A report in this month's Nature Medicine adds detail, and complexity, to the role of nitric oxide in the neurodegeneration of Parkinson's disease. Serge Przedborski, Gabriel Liberatore, and their collaborators at Columbia, Johns Hopkins, and the Robert Wood Johnson Medical School present evidence that different isoforms of the enzyme NO synthase (NOS), which catalyze the formation of NO from L-arginine and oxygen, apparently collaborate to injure neurons in Parkinson's.
In Parkinson's disease-as in Alzheimer's and other neurodegenerative diseases-evidence continues to mount that reactive oxygen species such as NO are involved in the death of neurons. Taking advantage of the excellent Parkinson's model caused by the neurotoxin MPTP, investigators have paid particular attention to the role of different isoforms of NOS and have shown that the constitutively expressed, neuronal NOS (nNOS) can play a role in neurodegeneration. Przedborski, Liberatore, and colleagues, using knockout mice, have now demonstrated that the inducible form of NOS (iNOS; induced only by pathological stimuli such as ischemia, trauma, or infection) is associated with neuronal degeneration.
They found that in mice lacking the gene for iNOS, twice as many dopaminergic neurons in the substantia nigra survived MPTP treatment. On the other hand, the iNOS deletion did not protect dopaminergic axons in the striatum (a target of the substantia nigra) nor did it prevent gliosis, suggesting that NO catalyzed by another isoform may also be at work in the MPTP-induced neurodegeneration.
For Parkinson's therapy, suggest the authors, it appears that combination therapies, such as are used for AIDS or cancer, will have the best chance of going beyond symptom control to actively preventing cell loss. In a News and Views letter in the same issue, Thomas Grunewald and Flint Beal of Cornell write, "Therapeutic strategies of the future may involve a combination of iNOS and nNOS inhibitors, PARP inhibitors, free radical scavengers, excitatory amino acid antagonists and immunomodulating agents."—Hakon Heimer
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- Liberatore GT, Jackson-Lewis V, Vukosavic S, Mandir AS, Vila M, McAuliffe WG, Dawson VL, Dawson TM, Przedborski S. Inducible nitric oxide synthase stimulates dopaminergic neurodegeneration in the MPTP model of Parkinson disease. Nat Med. 1999 Dec;5(12):1403-9. PubMed.
- Grünewald T, Beal MF. NOS knockouts and neuroprotection. Nat Med. 1999 Dec;5(12):1354-5. PubMed.