الفهرس 
INTRODUCTIONOnly 14 pages are availabe for public view
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Abstract
Parkinson’s disease (PD) is the second most common neurodegenerative disorder after Alzheimer’s disease in elderly characterized pathologically by a progressive degeneration of dopaminergic neurons projecting from the substantia nigra pars compacta (SNpc) to striatum resulting, primarily, in motor clinical symptoms.
The present study aimed to investigate the neuroprotective and therapeutic effects of curcumin, caffeine and their combination on experimentally induced animal model of PD. The analytical measurements were done on one hundred and ten male Wistar albino rats divided into eleven groups (10 each):
Control group: rats were i.p injected with the vehicle (50µl dimethylsulfoxide + 950µl sunflower oil) in a dose of 1 ml/kg b.w./day.
Curcumin (CUR) group: rats were orally administered with curcumin.
Caffeine (CAF) group: rats were i.p. injected with caffeine.
Curcumin plus caffeine (CUR+CAF) group: rats were orally administered with curcumin and i.p. injected with caffeine.
Parkinson’s disease model (ROT) group: rats were daily i.p. injected with rotenone at a dose of 1.5 mg/kg b.w. for 45 day to induce the animal model of PD.
Curcumin protected (CUR/Pr) group: rats received daily oral administration of curcumin followed by a daily i.p injection of rotenone with one hour interval.
Caffeine protected (CAF/Pr) group: rats received a daily i.p injection of caffeine followed by a daily i.p injection of rotenone with one hour interval.
Curcumin plus Caffeine protected (CUR+CAF/Pr) group: rats received a daily oral administration of curcumin and i.p injection of caffeine followed by a daily i.p injection of rotenone with one hour interval.
Curcumin treated (CUR/Tr) group: after the induction of PD, rats were orally administered with curcumin.
Caffeine treated (CAF/Tr) group: after the induction of PD, rats were i.p. injected with caffeine.
Curcumin plus Caffeine treated (CUR+CAF/Tr) group: after the induction of PD, rats were received oral administration of curcumin and i.p injection of caffeine.
The used curcumin dose was 80 mg/kg b.w. and the used caffeine dose was 30 mg/kg b.w.
After 45 days of daily treatment with the previous treatments, the following studies were made:
I. Behavioral studies: locomotor activity was measured by performing open field test (OFT). Also, the forelimb hanging test and traction test were used in this study to assess the motor neuron function and the performance of the skeletal muscle.
II. Biochemical studies: following behavioral testing, animals were sacrificed by sudden decapitation after being fasted for 12 hours and the brain of each animal was quickly removed and rapidly transferred to an ice-cold Petri dish. Each brain was divided into two halves; right and left. Each half was dissected to obtain the midbrain and the striatum. The right half was used to measure the levels of malondialdehyde (MDA), nitric oxide (NO), reduced glutathione (GSH), tumor necrosis factor-α (TNF-α) and activities of glutathione-S-transferase (GST), superoxide dismutase (SOD), acetylcholinesterase (AchE) and Na+/K+-ATPase.
III. Neurochemical studies: dopamine (DA), norepinephrine (NE) and serotonin (5-HT) were measured in midbrain and striatum of the left half
IV. Histopathological Examination: sections of midbrain and striatum stained with H&E were used to investigate the histopathological changes.
Results of the study indicated:
I. Behavioral studies: The daily rotenone injection significantly decreased locomotor activity in OFT, the time of the forelimb hanging test and the score of the traction test. However, protection and treatment with curcumin and/or caffeine prevented such significant decrease induced by rotenone in motor activity and muscular strength.
