Conclusion And Therapeutic Outlook

Numerous evidence exists on the pivotal role of OS in the pathogenesis of PD. Research on monogenetic forms of PD in the last few years has provided an increasing understanding of genetic contribution to idiopathic PD also. Moreover, the importance of proper mitochondrial function for the integrity of the nigrostriatal system is obvious, and it has been shown that this vital system affect plays a role in all forms of PD.

All three factors leading to pathological cascades - redox imbalance, influences of specific genes and mitochondrial dysfunction - seem to be closely linked and interconnected in a way that disturbance in each one of the systems has a deleterious influence on the other, promoting its dysfunction with the final consequence of neuronal death.

Therapeutic strategies should, therefore, focus on influencing these contributing factors in all diseases. Concerning redox imbalance, much effort has been taken to develop therapeutic strategies to prevent the deleterious effects of ROS either by directly scavenging or by triggering protective mechanisms inside the cell.

Several agents exerting antioxidative influence by modulating cellular energy metabolism in animal models seem promising as neuroprotective agents. These include coenzyme Qio, creatine, Ginkgo biloba, nicotinamide, acetyl-L-carnitine as well as non-narcotic analgesics, acetaminophen and aspirin (134,135). Alpha-lipoate may serve as an antioxidant by reducing glutathione disulfide increasing intracellular glutathione levels. Also, the recently developed subtype-selective inhibitors of iNOS and nNOS could exert a neuroprotective influence by diminishing OS.

Effort to find ways of decreasing the elevated iron levels in animal models of PD has led to the discovery of attenuation of iron-mediated dopaminergic neurodegeneration by the iron chelator desferal (10,136), lisuride and neuroprotection by the brain permeable iron chelator VK-28 (5[4-(2hydroxyl)-piperazine-1methyl]-quinoline-8-ol) (145).

Moreover, diet is becoming increasingly important as there is evidence that patients may influence disease development and progression by adapting specific dietary concepts. However, data concerning diet and nutritional supplements is controversial. The role of nutritionally administered iron has been supported by an epidemiological study revealing that iron taken in the highest quartile compared with those in the lowest quartile leads to an increased risk of PD (61).

The vitamins, tocopherol (vitamin E) and vitamin C are potent free-radical scavengers. However, although an important role of vitamin E for neuroprotection following amyloid A^-peptide-mediated neuronal damage in vitro has been established, the DATATOP trial showed that it could not reduce the dosage of l-DOPA in PD, indicating that restriction of its site of action to specific compartments may not be sufficient for radical defense in PD or that the beginning of the therapeutic application might have been too late. Similarly, vitamin C, which acts synergistically with vitamin E in the inhibition of oxidation reactions, has been shown to act in a neuroprotective manner in various in vitro and in vivo experiments, when it is applied in the oxidized form such as dehydroascorbic acid. Other nutritional components which have shown antioxidative properties in animal models of PD and in vitro experiments include selenium, flavonoids (essential compound in green tea, red wine, blueberries, etc.) (137), vitamin B6, B12 and folate and the heat shock protein expression inducing curcium, a powerful antioxidant derived from the curry spice turmeric (138).

Taken together, increasing knowledge about the interplay of OS, genetic influences and mitochondrial dysfunction should lead to improved cellular and animal models, taking into account all aspects, as a basis for the development of therapeutic strategies. Because of the knowledge, that neurodegeneration starts long before clinical diagnosis may be made based on motor deficits, all effort should be taken to find premotor markers. As neuroprotection in healthy subjects with good motor functions should be harmless and free of side effects, it might be useful to recommend a diet based on antioxidative capacities of many nutritional components. This could contain adequate amounts of fruits and vegetables, green tea and supplementation of antioxidative vitamins.

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