Neurochemical approaches to the amelioration of brain injury

  • Hanna M. Pappius
Part of the Journal of Neural Transmission book series (NEURAL SUPPL, volume 29)


The studies reported here represent a continuing search for mechanisms which may play a role in neurological disturbances resulting from brain injury. In particular, they are part of an effort to elucidate the involvement of both the serotonergic and noradrenergic neurotransmitter systems in the widespread decrease in cortical glucose utilization, interpreted as reflecting a functional depression, associated with a focal cortical lesion in the rat. Quinolinic acid, an endogenous metabolite of L-tryptophan, a neurotoxin and an N-methyl-D-asparate (NMDA) receptor agonist was found to accumulate in cortical areas of a traumatized rat hemisphere in parallel with a previously demonstrated increase of 5-hydroxyindoleacetic acid. Ketanserin (20mg/kg/day), a 5-HT2 receptor blocker ameliorated the depression of glucose utilization in traumatized brain while MK-801 (3mg/kg, before and after lesion), an NMDA receptor blocker, had no effect. Alpha1-adrenergic receptors, quantitated in vivo with [125I]-HEAT (iodo-2-[β-(4-hydroxyphenyl)-ethyl-aminomethyl]tetralone), were found to be elevated in cortical areas of the lesioned hemisphere, but not in other structures.


