Current Medicinal Chemistry - Central Nervous System Agents

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Nitric Oxide and Dopamine Neurons. Implications for Parkinsons Disease

Author(s): Maria A. Mena, Maria J. Casarejos, Santiago Canals.

Abstract:

There is evidence suggesting that nitric oxide (NO) may play an important role in dopamine (DA) cell death. NO may act as a neuroprotector or neurotoxic agent in dopamine neurons, depending on cell redox status. Glutathione (GSH) depletion is the earliest biochemical alteration shown to date in brains of Parkinsons disease (PD) patients. However, data from animal models show that GSH depletion by itself is not sufficient to induce nigral degeneration. Low NO concentrations have neurotrophic effects on DA cells via a cGMP-independent mechanism that may implicate up-regulation of GSH. On the other hand, higher levels of NO induce cell death in both DA neurons and mature oligodendrocytes that is totally reverted by soluble factors released from glia. Alterations in GSH levels change the neurotrophic effects of NO in dopamine function into neurotoxic, under these conditions, NO triggers a programmed cell death with markers of both apoptosis and necrosis characterised by an early production of free radicals followed by late activation of the sGC/cGMP/PKG pathway. Arachidonic acid metabolism through the 12-lipoxygenase (12-LOX) pathway is also central for this GSH-NO interaction. Neurotrophism of NO switches into neurotoxicity after GSH depletion, due to persistent activation of the ERK-1/2 signaling pathway in glial cells. The implication of these cell death signaling pathways in pathological conditions like Parkinsons disease, where GSH depletion, glial dysfunction and NO overproduction have been documented, are discussed.

Keywords: nitric oxide, dopamine neurons, tyrosine hydroxylase, neurotrophism, cell death, glutathione, ascorbic acid, cu/znsuperoxide dismutase, catalase, superoxide scavengers

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Article Details

VOLUME: 5
ISSUE: 3
Year: 2005
Page: [193 - 205]
Pages: 13
DOI: 10.2174/1568015054863846
Price: $58