Long-term neuroprotection with 2-iminobiotin, an inhibitor of neuronal and inducible nitric oxide synthase, after cerebral hypoxia-ischemia in neonatal rats.
The short- and long-term neuroprotective effects of 2-iminobiotin, a selective inhibitor of neuronal and inducible nitric oxide synthase, were studied in 12-day-old rats following hypoxia-ischemia. Hypoxia-ischemia was induced by occlusion of the right carotid artery followed by 90 minutes of hypoxia (FiO2 0.08). Immediately on reoxygenation, 12 and 24 hours later the rats were treated with vehicle or 2-iminobiotin at a dose of 5.5, 10, 30, or 60 mg/kg per day. Histologic analysis of brain damage was performed at 6 weeks after hypoxia-ischemia. To assess early changes of cerebral tissue, levels of HSP70, nitrotyrosine, and cytochrome c were determined 24 hours after reoxygenation. Significant neuroprotection was obtained using a dose of 30 mg/kg per day of 2-iminobiotin. Levels of HSP70 were increased in the ipsilateral hemisphere in both groups (P<0.05), but the increase was significantly (P<0.05) less in the rats receiving the optimal dose of 2-iminobiotin (30 mg/kg per day). Hypoxia-ischemia did not lead to increased levels of nitrotyrosine, nor did 2-iminobiotin influence levels of nitrotyrosine. In contrast, hypoxia-ischemia induced an increase in cytochrome c level that was prevented by 2-iminobiotin. In conclusion, 2-iminobiotin administered after hypoxia-ischemia provides long-term neuroprotection. This neuroprotection is obtained by mechanisms other than a reduction of nitrotyrosine formation in proteins.
van den Tweel
Evelyn R W
ER
Department of Neonatology, Wilhelmina Children's Hospital, University Medical Center Utrecht, Utrecht, The Netherlands.
van Bel
Frank
F
Kavelaars
Annemieke
A
Peeters-Scholte
Cacha M P C D
CM
Haumann
Johan
J
Nijboer
Cora H A
CH
Heijnen
Cobi J
CJ
Groenendaal
Floris
F
D000818:Animals; D000831:Animals, Newborn; D001710:Biotin / Q000008:administration & dosage* / Q000031:analogs & derivatives*; D001923:Brain Chemistry / Q000187:drug effects; D045304:Cytochromes c / Q000378:metabolism; D005260:Female; D018840:HSP70 Heat-Shock Proteins / Q000378:metabolism; D020925:Hypoxia-Ischemia, Brain / Q000188:drug therapy* / Q000378:metabolism* / Q000473:pathology; D008297:Male; D018696:Neuroprotective Agents / Q000008:administration & dosage*; D019001:Nitric Oxide Synthase / Q000037:antagonists & inhibitors / Q000378:metabolism; D052247:Nitric Oxide Synthase Type II; D010084:Oxidation-Reduction / Q000187:drug effects; D051381:Rats; D017208:Rats, Wistar; D014443:Tyrosine / Q000031:analogs & derivatives* / Q000378:metabolism
D018840:HSP70 Heat-Shock Proteins; D018696:Neuroprotective Agents; C002744:3-nitrotyrosine; D014443:Tyrosine; D001710:Biotin; D045304:Cytochromes c; D019001:Nitric Oxide Synthase; D052247:Nitric Oxide Synthase Type II; C496318:Nos2 protein, rat; C028072:2-iminobiotin