II. Biochemical studies:
1. Oxidative stress parameters: when normal rats were administered daily with curcumin and/or caffeine, no significant changes have been recorded in almost all the oxidative stress parameters. On the other hand, the present study revealed a state of oxidative and nitrosative stress in the midbrain and striatum of animal model of PD. This was evident from the significant increase in the levels of MDA and NO accompanied with the significant decrease in GSH, GST and SOD in the midbrain and striatum of rotenone-treated rats. The significant increase induced by rotenone in the MDA and NO levels was not recorded for midbrain and striatum of rats either protected or treated with curcumin, caffeine and their combination except for a slight significant increase in midbrain NO is still recorded. Moreover, protection and treatment of rotenone-intoxicated rats with curcumin and/or caffeine significantly increased midbrain and striatal GSH levels and normalized the activities of GST and SOD in midbrain and striatum of PD-induced rats except that a significant decrease in striatal GST is still recorded.
2. Enzyme activities: the daily rotenone injection significantly decreased the midbrain and striatal AchE and Na+/K+-ATPase activities. The protection and treatment with curcumin and/or caffeine prevented such significant decrease in enzyme activities.
3. Cytokines: when curcumin, caffeine and their combination were administered daily to normal rats no significant changes have been recorded in midbrain and striatal TNF-α. On the other hand, daily rotenone injection significantly increased midbrain and striatal TNF-α levels. However, the protection and therapy of rat model of PD with curcumin and/or caffeine restored the elevated TNF-α levels induced by rotenone in both the midbrain and the striatum.
II. Neurochemical studies: no significant changes were recorded in the levels of almost all monoamine (DA, NE and 5-HT) in the midbrain and striatum of normal adult male albino rats daily administered with curcumin and/or caffeine. On the other hand, a significant decrease in monoamine levels was recorded in midbrain and striatum of rotenone-intoxicated rats. Protection and treatment with curcumin and/or caffeine returned the decrease in midbrain and striatal monoamine levels to control-like value. However, protection and treatment with caffeine alone failed to normalize such significant decrease induced by rotenone in midbrain and striatal 5-HT levels.
IV. Histopathological Examination: the daily rotenone injection caused prominent degeneration of the neurons in the midbrain and striatum characterized by the presence of cytoplasmic inclusions of Lewy bodies in the midbrain, and severe focal encephalomalacia and gliosis in the striatum. However, protection of parkinsonian rats with curcumin and/or caffeine had been prevented almost all the histopathological changes induced by rotenone. This effect was more prominent in case of protection with curcumin and caffeine combination. The post-treatment of parkinsonian rats with curcumin and/or caffeine was unable to cure these histopathological changes but attenuated them.
B. Conclusion:
According to the results obtained from the present study, it could be concluded that the rat model of PD induced by rotenone represents a well established model that is characterized by many of the biochemical, neurochemical, histopathological and behavioral changes observed in PD.
Curcumin, caffeine and their combination offered significant neuroprotection and treatment in rotenone-induced rat model of PD. Neuroprotection shown by these agents may be attributed to inhibition of lipid peroxidation, reduction in NO levels, increase in GSH content and maintenance of endogenous antioxidant defense enzymes like GST and SOD. The antioxidant and anti-inflammatory properties for both curcumin and caffeine may be the mechanisms involved in neuronal protection and treatment in PD. In addition, both curcumin and caffeine were effective in restoring the deficiency in DA level in both the midbrain and striatum of rat model of PD. This effect represents the target for all the antiparkinsonian drugs. Also, curcumin and caffeine protection and treatment were effective in stopping the neurodegeneration induced by rotenone in the two studied brain regions. These effects of curcumin and caffeine resulted in improving the motor deficits recorded in PD rats.
Although the present investigation evaluates the effect of curcumin, caffeine and their combination as a protection and treatment against rat model of PD, the obtained results can’t determine which of these agents is more effective. This is due to the great similarity between the results of each agent obtained in the present study. It is clear from the previous discussion that curcumin may act mainly by saving DA level through suppressing its metabolism. In addition to this mechanism, caffeine can increase DA synthesis and antagonize adenosine receptors especially A2A and stimulate DA release. On the other hand, caffeine through its stimulatory effect may increase cholinergic activity. This effect may hinder the balance between DA/Ach.
In conclusion the present data revealed that both curcumin and caffeine either given alone or in combination were effective as protective and therapeutic agents against PD.