Nitric Oxide Production and Long-term Potentiation in the Rat Hippocampus Following Transient Cerebral Ischemia

Conference paper


The cerebral dysfunction such as deterioration of memory remains serious complications of ischemic reperfusion injury. Long-term potentiation (LTP) has been widely studied as a form of synaptic plasticity that represents a cellular mechanism of learning and memory. Numerous processes and molecules are reported to be involved in LTP mechanisms, and some elements including neurotrophic and transcription factors are likely to be common with those involved in neural death after cerebral ischemia. Nitric oxide (NO) is a molecule which has crucial roles in neuronal injury. In our study, we focused on LTP formation as a functional response to cerebral ischemia and elucidated the implication of NO production in LTP formation in the rat hippocampus following transient cerebral ischemia. NO production was evaluated by oxidative NO metabolite levels determined using in vivo brain microdialysis. Transient cerebral ischemia produced a marked inhibition of LTP in both Schaffer-CAl synapses and perforant path-dentategyrus synapses. The increase in hippocampal NO production was observed to precede LTP inhibition. Direct or indirect inhibition of an inducible NO synthase (iNOS) rescued ischemia-induced LTP inhibition. Centrally administered bacterial endotoxin, lipopolysaccharide, which is known to induce iNOS expression, could mimic the time-course changes in hippocampal NO production observed after ischemic insult. These findings suggest that iNOS-derived NO is partly responsible for the ischemia-induced impairment of LTP in the rat hippocampus.

