Gender-specific neuroprotection by 2-iminobiotin after hypoxia-ischemia in the neonatal rat via a nitric oxide independent pathway.
We have shown earlier that 2-iminobiotin (2-IB) reduces hypoxia-ischemia (HI)-induced brain damage in neonatal rats, and presumed that inhibition of nitric oxide synthases (NOS) was the underlying mechanism. We now investigated the effect of 2-IB treatment in P7 rat pups to determine the role of gender and the neuroprotective mechanism. Pups were subjected to HI (occlusion of right carotid artery and 120 mins FiO(2) 0.08) and received subcutaneous (s.c.) 10 mg/kg 2-IB at 0, 12 and 24 h after hypoxia. After 6 weeks, neuronal damage was assessed histologically. We determined cerebral nitrite and nitrate (NO(x)) and nitrotyrosine, heat-shock protein 70, cytosolic cytochrome c, cleaved caspase 3, nuclear translocation of apoptosis-inducing factor (AIF) and the effect of 2-IB on NOS activity in cultured cells. 2-Iminobiotin treatment reduced long-term brain damage in female but not male rats. Unexpectedly, 2-IB treatment did not reduce cerebral NO(x) or nitrotyrosine levels, and did not inhibit NOS activity in vitro. The gender-dependent neuroprotective effect of 2-IB was reflected in inhibition of the HI-induced increase in cytosolic cytochrome c and cleaved caspase 3 in females only. Hypoxia-ischemia-induced activation of AIF was observed in males only and was not affected by 2-IB. Post-HI treatment with 2-IB provides gender-specific long- and short-term neuroprotection in female P7 rats via inhibition of the cytochrome c-caspase 3 neuronal death pathway. 2-Iminobiotin did not alter cerebral NO(x) nor inhibited NOS in intact cells. Therefore, we conclude that it is highly unlikely that the neuroprotective effect of 2-IB involves NOS inhibition.
Nijboer
Cora H A
CH
Laboratory for Psychoneuroimmunology, University Medical Center Utrecht, Utrecht, The Netherlands.
Groenendaal
Floris
F
Kavelaars
Annemieke
A
Hagberg
Henrik H
HH
van Bel
Frank
F
Heijnen
Cobi J
CJ
D000818:Animals; D000831:Animals, Newborn / Q000502:physiology*; D001710:Biotin / Q000031:analogs & derivatives* / Q000494:pharmacology; D015153:Blotting, Western; D020169:Caspases / Q000378:metabolism; D004791:Enzyme Inhibitors / Q000494:pharmacology; D005260:Female; D006146:Guanidines / Q000494:pharmacology; D018840:HSP70 Heat-Shock Proteins / Q000378:metabolism; D020925:Hypoxia-Ischemia, Brain / Q000188:drug therapy* / Q000401:mortality / Q000473:pathology; D018696:Neuroprotective Agents; D009569:Nitric Oxide / Q000502:physiology*; D052248:Nitric Oxide Synthase Type I / Q000037:antagonists & inhibitors / Q000378:metabolism; D052247:Nitric Oxide Synthase Type II / Q000037:antagonists & inhibitors / Q000378:metabolism; D011247:Pregnancy; D051381:Rats; D017208:Rats, Wistar; D012727:Sex Characteristics; D015398:Signal Transduction / Q000187:drug effects*; D014443:Tyrosine / Q000031:analogs & derivatives / Q000494:pharmacology; D019323:omega-N-Methylarginine / Q000494:pharmacology
D004791:Enzyme Inhibitors; D006146:Guanidines; D018840:HSP70 Heat-Shock Proteins; D018696:Neuroprotective Agents; D019323:omega-N-Methylarginine; D009569:Nitric Oxide; C002744:3-nitrotyrosine; D014443:Tyrosine; D001710:Biotin; D052248:Nitric Oxide Synthase Type I; D052247:Nitric Oxide Synthase Type II; D020169:Caspases; C028072:2-iminobiotin; C004479:pimagedine