title: Lymphocyte cytochrome c oxidase, cyclic GMP and cholinergic muscarinic receptors as peripheral indicators of carbon monoxide neurotoxicity after acute and repeated exposure in the rat.
abstract: Changes in cerebral cytochrome oxidase (COX) activity, nitric oxide (NO)-cyclic GMP (cGMP) pathway and cholinergic muscarinic receptors (MRs) have been reported in rodents acutely exposed to carbon monoxide (CO). These endpoints measurable in lymphocytes may serve as peripheral markers of CO neurotoxicity. The early and delayed effects of repeated and acute in vivo CO inhalation were investigated on COX activity, cGMP formation and MR binding in rat brain and lymphocytes to assess whether each endpoint was similarly affected both centrally and peripherally. Male Wistar rats either inhaled 500 ppm CO, 6 h/day, 5 days/week, 4 weeks (repeated exposure) or 2,400 ppm, 1 h (single exposure). Neither treatment altered brain or lymphocyte COX activity 1 and 7 days post-treatment. Also ineffective were repeated and acute CO treatments towards (3)H-quinuclidinyl benzilate (QNB) binding to MRs in cerebral cortex, hippocampus, striatum, cerebellum (respective controls, mean+/-S.D.: 171 +/- 45, 245 +/- 53, 263 +/- 14 and 77 +/- 7 fmol/mg protein) and lymphocytes (24 +/- 10 fmol/million cells) at the same time points. In lymphocytes control cGMP levels averaged 1.98 +/- 0.99 pmol/mg protein under basal conditions, and 3.94 +/- 0.55 pmol/mg protein after NO-stimulation. One day after chronic treatment cessation, the CO-treated group displayed about a 50% decrease in both basal and NO-stimulated cGMP values, which persisted up to 7 days after, compared to air-exposed rats. Acutely, CO caused a delayed enhancement (+140%) of NO-induced activation of soluble guanylate cyclase. The finding that the NO-cGMP pathway is a target for the delayed effects of CO in peripheral blood cells is in accordance with our data in brain [Hernández-Viadel, M., Castoldi, A.F., Coccini, T., Manzo, L., Erceg, S., Felipo, V., 2004. In vivo exposure to carbon monoxide causes delayed impairment of activation of soluble guanylate cyclase by nitric oxide in rat brain cortex and cerebellum. Journal of Neurochemistry 89, 1,157-1,165], and supports the use of this peripheral endpoint as a biomarker of CO central effects.
authors.affiliation: Toxicology Division, IRCCS Salvatore Maugeri Foundation, Institute of Pavia, Via Ferrata 8, 27100 Pavia, Italy. acastoldi@fsm.it
authors.forename: Anna F
authors.initials: AF
authors.lastname: Castoldi
authors.forename: Teresa
authors.initials: T
authors.lastname: Coccini
authors.forename: Giovanna
authors.initials: G
authors.lastname: Randine
authors.forename: Mariluz
authors.initials: M
authors.lastname: Hernández-Viadel
authors.forename: Vicente
authors.initials: V
authors.lastname: Felipo
authors.forename: Luigi
authors.initials: L
authors.lastname: Manzo
mesh_terms: D000818:Animals; D015415:Biomarkers / Q000097:blood; D001921:Brain / Q000187:drug effects* / Q000378:metabolism; D002248:Carbon Monoxide / Q000633:toxicity*; D002249:Carbon Monoxide Poisoning / Q000097:blood*; D006152:Cyclic GMP / Q000378:metabolism*; D004305:Dose-Response Relationship, Drug; D003576:Electron Transport Complex IV / Q000378:metabolism*; D006162:Guanylate Cyclase / Q000097:blood; D019570:Inhalation Exposure; D008214:Lymphocytes / Q000201:enzymology*; D008297:Male; D009474:Neurons / Q000187:drug effects / Q000473:pathology; D051381:Rats; D017208:Rats, Wistar; D011976:Receptors, Muscarinic / Q000378:metabolism*
chemical_list: D015415:Biomarkers; D011976:Receptors, Muscarinic; D002248:Carbon Monoxide; D003576:Electron Transport Complex IV; D006162:Guanylate Cyclase; D006152:Cyclic GMP