Central Nervous System Agents in Medicinal Chemistry

(Formerly Current Medicinal Chemistry - Central Nervous System Agents)

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Induced Adaptive Resistance to Nitrooxidative Stress in the CNS: Therapeutic Implications

Author(s): Amy Bishop, Renea Gooch, James Anderson.

Abstract:

NO is a free radical that is normally released and utilized by the CNS for a variety of normal physiological functions such as neurotransmission and differentiation. However, if NO released in inappropriate locations, in excess or at a high flux rate, it is toxic. In the CNS, after injury or during disease, NO is released by astrocytes, activated microglia, or macrophages that have migrated across the blood-brain barrier, and is concomitant with massive cell death. Nitrotyrosine formation, a marker for NO-mediated damage, is seen in CNS injury and in many neurodegenerative diseases such as Alzheimers, ALS, multiple sclerosis and spinal injury. In our lab we have found that motor neurons pretreated with sub-toxic doses of NO gain resistance to normally toxic doses of NO. This phenomenon, induced adaptive resistance (IAR), is demonstrated by a significant decrease in the percentage of apoptotic cells in response to a toxic dose of NO. IAR is dependent on the heme-metabolizing enzyme, heme oxygenase-1 (HO1), as indicated by 1) an increase in HO1 expression, 2) loss of resistance in CNS cells incubated with HO1 inhibitors, and 3) lack of native NO resistance in cells isolated from spinal cords of HO1-null mice. The overall aim of this review is to elucidate and dissect the IAR phenomenon and the HO1 signal transduction axis on which it depends, and by so doing, begin to understand native resistance mechanisms in the CNS that can be manipulated to protect neurons against NO-mediated damage seen in CNS injury and neurodegenerative disease.

Keywords: Oxidative stress, motor neuron(s), induced adaptive resistance, nitric oxide, heme oxygenase, carbon monoxide, neural protection, cell death

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Article Details

VOLUME: 6
ISSUE: 4
Year: 2006
Page: [281 - 291]
Pages: 11
DOI: 10.2174/187152406779010895
Price: $58