Mitigation of peroxynitrite-mediated nitric oxide (NO) toxicity as a mechanism of induced adaptive NO resistance in the CNS.
During CNS injury and diseases, nitric oxide (NO) is released at a high flux rate leading to formation of peroxynitrite (ONOO(*)) and other reactive nitrogenous species, which nitrate tyrosines of proteins to form 3-nitrotyrosine (3NY), leading to cell death. Previously, we have found that motor neurons exposed to low levels of NO become resistant to subsequent cytotoxic NO challenge; an effect dubbed induced adaptive resistance (IAR). Here, we report IAR mitigates, not only cell death, but 3NY formation in response to cytotoxic NO. Addition of an NO scavenger before NO challenge duplicates IAR, implicating reactive nitrogenous species in cell death. Addition of uric acid (a peroxynitrite scavenger) before cytotoxic NO challenge, duplicates IAR, implicating peroxynitrite, with subsequent 3NY formation, in cell death, and abrogation of this pathway as a mechanism of IAR. IAR is dependent on the heme-metabolizing enzyme, heme oxygenase-1 (HO1), as indicated by the elimination of IAR by a specific HO1 inhibitor, and by the finding that neurons isolated from HO1 null mice have increased NO sensitivity with concomitant increased 3NY formation. This data indicate that IAR is an HO1-dependent mechanism that prevents peroxynitrite-mediated NO toxicity in motor neurons, thereby elucidating therapeutic targets for the mitigation of CNS disease and injury.
Bishop
Amy
A
Department of Biological Sciences, University of Alabama at Huntsville, Huntsville, Alabama 35899, USA. bishopa@uah.edu
Gooch
Renea
R
Eguchi
Asuka
A
Jeffrey
Stephanie
S
Smallwood
Lorraine
L
Anderson
James
J
Estevez
Alvaro G
AG
D000222:Adaptation, Physiological / Q000187:drug effects / Q000502:physiology*; D000818:Animals; D016923:Cell Death / Q000187:drug effects / Q000502:physiology; D002478:Cells, Cultured; D002490:Central Nervous System / Q000187:drug effects / Q000378:metabolism / Q000473:pathology*; D002493:Central Nervous System Diseases / Q000139:chemically induced / Q000378:metabolism / Q000473:pathology; D005260:Female; D051379:Mice; D008807:Mice, Inbred BALB C; D018345:Mice, Knockout; D009046:Motor Neurons / Q000187:drug effects / Q000378:metabolism / Q000473:pathology; D009569:Nitric Oxide / Q000037:antagonists & inhibitors* / Q000378:metabolism / Q000633:toxicity*; D030421:Peroxynitrous Acid / Q000378:metabolism*; D011247:Pregnancy; D026361:Reactive Nitrogen Species / Q000378:metabolism
D026361:Reactive Nitrogen Species; D030421:Peroxynitrous Acid; D009569:Nitric Oxide