Plasticity of the central nervous system (CNS) following perinatal asphyxia: does nicotinamide provide neuroprotection?
We have investigated the idea that nicotinamide, a non-selective inhibitor of the sentinel enzyme Poly(ADP-ribose) polymerase-I (PARP-1), provides neuroprotection against the long-term neurological changes induced by perinatal asphyxia. Perinatal asphyxia was induced in vivo by immersing foetuses-containing uterine horns removed from ready-to-deliver rats into a water bath for 20 min. Sibling caesarean-delivered pups were used as controls. The effect of perinatal asphyxia on neurocircuitry development was studied in vitro with organotypic cultures from substantia nigra, neostriatum and neocortex, platted on a coverslip 3 days after birth. After approximately one month in vitro (DIV 25), the cultures were treated for immunocytochemistry to characterise neuronal phenotype with markers against the N-methyl-D-aspartate receptor subunit 1 (NR1), the dopamine pacemaker enzyme tyrosine hydroxylase (TH), and nitric oxide synthase (NOS), the enzyme regulating the bioavailability of NO. Nicotinamide (0.8 mmol/kg, i.p.) or saline was administered to asphyctic and caesarean-delivered pups 24, 48 and 72 h after birth. It was found that nicotinamide treatment prevented the effect of perinatal asphyxia on several neuronal parameters, including TH- and NOS-positive neurite atrophy and NOS-positive neuronal loss; supporting the idea that nicotinamide constitutes a therapeutic alternative for the effects produced by sustained energy-failure conditions, as occurring during perinatal asphyxia.
Klawitter
V
V
Programme of Molecular and Clinical Pharmacology, ICBM, Medical Faculty, University of Chile, Santiago, Chile.
Morales
P
P
Bustamante
D
D
Goiny
M
M
Herrera-Marschitz
M
M
D000818:Animals; D001238:Asphyxia Neonatorum / Q000188:drug therapy / Q000378:metabolism* / Q000473:pathology*; D001479:Basal Ganglia / Q000378:metabolism* / Q000473:pathology*; D004195:Disease Models, Animal; D005260:Female; D006801:Humans; D007231:Infant, Newborn; D019579:Neocortex / Q000378:metabolism / Q000473:pathology; D017072:Neostriatum / Q000378:metabolism / Q000473:pathology; D016501:Neurites / Q000473:pathology; D018696:Neuroprotective Agents / Q000008:administration & dosage / Q000494:pharmacology*; D009536:Niacinamide / Q000008:administration & dosage / Q000494:pharmacology*; D019001:Nitric Oxide Synthase / Q000378:metabolism; D009924:Organ Culture Techniques; D051381:Rats; D017208:Rats, Wistar; D016194:Receptors, N-Methyl-D-Aspartate / Q000378:metabolism; D013378:Substantia Nigra / Q000378:metabolism / Q000473:pathology; D014446:Tyrosine 3-Monooxygenase / Q000378:metabolism
C409466:NR1 NMDA receptor; D018696:Neuroprotective Agents; D016194:Receptors, N-Methyl-D-Aspartate; D009536:Niacinamide; D019001:Nitric Oxide Synthase; D014446:Tyrosine 3-Monooxygenase