, DHA has protective effects on dopaminergic neurons in MPTP-induced experimental Parkinson model. HO-1 and HO-2 expression levels could be effective on this mechanism of protection. Key Words: Heme oxygenase, Docosahexaenoic acid, Nuclear factor E2- related factor 2, Parkinson