Key Words

Cerebral ischemia Long-term potentiation Nitric oxide Hippocampus 


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  1. 1.
    Pulsinelli WA, Brierley JB (1979) A new model of bilateral hemispheric ischemia in the unanesthetized rat. Stroke 10: 267–272PubMedCrossRefGoogle Scholar
  2. 2.
    Kirino T, Sano K (1984) Fine structural nature of delayed neuronal death following ischemia in the gerbil hippocampus. Acta Neuropathol (Berl) 62: 209–218CrossRefGoogle Scholar
  3. 3.
    Astrup JA, Siesjö Bo K, Symon L (1981) Thresholds in cerebral ischemia — the ischemic penumbra. Stroke 12: 723–725PubMedCrossRefGoogle Scholar
  4. 4.
    Mori K, Yoshioka M, Suda N, Togashi H, Matsumoto M, Ueno K, Saito H (1998) An incomplete cerebral ischemia produced a delayed dysfunction in the rat hippocampal system. Brain Res: 795: 221–226PubMedCrossRefGoogle Scholar
  5. 5.
    Bliss TVP, Lømo T (1973) Long-lasting potentiation of synaptic transmission in the dentate area of the anesthetized rabbit following stimulation of the perforant path. J Physiol 232: 331–356PubMedGoogle Scholar
  6. 6.
    McEachern JC, Shaw CA (1996) An alternative to the LTP orthodoxy: a plasticity-pathology continuum model. Brain Res Rev 22: 51–92PubMedCrossRefGoogle Scholar
  7. 7.
    Nathan C, Xie QW (1994) Nitric oxide synthases: roles, tolls, and controls (review). Cell 78:915–918PubMedCrossRefGoogle Scholar
  8. 8.
    Iadecola C (1997) Bright and dark sides of nitric oxide in ischemic brain injury. TINS 20: 132–139PubMedGoogle Scholar
  9. 9.
    Tokuda M, Ahmed BY, Lu YF, Matsui H, Miyamoto O, Yamaguchi F, Konishi R, Hatase O (1997) Involvement of calmodulin-dependent protein kinases-I and-IV in long-term potentiation. Brain Res 755: 162–166PubMedCrossRefGoogle Scholar
  10. 10.
    Villacres EC, Wong ST, Chavkin C, Storm DR (1998) Type I adenylyl cyclase mutant mice have impaired mossy fiber long-term potentiation. J Neurosci 18:3186–3194PubMedGoogle Scholar
  11. 11.
    Klann E, Roberson ED, Knapp LT, Sweatt JD (1998) A role for superoxide in protein kinase C activation and induction of long-term potentiation. J Biol Chem 273: 4516–4522PubMedCrossRefGoogle Scholar
  12. 12.
    Kojima N, Wang J, Mansuy IM, Grant SG, Mayford M, Kandel ER (1997) Rescuing impairment of long-term potentiation in fyn-deficient mice by introducing Fyn transgene. Proc Natl Acad Sci USA 94: 4761–4765PubMedCrossRefGoogle Scholar
  13. 13.
    Massicotte G, Oliver MW, Lynch G, Baudry M (1990) Effects of bromophenacyl bromide, a phospholipase A2 inhibitor, on the induction and maintenance of LTP in hippocampal slices. Brain Res 537: 49–53PubMedCrossRefGoogle Scholar
  14. 14.
    Bramham CR, Alkon DL, Lester DS (1994) Arachidonic acid and diacylglycerol act synergistically through protein kinase C to persistently enhance synaptic transmission in the hippocampus. Neuroscience 60, 737–743PubMedCrossRefGoogle Scholar
  15. 15.
    Kato K, Clark GD, Bazan NG, Zorumski CF (1994) Platelet-activating factor as a potential retrograde messenger in CA1 hippocampal long-term potentiation. Nature 367: 175–179PubMedCrossRefGoogle Scholar
  16. 16.
    Namgung U, Matsuyama S, Routtenberg A (1997) Long-term potentiation activates the GAP-43 promotor: selective participation of hippocampal mossy cells. Proc Natl Acad Sci USA 94: 11675–11680PubMedCrossRefGoogle Scholar
  17. 17.
    Musleh W, Bi X, Tocco G, Yaghoubi S, Baudry M (1997) Glycine-induced long-term potentiation is associated with structural and functional modifications of alpha-amino-3-hydroxyl-5-methyl-4-isoxazolepropionic acid receptors. Proc Natl Acad Sci USA 94 9451–9456PubMedCrossRefGoogle Scholar
  18. 18.
    Coogan A, O’Connor JJ (1997) Inhibition of NMDA receptor-mediated synaptic transmission in the rat dentate gyrus in vitro by IL-1 beta. Neuroreport 8: 2107–2110PubMedCrossRefGoogle Scholar
  19. 19.
