본문 바로가기
KERD
논문KCI 등재

The Neuroprotective Effects of 6-cyano-7-nitroquinoxalin -2,3-dione (CNQX) Via Mediation of Nitric Oxide synthase on Hypoxic-ischemic Brain Injury in Neonatal Rats

정지은|Eun Jin Choi|김진경|김우택|정혜리|Kyung Hae Keum
대한신생아학회 (THE KOREAN SOCIETY OF NEONATOLOGY)|2011.05|Neonatal medicine|제18권 제1호|pp. 59-69

1

조회

0

다운로드

0

인용

0

참고문헌

키워드

Nitric oxide synthaseNeuroprotectionCerebral ischemiaCNQX

초록

Purpose: Current studies have demonstrated the neuroprotective effects of 6-cyano-7-nitroquinoxalin-2,3-dione (CNQX) in many animal models of brain injury, including hypoxic-ischemic (HI) encephlopathy, trauma and excitotoxicity, but limited data are available for those during the neonatal periods. Here we investigated whether CNQX can protect the developing rat brain from HI injury via mediation of nitric oxide synthase. Methods: In an in vivo model, left carotid artery ligation was done in 7-day-old Sprague-Dawley (SD) rat pups. The animals were divided into six groups; normoxia (N), hypoxia (H), hypoxia with sham-operation (HS), hypoxia with operation (HO), HO treated with vehicle (HV), and HO treated with CNQX at a dose of 10 mg/kg (HC). Hypoxia was made by exposure to a 2 hr period in the hypoxic chamber (92% N_2, 8% O_2). In an in vitro model, embryonic cortical neuronal cell culture of SD rats at 18-day gestation was done. The cultured cells were divided into three groups: normoxia (N), hypoxia (H), and hypoxia treated with CNQX (HC). The N group was prepared in 5% CO_2 incubators and the other groups were placed in 1% O_2 incubators (94% N2, 5% CO_2) for 16 hr. Results: In the in vitvo and in vivo models, the expressions of iNOS and eNOS were reduced in the hypoxia group when compared to the normoxia group, whereas they were increased in the CNQX-treated group compared to the hypoxia group. In contrast, the expression of nNOS was showed reversely. Conclusion: CNQX has neuroprotective property over perinatal HI brain injury via mediation of nitric oxide synthase.

Abstract

Purpose: Current studies have demonstrated the neuroprotective effects of 6-cyano-7-nitroquinoxalin-2,3-dione (CNQX) in many animal models of brain injury, including hypoxic-ischemic (HI) encephlopathy, trauma and excitotoxicity, but limited data are available for those during the neonatal periods. Here we investigated whether CNQX can protect the developing rat brain from HI injury via mediation of nitric oxide synthase. Methods: In an in vivo model, left carotid artery ligation was done in 7-day-old Sprague-Dawley (SD) rat pups. The animals were divided into six groups; normoxia (N), hypoxia (H), hypoxia with sham-operation (HS), hypoxia with operation (HO), HO treated with vehicle (HV), and HO treated with CNQX at a dose of 10 mg/kg (HC). Hypoxia was made by exposure to a 2 hr period in the hypoxic chamber (92% N_2, 8% O_2). In an in vitro model, embryonic cortical neuronal cell culture of SD rats at 18-day gestation was done. The cultured cells were divided into three groups: normoxia (N), hypoxia (H), and hypoxia treated with CNQX (HC). The N group was prepared in 5% CO_2 incubators and the other groups were placed in 1% O_2 incubators (94% N2, 5% CO_2) for 16 hr. Results: In the in vitvo and in vivo models, the expressions of iNOS and eNOS were reduced in the hypoxia group when compared to the normoxia group, whereas they were increased in the CNQX-treated group compared to the hypoxia group. In contrast, the expression of nNOS was showed reversely. Conclusion: CNQX has neuroprotective property over perinatal HI brain injury via mediation of nitric oxide synthase.

참고문헌 (40)

