Effects of selective nitric oxide synthase inhibition on IGF-1, caspases and cytokines in a newborn piglet model of perinatal hypoxia-ischaemia.
Selective inhibition of neuronal and inducible nitric oxide synthase (NOS) with 2-iminobiotin previously showed a reduction in brain cell injury. In the present study, we investigated the effects of 2-iminobiotin treatment on insulin-like growth factor-1 (IGF-1) expression, caspase activity and cytokine expression in a newborn piglet model of perinatal hypoxia-ischaemia. Newborn piglets were subjected to 1 h of hypoxia-ischaemia and were treated intravenously with vehicle or 2-iminobiotin. Vehicle-treated piglets showed reduced IGF-1 mRNA expression and increased caspase-3 activity and DNA fragmentation. 2-Iminobiotin treatment, administered immediately upon reperfusion, prevented these observations. No differences in caspase-8 and -9 activity and cytokine [interleukin (IL)-1alpha/beta, IL-6, tumour necrosis factor (TNF)-alpha, transforming growth factor (TGF)-beta] mRNA expression were demonstrated between vehicle- and 2-iminobiotin-treated piglets at 24 h following hypoxia-ischaemia. IGF-1 mRNA correlated inversely with caspase-3 and transferase-mediated dUTP-biotin in situ nick end labelling score in the cortex, but positively with caspase-8. Cytokine mRNA did not correlate with IGF-1 mRNA, caspase-3 activity or DNA fragmentation. The present results indicate that the previously demonstrated neuroprotective effect of 2-iminobiotin treatment after perinatal hypoxia-ischaemia coincided with a preservation of the endogenous IGF-1 production and reduced caspase-3 activity, but not with a significant decrease in cytokine production.
Peeters-Scholte
Cacha
C
Department of Neonatology, Wilhelmina Children's Hospital, University Medical Center Utrecht, Utrecht, The Netherlands.
Koster
Johanna
J
van den Tweel
Evelyn
E
Blomgren
Klas
K
Hamers
Nicole
N
Zhu
Changlian
C
van Buul-Offers
Sylvia
S
Hagberg
Henrik
H
van Bel
Frank
F
Heijnen
Cobi
C
Groenendaal
Floris
F
D000818:Animals; D000831:Animals, Newborn; D001710:Biotin / Q000031:analogs & derivatives* / Q000494:pharmacology*; D001921:Brain / Q000187:drug effects* / Q000378:metabolism / Q000473:pathology; D020169:Caspases / Q000378:metabolism; D016207:Cytokines / Q000378:metabolism; D053938:DNA Fragmentation / Q000187:drug effects; D004789:Enzyme Activation / Q000187:drug effects; D004791:Enzyme Inhibitors / Q000494:pharmacology*; D020925:Hypoxia-Ischemia, Brain / Q000378:metabolism*; D020287:In Situ Nick-End Labeling; D007334:Insulin-Like Growth Factor I / Q000096:biosynthesis; D023421:Models, Animal; D019001:Nitric Oxide Synthase / Q000037:antagonists & inhibitors; D052248:Nitric Oxide Synthase Type I; D052247:Nitric Oxide Synthase Type II; D020401:Primed In Situ Labeling; D012333:RNA, Messenger / Q000032:analysis; D013552:Swine
D016207:Cytokines; D004791:Enzyme Inhibitors; D012333:RNA, Messenger; D007334:Insulin-Like Growth Factor I; D001710:Biotin; D019001:Nitric Oxide Synthase; D052248:Nitric Oxide Synthase Type I; D052247:Nitric Oxide Synthase Type II; D020169:Caspases; C028072:2-iminobiotin