    Li AJ, Katafuchi T, Oda S, Hori T, Oomura Y (1997) Interleukin-6 inhibits long-term potentiation in rat hippocampal slices. Brain Res 748: 30–38PubMedCrossRefGoogle Scholar
  20. 20.
    Kang H, Welcher AA, Shelton D, Schuman EM (1997) Neurotrophins and time different roles for TrkB signaling in hippocampal long-term potentiation. Neuron 19: 653–664PubMedCrossRefGoogle Scholar
  21. 21.
    Morimoto K, Sato K, Sato S, Yamada N, Hayabara T (1998) Time-dependent changes in neurotrophic factor mRNA expression after kindling and long-term potentiation Brain Res Bull 45: 599–605PubMedCrossRefGoogle Scholar
  22. 22.
    Huang YY, Bach ME, Lipp HP, Zhuo M, Wolfer DP, Hawkins RD, Schoonjans L. Kandel ER, Godfraind JM, Mulligan R, Collen D, Carmeliet P (1996) Mice lacking the gene encoding tissue-type plasminogen activator show a selective interference with late-phase long-term potentiation in both Schaffer collateral and mossy fiber pathways. Proc Natl Acad Sci USA 93: 8699–8704PubMedCrossRefGoogle Scholar
  23. 23.
    Togashi H, Yoshioka M (1998) Transient cerebral ischemia and long-term potentiation in the rat hippocampus. Folia Pharmacol Jpn 111: 55–63 (in Japanese)CrossRefGoogle Scholar
  24. 24.
    Kokaia Z, Zhao Q, Kokaia M, Elmer E, Metsis M, Smith ML, Siesjo BK, Lindvall O (1995) Regulation of brain-derived neurotrophic factor gene expression after transient middle cerebral artery occlusion with and without brain damage. Exp Neurol 136: 73–78PubMedCrossRefGoogle Scholar
  25. 25.
    Ferrer I, Ballabriga J, Marti E, Perez E, Alberch J, Arenas E (1998) BDNF up-regulates TrkB protein and prevents the death of CA1 neurons following transient forebrain ischemia. Brain Pathol 8: 253–261PubMedCrossRefGoogle Scholar
  26. 26.
    Chan KM, Lam DT, Pong K, Widmer HR, Hefti F (1996) Neurotrophin-4/5 treatment reduces infarct size in rats with middle cerebral artery occlusion. Neurochem Res 21: 763–767PubMedCrossRefGoogle Scholar
  27. 27.
    Hicks D, Heidinger V, Mohand-Said S, Sahel J, Dreyfus H (1998): Growth factors and gangliosides as neuroprotective agents in exitotoxicity and ischemia. Gen Pharmacol 30: 265–273PubMedCrossRefGoogle Scholar
  28. 28.
    Cuevas P, Carceller F, Reimers D. Saenz de Tejada I, Gimenez-Gallego G (1998) Acidic fibroblast growth factor rescues gerbil hippocampal neurons from ischemic apoptotic death. Neurol Res 20(3): 271–274PubMedGoogle Scholar
  29. 29.
    Beilharz EJ, Bassett NS, Sirimanne ES, Williams CE, Gluckman PD (1995) Insulin-like growth factor II is induced during wound repair following hypoxic-ischemic injury in the developing rat brain. Brain Res Mol Brain Res 29: 81–91PubMedCrossRefGoogle Scholar
  30. 30.
    Cobbs CS, Chen J, Greenberg DA, Graham SH (1998) Vascular endothelial growth factor expression in transient focal cerebral ischemia in the rat. Neurosci Lett 249: 79–82PubMedCrossRefGoogle Scholar
  31. 31.
    Sakata M, Yanamoto H, Hashimoto N, Iihara K, Tsukahara T, Taniguchi T, Kikuchi H (1998) Induction of infarct tolerance by platelet-derived growth factor against reversible focal ischemia. Brain Res 784: 250–255PubMedCrossRefGoogle Scholar
  32. 32.
    Miyazawa T, Matsumoto K, Ohmichi H, Katoh H, Yamashita T, Nakamura T (1998) Protection of hippocampal neurons from ischemia-induced delayed neuronal death by hepatocyte growth factor: a novel neurotrophic factor. J Cereb Blood Flow Metab 18: 345–348PubMedCrossRefGoogle Scholar
  33. 33.
    Vivien D, Bernaudin M, Buisson A, Divoux D, MacKenzie ET, Nouvelot A (1998) Evidence of type I and type II transforming growth factor-beta receptors in central nervous tissues: changes induced by focal cerebral ischemia. J Neurochem 70: 2296–2304PubMedCrossRefGoogle Scholar
  34. 34.
    Kitagawa H, Hayashi T, Mitsumoto Y, Koga N, Itoyama Y, Abe K (1998): Reduction of ischemic brain injury by topical application of glial cell line-derived neurotrophic factor after permanent middle cerebral artery occlusion in rats. Stroke 29: 1417–1422PubMedCrossRefGoogle Scholar
