title: Inhibition of nNOS and iNOS following hypoxia-ischaemia improves long-term outcome but does not influence the inflammatory response in the neonatal rat brain.
abstract: In this study, we tested the hypothesis that combined inhibition of nNOS and iNOS will reduce neuronal damage and the inflammatory response induced by perinatal hypoxia-ischaemia (HI). In 12-day-old rats, HI was induced by right carotid artery occlusion followed by 90 min of 8% O2. Immediately upon reoxygenation, the rats were treated with NOS inhibitors (n = 24) or placebo (n = 24). Neuropathology was scored at 6 weeks after HI on a 4-point scale (n = 12 per group). The expression of heat shock protein 70 (HSP70) and mRNA expression for cytokines were measured 12 h after HI (n = 12 per group). Histopathological analysis showed that the ipsilateral hemisphere in the NOS inhibition group was less damaged than in the placebo group (p < 0.05). HI induced a significant increase in HSP70 levels (p < 0.05) in the ipsilateral hemispheres, which tended to be lower in the NOS inhibition group (p = 0.07). HI induced an increase in mRNA expression for IL-1beta, TNF-alpha and TNF-beta, but there was no difference between the ipsi- and contralateral hemispheres. Combined inhibition of nNOS and iNOS did not induce any change in cytokine expression. We conclude that the long-term neuroprotective effects of combined nNOS and iNOS inhibition were not achieved by an altered cytokine response.
authors.affiliation: Department of Neonatology, Wilhelmina Children's Hospital, University Medical Center, Utrecht, The Netherlands.
authors.forename: Evelyn R W
authors.initials: ER
authors.lastname: van den Tweel
authors.forename: Cacha M P C D
authors.initials: CM
authors.lastname: Peeters-Scholte
authors.forename: Frank
authors.initials: F
authors.lastname: van Bel
authors.forename: Cobi J
authors.initials: CJ
authors.lastname: Heijnen
authors.forename: Floris
authors.initials: F
authors.lastname: Groenendaal
mesh_terms: D000818:Animals; D015153:Blotting, Western; D016207:Cytokines / Q000096:biosynthesis; D004791:Enzyme Inhibitors / Q000494:pharmacology*; D005260:Female; D007839:Functional Laterality; D006146:Guanidines / Q000494:pharmacology; D018840:HSP70 Heat-Shock Proteins / Q000096:biosynthesis; D020925:Hypoxia-Ischemia, Brain / Q000201:enzymology* / Q000503:physiopathology; D007191:Indazoles / Q000494:pharmacology*; D008297:Male; D018696:Neuroprotective Agents / Q000494:pharmacology; D019001:Nitric Oxide Synthase / Q000037:antagonists & inhibitors*; D052248:Nitric Oxide Synthase Type I; D052247:Nitric Oxide Synthase Type II; D012333:RNA, Messenger / Q000032:analysis; D051381:Rats; D017208:Rats, Wistar
chemical_list: D016207:Cytokines; D004791:Enzyme Inhibitors; D006146:Guanidines; D018840:HSP70 Heat-Shock Proteins; D007191:Indazoles; D018696:Neuroprotective Agents; D012333:RNA, Messenger; D019001:Nitric Oxide Synthase; D052248:Nitric Oxide Synthase Type I; D052247:Nitric Oxide Synthase Type II; C496322:Nos1 protein, rat; C496318:Nos2 protein, rat; C004479:pimagedine; C080122:7-nitroindazole