cytochrome-c-t and 2-iminobiotin

Previously, we demonstrated neuroprotection with 2-iminobiotin (2-IB) after cerebral hypoxia-ischemia (HI) in female, but not in male P7 rats. Given the different patterns of brain injury in more immature rats, we examined whether these gender differences could also be observed in P3 rats. HI was induced by unilateral carotid ligation and FiO2 reduction, followed by 2-IB administration. HSP70 protein expression and cytochrome c release from the mitochondria, markers of short-term outcome, were induced by HI to the same extent in male and female animals. However, reduction in HSP70 production and cytochrome c release by 2-IB was seen in female rats only. Long-term cerebral injury after HI, assessed with histology, was similar in male and female P3 rats, but long-term neuroprotection by 2-IB was observed in female rats only. In conclusion, 2-IB provides neuroprotection after cerebral HI in female, but not in male immature P3 rats.

Topics: Aging; Animals; Animals, Newborn; Biotin; Birth Injuries; Brain; Cell Death; Cytochromes c; Cytoprotection; Disease Models, Animal; Female; HSP70 Heat-Shock Proteins; Hypoxia-Ischemia, Brain; Male; Mitochondria; Nerve Degeneration; Neuroprotective Agents; Oxidative Stress; Rats; Rats, Wistar; Sex Characteristics; Time; Treatment Outcome

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.

Topics: Animals; Animals, Newborn; Biotin; Brain Chemistry; Cytochromes c; Female; HSP70 Heat-Shock Proteins; Hypoxia-Ischemia, Brain; Male; Neuroprotective Agents; Nitric Oxide Synthase; Nitric Oxide Synthase Type II; Oxidation-Reduction; Rats; Rats, Wistar; Tyrosine