  1. Vannucci RC, "Interventions for perinatal hypoxicischemic encephalopathy", Pediatrics, 100, pp.1004~1014 (1997)
  2. Monaghan DT, "The excitatory amino acid receptors: their classes, pharmacology, and distinct properties in the function of the central nervous system", Annu Rev Pharmacol Toxicol, 29, pp.365~402 (1989)
  3. Varju P, "Schedule of NMDA receptor subunit expression and functional channel formation in the course of in vitro-induced neurogenesis", J Neurochem, 77, pp.1444~1456 (2001)
  4. Dingledine R, "The glutamate receptor ion channels", Pharmacol Rev, 51, pp.7~61 (1999)
  5. Nikam SS, "AMPA receptor antagonists", Curr Med Chem, 8, pp.155~170 (2001)
  6. Alabadí JA, "7- Nitroindazole, a selective inhibitor of nNOS, increases hippocampal extracellular glutamate concentration in status epilepticus induced by kainic acid in rats", Brain Res, 839, pp.305~312 (1999)
  7. Moncada S, "Biosynthesis of nitric oxide from L-arginine. A pathway for the regulation of cell function and communication", Biochem Pharmacol, 38, pp.1709~1715 (1989)
  8. Heales SJ, "Nitric oxide, mitochondria and neurological disease", Biochim Biophys Acta, 1410, pp.215~228 (1999)
  9. Sengpiel B, "NMDA-induced superoxide production and neurotoxicity in cultured rat hippocampal neurons: role of mitochondria", Eur J Neurosci, 10, pp.1903~1910 (1998)
  10. Patel M, "Age dependence of seizure-induced oxidative stress", Neuroscience, 118, pp.431~437 (2003)
  11. Gunasekar PG, "NMDA receptor activation produces concurrent generation of nitric oxide and reactive oxygen species: implication for cell death", J Neurochem, 65, pp.2016~2021 (1995)
  12. Iwasaki Y, "CNQX prevents spinal motor neuron death following sciatic nerve transection in newborn rats", J Neurol Sci, 134, pp.21~25 (1995)
  13. Zhou Y, "An AMPA glutamatergic receptor activation-nitric oxide synthesis step signals transsynaptic apoptosis in limbic cortex", Neuropharmacology, 51, pp.67~76 (2006)
  14. Radenovic L, "Differential effects of NMDA and AMPA", kainate receptor antagonists on nitric oxide production in rat brain following intrahippocampal injection, 2005, pp.67, 133~141
  15. Levine S, "Anoxic-ischemic encephalopathy in rats", Am J Pathol, 36, pp.1~17 (1960)
  16. Brewer GJ, "Isolation and culture of adult rat hippocampal neurons", J Neurosci Methods, 71, pp.143~155 (1997)
  17. Calvert JW, "Pathophysiology of an hypoxic-ischemic insult during the perinatal period", Neurol Res, 27, pp.246~260 (2005)
  18. Delivoria-Papadopoulos M, "Mechanisms of cerebral injury in perinatal asphyxia and strategies for prevention", J Pediatr, 132, pp.30~34 (1998)
  19. Gunn AJ, "The ‘pharmacology’ of neuronal rescue with cerebral hypothermia", Early Hum Dev, 53, pp.19~35 (1998)
  20. Matute C, "Glutamate receptor-mediated toxicity in optic nerve oligodendrocytes", Proc Natl Acad Sci U S A, 94, pp.8830~8835 (1997)
  21. Dirnagl U, "Pathobiology of ischaemic stroke: an integrated view", Trends Neurosci, 22, pp.391~397 (1999)
  22. Komuro H, "Modulation of neuronal migration by NMDA receptors", Science, 260, pp.95~97 (1993)
  23. Kawasaki H, "Activation and involvement of p38 mitogenactivated protein kinase in glutamate-induced apoptosis in rat cerebellar granule cells", J Biol Chem, 272, pp.18518~18521 (1997)
  24. Ashwal S, "Animal models of neonatal stroke", Curr Opin Pediatr, 13, pp.506~516 (2001)
  25. Ignarro LJ, "Biosynthesis and metabolism of endothelium-derived nitric oxide", Annu Rev Pharmacol Toxicol, 30, pp.535~560 (1990)
  26. Bult H, "Nitric oxide as an inhibitory non-adrenergic non-cholinergic neurotransmitter", Nature, 345, pp.346~347 (1990)
  27. Garthwaite J, "NMDA receptor activation induces nitric oxide synthesis from arginine in rat brain slices", Eur J Pharmacol, 172, pp.413~416 (1989)
  28. Bredt DS, "Cloned and expressed nitric oxide synthase structurally resembles cytochrome P-450 reductase", Nature, 351, pp.714~718 (1991)
  29. Dienel GA, "Astrocytic contributions to bioenergetics of cerebral ischemia", Glia, 50, pp.362~388 (2005)
  30. Dawson TM, "Nitric oxide synthase and neuronal NADPH diaphorase are identical in brain and peripheral tissues", Proc Natl Acad Sci U S A, 88, pp.7797~7801 (1991)
  31. Lamas S, "Endothelial nitric oxide synthase: molecular cloning and characterization of a distinct constitutive enzyme isoform", Proc Natl Acad Sci U S A, 89, pp.6348~6352 (1992)
  32. Lowenstein CJ, "Nitric oxide: a physiologic messenger", Ann Intern Med, 120, pp.227~237 (1994)
  33. Galea E, "Cloning and expression of inducible nitric oxide synthase from rat astrocytes", J Neurosci Res, 37, pp.406~414 (1994)
  34. Samdani AF, "Nitric oxide synthase in models of focal ischemia", Stroke, 28, pp.1283~1288 (1997)
  35. Forman LJ, "Augmentation of nitric oxide, superoxide, and peroxynitrite production during cerebral ischemia and reperfusion in the rat", Neurochem Res, 23, pp.141~148 (1998)
  36. Iadecola C, "Delayed reduction of ischemic brain injury and neurological deficits in mice lacking the inducible nitric oxide synthase gene", J Neurosci, 17, pp.9157~9164 (1997)
  37. Stagliano NE, "The role of nitric oxide in the pathophysiology of thromboembolic stroke in the rat", Brain Res, 759, pp.32~40 (1997)
  38. Dimmeler S, "Phosphorylation of the endothelial nitric oxide synthase at Ser-1177 is required for VEGFinduced endothelial cell migration", FEBS Lett, 477, pp.258~262 (2000)
  39. Higuchi Y, "Increase in nitric oxide in the hypoxic-ischemic neonatal rat brain and suppression by 7-nitroindazole and aminoguanidine", Eur J Pharmacol, 342, pp.47~49 (1998)
  40. Tsuji M, "Protective effect of aminoguanidine on hypoxic-ischemic brain damage and temporal profile of brain nitric oxide in neonatal rat", Pediatr Res, 47, pp.79~83 (2000)

이 간행물의 다른 논문 (22건)

혈액응고 기전에 대한 고찰유철주pp. 1-5신생아 혈액 응고질환: 출혈 경향을 보이는 신생아에 대한 진단적 접근김천수pp. 6-13Disorders in Hemostasis성태정pp. 14-22신생아 혈전색전증김도현pp. 23-33신생아에서의 항응고요법, 혈전용해요법 및 혈액제제 사용최창원pp. 34-41
원문 보기