الفهرس 
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Abstract
Parkinson’s disease PD) is a progressive neurodegenerative disease with impaired motor function including bradykinesia, rigidity, postural instability and resting tremors. The development of clinically identifiable PD symptoms results from loss in more than 50% of the DAergic neurons in the SNpc and a marked reduction in the release of dopamine by those neurons that project into the neostriatum.
The causes of the majority of PD cases remain undefined, but multiple factors such as age-related neurodegeneration, genetic constitution and toxin exposure may play a role. Evidence suggests that subsequent oxidative stress inflammation and apoptosis play a major role in promoting neurodegeneration .
Rotenone, a potent mitochondrial complex I inhibitor, is one of the most relevant neurotoxins to induce Parkinsonian symptoms. The rotenone model is able to recapitulate slow and specific loss of DA neurons.The neurotoxicity of rotenone may be related to its ability to generate ROS, increased levels of cytokines and/or decreased neurotrophins leading to neuronal apoptosis.
Adenosine is a neuromodulator that coordinates responses to dopamine and other neurotransmitters in areas of the brain that are responsible for motor function, mood, learning and memory. Adenosine comprises four distinct receptor subtypes designated A1, A2A, A2B, and A3.
In the current study, the effect of A1 and A2A antagonists on rotenone-induced rat model of PD and DAergic neurotoxicity were evaluated.
In this study, Thirty two adult male albino rats weighing 200 ±20 g were used and subdivided randomly into four groups, eight rats each. Experimental Parkinsonism was induced in groups II, III and IV by six i.p. injections of rotenone (1.5 mg/kg/every other day). Rotenone treated rats received ZM 241385 (at a dose of 3.3 mg/kg/day) (group III) or 8-cyclopentyl-1, 3-dipropylxanthine (at a dose of 5 mg/kg/day) (group IV), 10 min before rotenone injection and were continued daily till the end of experiment.
Motor assessment in the form of stride length measuring test and grid walking test were performed after each rotenone injection and at the 13th day after treatment and results were recorded. At the end of study; day 13, motor reassessment was re-performed, then rats were sacrificed by decapitation and brain tissues were collected to measure dopamine concentration, using HPLC, in different groups. Besides, examination of histopathological changes in such tissues was done.
The results of the current study demonstrated that, rotenone-treated rats exhibited significant difference between the stride length of forelimbs and hindlimbs of rats (stride length test) and increase in the number of foot slips (gride walking test) beginning from the third injection and continued all over the study. In addition, ZM 241385 treated group showed significant increase in the stride length and enhanced motor coordination in the treated rats as manifested by decrease in the number of foot slips, while treatment with 8-cyclopentyl-1, 3-dipropylxanthine resulted in insignificant changes compared to rotenone group in both tests.
Moreover, Biochemical analysis in the brain tissue with HPLC showed significant decrease in dopamine level in rotenone treated group compared to vehicle control group. While treatment of Parkinsonian rats with ZM 241385 resulted in a significant increase in the dopamine level. Treatment with 8-cyclopentyl-1, 3-dipropylxanthine showed insignificant change compared to rotenone group.
In addition, H&E stain of the SNpc region in rotenone group demonstrated complete loss of some cells and others were distorted, angulated and shrunken leaving vacuoles in intercellular spaces. Marked decrease of pars compacta cells dendritic arborizations with PTHA stain was also observed. With cresyl violet stain, there was marked decrease of the Nissl’s granules in the perikarya of pars compacta cells. On the other hand, immunohistological stain for TH activity showed decreased staining of the soma and processes of all pars compacta cells.
Treatment with ZM 241385 improved histopathological examination of the SN region; H&E stain showed multipolar neurons with nucleoli and basophilic granular cytoplasm, the dendritic arborizations of pars compacta cells were increased in length with PTHA, increase of the Nissl’s granules with cresyl violet stain and increased positive staining for TH immunostaining.
In 8-cyclopentyl-1, 3-dipropylxanthine-treated group; pars compacta cells appeared almost the same like rotenone treated group.
Analysis and evaluation of the current results showed that treatment with ZM 241385 (A2A antagonist) increasing dopamine level, and hence enhancing the motor activity and motor coordination leading to better results in inhibiting PD progression. While 8-cyclopentyl-1, 3-dipropylxanthine (A1 antagonist) showed no effect.
It was concluded from this study that the use of A2A antagonist showed a preventive effect in PD in rats injection of rotenone, while A1 antagonist has no effect.