Neuroprotective strategies in Parkinson's disease using the models of 6-hydroxydopamine and MPTP.
The etiology of Parkinson's disease is not known. Nevertheless a significant body of biochemical data from human brain autopsy studies and those from animal models point to an on going process of oxidative stress in the substantia nigra which could initiate dopaminergic neurodegeneration. It is not known whether oxidative stress is a primary or secondary event. Nevertheless, oxidative stress as induced by neurotoxins 6-hydroxydopamine and MPTP (N-methyl-4-phenyl-1,2,3,6-tetrahydropyridine) has been used in animal models to investigate the process of neurodegeneration with intend to develop antioxidant neuroprotective drugs. It is apparent that in these animal models radical scavengers, iron chelators, dopamine agonists, nitric oxide synthase inhibitors and certain calcium channel antagonists do induce neuroprotection against such toxins if given prior to the insult. Furthermore, recent work from human and animal studies has provided also evidence for an inflammatory process. This expresses itself by proliferation of activated microglia in the substantia nigra, activation and translocation of transcription factors, NF kappa-beta and elevation of cytotoxic cytokines TNF alpha, IL1-beta, and IL6. Both radical scavengers and iron chelators prevent LPS (lipopolysaccharide) and iron induced activation of NF kappa-B. If an inflammatory response is involved in Parkinson's disease it would be logical to consider antioxidants and the newly developed non-steroid anti-inflammatory drugs such as COX2 (cyclo-oxygenase) inhibitors as a form of treatment. However to date there has been little or no success in the clinical treatment of neurodegenerative diseases per se (Parkinson's disease, ischemia etc.), where neurons die, while in animal models the same drugs produce neuroprotection. This may indicate that either the animal models employed are not reflective of the events in neurodegenerative diseases or that because neuronal death involves a cascade of events, a single neuroprotective drug would not be effective. Thus, consideration should be given to multi-neuroprotective drug therapy in Parkinson's disease, similar to the approach taken in AIDS and cancer therapy.
Grünblatt
E
E
Technion-Faculty of Medicine, Haifa, Israel.
Mandel
S
S
Youdim
M B
MB
D000818:Animals; D004195:Disease Models, Animal; D006801:Humans; D020267:MPTP Poisoning / Q000378:metabolism*; D018696:Neuroprotective Agents / Q000494:pharmacology*; D016627:Oxidopamine / Q000633:toxicity*; D010300:Parkinson Disease / Q000235:genetics / Q000378:metabolism* / Q000473:pathology / Q000628:therapy; D013378:Substantia Nigra / Q000187:drug effects / Q000378:metabolism / Q000473:pathology
D018696:Neuroprotective Agents; D016627:Oxidopamine