1400W blocks death pathway of LPS-induced activated-microglia to preOLs
HE Ya-Fang, CHEN Hui-Jin, QIAN Long-Hua, CHEN Guan-Yi
Shanghai Institute for Pediatric Research, Xinhua Hospital Affiliated to Shanghai Jiao Tong University School of Medicine, Shanghai 200092, China. Email: hjchenk@online.sh.cn
Abstract OBJECTIVE: To explore the efficacy of inductible nitric oxide synthase (iNOS) inhibitor 1400W in vivo in blocking the death pathway of lipopolysaccharide (LPS)-induced activated-microglia to preoligodendrocytes (preOLs) in neonatal rats with infective-type periventricular leukomalacia (PVL) induced by LPS. METHODS: Two-day-old neonatal rats were randomly divided into: a sham-operated group, an untreated PVL group, and four 1400W-treated PVL groups that were subcutaneously administrated with 20 mg/kg of 1400W at 0 h, 8 hrs, 16 hrs, and 24 hrs after LPS induction, respectively. The brain specimens were obtained 5 days after LPS induction. The pathological assessment of cerebral white matter was performed under a light microscope. Concentrations of nitric oxide (NO) were measured by nitric acid-deoxidize colorimetry. Synthesis of iNOS was determined by Western blot analysis. Peroxynitrite (ONOO) level and the amount of preOLs were determined by immunocytochemistry. RETHODS: The obvious injuries of periventricular white matter, massive loss of positive O4-labelled preOLs, and increased levels of NO, ONOO and iNOS were observed in neonatal rats with PVL. Compared to the untreated PVL group, the use of 1400W at 0 h, 8 hrs and 16 hrs after LPS induction significantly improved white matter injuries, reduced the levels of NO, ONOO and iNOS, and increased the amount of O4-labelled preOLs. However, the use of 1400W at 24 hrs after LPS induction did not result in the improvements. CONCLUSIONS: iNOS inhibitor 1400W can effectively block the toxicity of LPS-activated microglia to preOLs and protect cerebral white matter through inhibiting iNOS and reducing the production of NO and ONOO. The use of 1400W within 16 hrs after LPS induction may provide cerebral protections in neonatal rats with PVL.［Chin J Contemp Pediatr, 2010, 12(5):357-362］
HE Ya-Fang,CHEN Hui-Jin,QIAN Long-Hua et al. 1400W blocks death pathway of LPS-induced activated-microglia to preOLs[J]. 中国当代儿科杂志, 2010, 12(05): 357-362.
HE Ya-Fang,CHEN Hui-Jin,QIAN Long-Hua et al. 1400W blocks death pathway of LPS-induced activated-microglia to preOLs[J]. CJCP, 2010, 12(05): 357-362.
［1］Back SA, Riddle A, McClure MM. Maturation-dependent vulnerability of perinatal white matter in premature birth ［J］. Stroke, 2007, 38(2):724-730.
［2］Czapski GA, Cakala M, Chalimoniu K, Gajkowska B, Strosznajder JB. Role of nitric oxide in the brain during lipopolysaccharide-evoked systemic inflammation［J］. J Neurosci Res, 2007, 85(8):1694-1703.
［5］Pang Y, Cai Z, Rhodes PG. Disturbance of oligodendrocyte development, hypomyelination and white matter injury in the neonatal rat brain after intracerebral injection of lipopolysaccharide ［J］. Brain Res Dev Brain Res B, 2003, 140(2):205-214.
［6］Uehara H, Yoshioka H, Naqai H, Ochiai R, Naito T, Hasegawa K, Sawada T . Doxapram accentuates white matter injury in neonatal rats following bilateral carotid artery occlusion ［J］. Neurosci Lett, 2000, 281(2-3): 191-194.
［7］Wilkinson BL, Landreth GE. The microglial NADPH oxidase complex as a source of oxidative stress in Alzheimer's disease［J］. J Neuroinflammation, 2006, 3:30.
［8］Mander P, Brown GC. Activation of microglial NADPH oxidase is synergistic with glial iNOS expression in inducing neuronal death: a dual-key mechanism of inflammatory neurodegeneration ［J］. J Neuroinflammation, 2005, 2:20.
［9］Li J, Baud O, Vartanian T, Volpe JJ, Rosenberg PA. Peroxynitrite generated by inducible nitric oxide synthase and NADPH oxidase mediates microglial toxicity to oligodendrocytes ［J］. Proc Nat Ncad Sci USA, 2005, 102(28): 9936-9941.
［10］Jafarian-Tehrani M, Louin G, Royo NC, Besson VC, Bohme GA, Plotkine M, et al. 1400W, a potent selective inducible NOS inhibitor, improves histopathological outcome following traumatic brain injury in rats［J］. Nitric Oxide, 2005, 12(2):61-69.
［11］Iadecola C, Zhang F, Casey R, Nagayama M, Ross M. Delayed reduction of ischemic brain injury and neurological deficits in mice lacking the inducible nitric oxide synthase gene［J］. J Neurosci, 1997, 17(23):9157-9164.
［12］Gahm C, Holmin S, Mathiesen T. Nitric oxide synthase expression after human brain contusion［J］. Neurosurgery, 2002, 50(6):1319-1326.
［13］Lu J, Moochhala S, Shirhan M, Ng KC, Teo AL, Tan MH, et al. Neuroprotection by aminoguanidine after lateral fluid-percussive brain injury in rats: a combined magnetic resonance imaging, histopathologic and functional study［J］. Neuropharmacology, 2003,44(2):253-263.
［14］Garvey EP, Oplinger JA, Furfine ES, Kiff RJ, Laszlo F, Whittle BJ, et al. 1400W is a slow, tight binding, and highly selective inhibitor of inducible nitric-oxide synthase in vitro and in vivo［J］. J Biol Chem, 1997, 272(8):4959-4963.
［15］Lehnardt S, Lachance C, Patrizi S, Lefebvre S, Follett PL, Jensen FE, et al. The toll-like receptor TLR4 is necessary for lipopolysaccharideinduced oligodendrocyte injury in the CNS［J］. J Neurosci, 2002, 22(7): 2478-2486.
［16］Grammatikopoulos G, Pignatelli M, D′Amico F, Fiorillo C, Fresiello A, Sadile AG. Selective inhibition of neuronal nitric oxide synthesis reduces hyperactivity and increases non-selective attention in the Naples High-Excitability rat［J］. Behav Brain Res,2002, 130(1-2):127-132.
［17］Jack C, Antel J, Bruck W, Kuhlmann T. Contrasting Potential of nitric oxide and peroxynitrite to mediate oligodendrocyte injury in multiple sclerosis ［J］. Glia, 2007, 55(9):926-934.