  35. 35.
    Lin TN, Wang PY, Chi SI, Kuo JS (1998) Differential regulation of ciliary neurotrophic factor (CNTF) and CNTF receptor alpha (CNTFR alpha) expression following focal cerebral ischemia. Brain Res Mol Brain Res 55: 71–80PubMedCrossRefGoogle Scholar
  36. 36.
    Himori N, Matsuura A (1989) A simple technique for occlusion and reperfusion of coronary artery in conscious rats. Am J Physiol 256 (Heart Circ Physiol 25): H1719–H1725PubMedGoogle Scholar
  37. 37.
    Mori K, Yoshioka M, Suda N, Ueno K, Togashi H, Saito H (1997) Effects of bifemelane on imcomplete cerebral ischemia-induced inhibition of LTP in the rat hippocampal neurons in vivo. Jpn J Pharmacol 73(suppl I), 271PGoogle Scholar
  38. 38.
    Mori K, Togashi H, Itoh Y, Matsumoto M, Ueno K, Yoshioka M (1998) Effects of transient cerebral ischemia on nitric oxide metabolites and long-term potentiation in vivo: its blockade by IL-1β analog. In: Moncada S Toda N, Maeda H, Higgs EA (ed) The Biology of Nitric Oxide, Part 6. Portland Press, London, pp124Google Scholar
  39. 39.
    Iga Y, Yoshioka M, Togashi H, Saito H (1993) Inhibitory action of Nω-nitro-L-arginme methyl ester on in vivo long-term potentiation in the rat dentate gyrus. Eur J Pharmacol 238: 395–398PubMedCrossRefGoogle Scholar
  40. 40.
    Shintani F, Kanba S, Nakaki T, Sato K, Yagi G, Kato R, Asai M (1994) Measurement by in vivo brain microdialysis of nitric oxide release in the rat cerebellum. J Psychiatr Neurosci 19: 217–221Google Scholar
  41. 41.
    Togashi H, Mori K, Ueno K, Matsumoto M, Suda N, Saito H, Yoshioka M (1998) Consecutive evaluation of nitric oxide production after transient cerebral ischemia in the rat hippocampus using in vivo brain microdialysis. Neurosci Lett 240: 53–57PubMedCrossRefGoogle Scholar
  42. 42.
    Jacobs RA, Satta MA, Dahia PLM, Chew SL, Grossman AB (1997) Induction of nitric oxide synthase and interleukin-1β, but not heme oxygenase, messenger RNA in rat brain following peripheral administration of endotoxin. Mol Brain Res 49: 238–246PubMedCrossRefGoogle Scholar
  43. 43.
    Iadecola C, Zhang F, Casey R, Clark HB, Ross ME (1996) Inducible nitric oxide synthase gene expression in vascular cells after transient focal cerebral ischemia. Stroke 27: 1373–1380PubMedCrossRefGoogle Scholar
  44. 44.
    Dinarello CA (1988) Biology of interleukin l. FASEB J 2: 108–115PubMedGoogle Scholar
  45. 45.
    Hagan P, Barks JD, Yabut M, Davidson BL, Roessler B, Silverstein FS (1906) Adenovirus-mediated over-expression of interleukin-1 receptor antagonist reduces susceptibility to excitotoxic brain injury in perinatal rats. Neurosci 75: 1033–1045CrossRefGoogle Scholar
  46. 46.
    Wang X, Barone FC, Aiyar NV, Feuerstein GZ (1997) Interleukin-1 receptor and receptor antagonist gene expression after focal stroke in rats. Stroke 28: 155–161PubMedCrossRefGoogle Scholar
  47. 47.
    Rothwell NJ, Hopkins SJ (1995) Cytokines and the nervous system II: actions and mechanisms of action. TINS 18: 130–136PubMedGoogle Scholar
  48. 48.
    Yoshida T, Limmroth V, Irikura K, Moskowitz MA (1994) The NOS inhibitor. 7-nitroindazole, decreases focal infarct volume but not the response to topical acetylcholine in pial vessels. J Cereb Blood Flow Metab 14: 924–929PubMedCrossRefGoogle Scholar
  49. 49.
    Zhang ZG, Reif D, Macdonald J, Tang WX, Kamp DK, Gentile RJ, Shakespeare WC. Murray RJ, Chopp M (1996) ARL 17477, a potent and selective neuronal NOS inhibitor decreases infarct volume after transient middle cerebral artery occlusion in the rats J Cereb Blood Flow Metab 16: 599–604PubMedCrossRefGoogle Scholar

Copyright information

© Springer Japan 1999

Authors and Affiliations

  1. 1.Department of PharmacologyHokkaido University Graduate School of MedicineSapporoJapan
  2. 2.Department of AnesthesiologyHokkaido University School of MedicineSapporoJapan

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