155 Combined Inhibition of Neuronal and Inducible Nos Provides Neuroprotection After Hypoxia-Ischaemia in P3 and P7 Rat Pups

Abstract

Background, aim: Nitric oxide (NO) contributes to neuronal damage following perinatal hypoxia-ischaemia (HI). We examined the neuroprotective effects of 2-iminobiotin (2-IB), a selective inhibitor of neuronal nitric oxide synthase (nNOS) and inducible nitric oxide synthae (iNOS), after HI in P3 and P7 rat pups as model of more immature developmental stages of the human brain.

Methods: P3 and P7 rat pups were subjected to occlusion of the right carotid artery followed by 60 (P3) or 120 min (P7) of hypoxia (FiO2 0.08). Immediately after HI, and 12 and 24 h later, pups received s.c. 10 mg/kg 2-IB or vehicle. Heat-Shock Protein-70 (HSP70) was determined 48 h post-HI using Western blotting. Cytochrome c and nitrotyrosine were determined at 24 h post-HI. At 6 weeks post-HI neuronal damage of hippocampus and cortex was assessed using a 4-point histological scale, the maximal score of normal animals being 33.

Results: In both P3 and P7 rat pups, 2-IB reduced HSP70 production after HI by 50%. The increase in cytochrome c was also 50% reduced by 2-IB treatment (P<0.05). No changes in nitrotyrosine levels were observed in any group at 24h post-HI. Brain histology score of the ipsilateral hemisphere rose significantly from 27 ± 2 (P3, vehicle) to 29 ± 2 (P3, 2-IB) and from 5 ± 5 (P7, vehicle) to 13 ± 9 (P7, 2-IB).

Conclusion: selective inhibition of nNOS and iNOS post-HI provides both short-term (HSP70, cytochrome c) as well as long-term neuroprotection (histology) in both the P3 and the P7 rat without affecting nitrotyrosine levels.

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