Current Medicinal Chemistry - Central Nervous System Agents

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Oxidative/Nitrosative Brain Damage in Stress: Possible Target for Neuropsychopharmacological Drugs

Author(s): Jose L.M. Madrigal, Borja Garcia-Bueno, Antonio Cardenas, Ignacio Lizasoain, Maria A Moro, Pedro Lorenzo, Juan C. Leza.

Abstract:

It has been reported that the mechanisms more directly implicated in the development and maintenance of stress-induced brain pathology in animals and humans are the high and persistent levels of glucocorticoids and excitatory amino acids. Recent findings indicate a key role for nitric oxide (NO) and the excess of pro-oxidants in various brain structures as responsible of both neuronal functional impairment (decrease in glutamate uptake, mitochondrial damage) and structural damage. Similarly, other known source of oxidants, cyclooxygenase-2 (COX-2) accounts for stress-induced brain damage. The stress-induced activation of both biochemical pathways depends on the activation of the NMDA subtype of glutamate receptor and on the activation of the transcription factor nuclear factor κB (NFκB). In the case of iNOS, the release of the cytokine TNFα also accounts for its activity. Different pharmacological strategies acting at different sites in iNOS or COX-2 pathways have been shown to be neuroprotective in stress-induced brain damage: NMDA receptor blockers, inhibitors of TNFα activation and release, inhibitors of NFκB activity, and specific inhibitors of iNOS and COX-2 activities. This article reviews the main contributions addressing a possible new pharmacological target for stress-induced neuropsychiatric disorders.

Keywords: cyclooxygenase, neuroinflammation, neurodegeneration, neuroprotection nitric oxide, stress

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Article Details

VOLUME: 4
ISSUE: 4
Year: 2004
Page: [235 - 242]
Pages: 8
DOI: 10.2174/1568015043356850
Price: $58