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NEUROPHARMACOLOGY

NAP Enhances Neurodevelopment of Newborn Apolipoprotein E-Deficient Mice Subjected to Hypoxia

The Institute for Child Development and the Pediatric Neurology Unit, Tel Aviv Sourasky Medical Center, Tel Aviv, Israel (M.R., H.B., S.H.); and the Lily and Avraham Gildor Chair for the Investigation of Growth Factors, the Dr. Diana and Zelman Elton (Elbaum) Laboratory for Molecular Neuroendocrinology, Department of Human Molecular Genetics and Biochemistry (I.G.), the David Glasberg Tower for Medical Research (N.K.), Department of Physiology and Pharmacology (Z.S.), Sackler Faculty of Medicine, Tel Aviv University, Tel Aviv, Israel

Perinatal hypoxic injury is associated with significant neonatal morbidity and long-term neurodevelopmental complications. NAP, a peptide derived from ADNP (activity-dependent neuroprotective protein), has previously shown neuroprotective abilities in various adult animal models. To evaluate its neuroprotective role in neonatal hypoxic-ischemic injury, we evaluated the neurodevelopmental outcome in apolipoprotein E (ApoE)-deficient (knockout) mice (a breed prone to brain damage during hypoxic insult) exposed to postnatal global hypoxic damage with and without treatment with NAP. ApoE-deficient (n = 80) and control (C57B6) mice pups (n = 81) were exposed to postnatal global hypoxia (35 min of 8% O₂ within 24 h of birth) or room air with or without subsequent subcutaneous NAP treatment during postnatal days 1 to 14. Pups were then evaluated for neonatal motor reflex attainment, spatial learning ability in the Morris water maze, and locomotor open-field activity. The C57B6 and ApoE-deficient anoxic groups showed significantly slower achievement of neonatal reflexes, diminished locomotor activity, and diminished spatial learning ability compared with their control groups. This was more pronounced in the anoxic ApoE-deficient pups. NAP treatment had a pronounced effect on neurodevelopmental outcome in both breeds, particularly in the ApoE-deficient mice. ApoE-deficient and control mouse pups exposed to postnatal hypoxia and treated with NAP showed improvement in neurodevelopmental outcome compared with nontreated mice pups. ApoE-deficient mice show a greater susceptibility to hypoxic damage and better response to NAP treatment.

Address correspondence to: Dr. IIlana Gozes, Professor of Clinical Biochemistry, The Lily and Avraham Gildor Chair for the Investigation of Growth Factors Head, the Dr. Diana and Zelman Elton (Elbaum), Laboratory for Molecular Neuroendocrinology Sackler Faculty of Medicine, Tel Aviv University, Tel Aviv 69978, Israel. e-mail: igozes{at}post.tau.ac.il.