Biogenic Amine Quinolinic Acid Cereb Blood Flow Injured Brain Functional Disturbance 
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  1. Diggory GL, Buckett WR (1985) Decreased 5-HTp but not 5-HT1 receptor binding in cortex of rat after chronic administration of dothiepin. Application of the Woolf plot to analysis of binding parameters. Neuropharmacology 24: 275–278.PubMedCrossRefGoogle Scholar
  2. Dyve S, Gjedde A, Diksic M, Sherwin A, Hakim A (1989) In vivo quantification of blood-brain transfer and binding of [125I]HEAT, an α1 adrenoceptor antagonist. Synapse 3: 205–212.PubMedCrossRefGoogle Scholar
  3. Ferron A, Descarries L, Reader TA (1982) Altered neuronal responsiveness to biogenic amines in rat cerebral cortex after serotonin denervation or depletion. Brain Res 231: 93–108.PubMedCrossRefGoogle Scholar
  4. Foster AC, Collins JF, Schwarcz R (1983) On the excitotoxic properties of quinolinic acid, 2,3-piperidine dicarboxylic acids and structurally related compounds. Neuropharmacology 22: 1331–1342.PubMedCrossRefGoogle Scholar
  5. Gal EM, Sherman AD (1978) Synthesis and metabolism of L-kynurenine in rat brain. J Neurochem 30: 607–613.PubMedCrossRefGoogle Scholar
  6. Gal EM, Sherman AD (1980) L-kynurenine: its synthesis and possible regulatory function in brain. Neurochem Res 5: 223–229.PubMedCrossRefGoogle Scholar
  7. Heyes MP, Markey SP (1988) Quantification of quinolinic acid in rat brain, whole blood, and plasma by gas chromatography and negative chemical ionization mass spectro-metry: effects of systemic L-tryptophan administration on brain and blood quinolinic acid concentrations. Anal Biochem 174: 349–359.PubMedCrossRefGoogle Scholar
  8. Janowsky A, Okada F, Manier DH, Applegate CD, Sulser F, Steranka LR (1982) Role of serotonergic input in the regulation of the β adrenergic receptor-coupled adenylate cyclase system. Science 218: 900–901.PubMedCrossRefGoogle Scholar
  9. Lapin IP (1982) Convulsant action of intracerebroventicularly administered L-kynurenine sulphate, quinolinic acid and other derivatives of succinic acid, and effects of amino acids: structure-activity relationships. Neuropharmacology 21: 1227–1233.PubMedCrossRefGoogle Scholar
  10. Leysen JE, Awouters F, Kennis L, Laduron PM, Vandenberk J, Janssen PAJ (1981) Receptor binding profile of R 41468, a novel antagonist at 5-HT2 receptors. Life Sci 28: 1015–1022.PubMedCrossRefGoogle Scholar
  11. Moore RY (1982) Catecholamine neuron systems in brain. Ann Neurol 12: 321–327.PubMedCrossRefGoogle Scholar
  12. Pappius HM (1981) Local cerebral glucose utilization in termally traumatized rat brain. Ann Neurol 9: 484–491.PubMedCrossRefGoogle Scholar
  13. Pappius HM (1985) The continuing search for mechanisms underlying functional disturbances in traumatized brain. In: Inaba Y, Klatzo I, Spatz M (eds) Brain edema. Proceedings of the Sixth International Symposium on Brain Edema, Tokyo, Japan. Springer, Berlin Heidelberg New York Tokyo, pp 286–293.Google Scholar
  14. Pappius HM (1988) Significance of biogenic amines in functional disturbances resulting from brain injury. Metab Br Dis 3: 303–310.CrossRefGoogle Scholar
  15. Pappius HM, Dadoun R (1986) Biogenic amines in injured brain. Trans Am Soc Neurochem 17: 298.Google Scholar
  16. Pappius HM, Dadoun R (1987) The effects of injury on the indoleamines in cerebral cortex. J Neurochem 49: 321–325.PubMedCrossRefGoogle Scholar
  17. Pappius HM, Dadoun R, McHugh M (1988) The effect of p-chlorophenylalanine on cerebral metabolism and biogenic amine content of traumatized brain. J Cereb Blood Flow Metab 8: 324–334.PubMedCrossRefGoogle Scholar
  18. Pappius HM, Wolfe LS (1983a) Functional disturbances in brain following injury: search for underlying mechanisms. Neurochem Res 8: 63–72.PubMedCrossRefGoogle Scholar
  19. Pappius HM, Wolfe LS (1983b) Involvement of serotonin and catecholamines in functional depression of traumatized brain. J Cereb Blood Flow Metab 3 [Suppl 1]: 226–227.Google Scholar
  20. Pappius HM, Wolfe LS (1983c) The effects of indomethacin and ibuprofen on cerebral metabolism and blood flow in traumatized brain. J Cereb Blood Flow Metab 3: 448–459.PubMedCrossRefGoogle Scholar
  21. Pappius HM, Wolfe LS (1984) Effects of drugs on local cerebral glucose utilization in traumatized brain: mechanisms of action of steroids revisited. In: Go G, Baethmann A (eds) Recent progress in the study and therapy of brain edema. Proceedings of the Fifth International Symposium on Brain Edema, Groningen, The Netherlands. Plenum Press, New York, pp 11–26.Google Scholar
  22. Pappius HM, Wolfe LS (1986) Neurochemical sequelae of brain damage and their role in functional disturbances. In: Baethmann A, Go KG, Unterberg (eds) Mechanisms of secondary brain damage. Proceedings of a NATO Advanced Research Workshop, Mauls/Sterzing, Italy. Plenum Press, New York, pp 151–167.Google Scholar
  23. Pappius HM (1981) Local cerebral glucose utilization in thermally traumatized rat brain. Ann Neurol 9: 484–491.PubMedCrossRefGoogle Scholar
  24. Perkins NM, Stone TW (1983) Pharmacology and regional variations of quinolinic acid-evoked excitations in the rat cerebral nervous system. J Pharmacol Exp Ther 226: 551–557.PubMedGoogle Scholar
  25. Schwarcz R, Whetsell WO, Mangano RM (1983) Quinolinic acid: an endogenous metabolite that produces axon-sparing lesions in rat brain. Science 219: 316–318.PubMedCrossRefGoogle Scholar
  26. Sokoloff L, Reivich M, Kennedy C, Des Rosiers MH, Patlak CS, Pettigrew KD, Sakurada O, Shinohara M (1977) The (14C)deoxyglucose method for the measurement of local cerebral glucose utilization: theory, procedure and normal values in the conscious and anesthetized albino rat. J Neurochem 28: 897–916.PubMedCrossRefGoogle Scholar
  27. Stockmeier CA, Martino AM, Kellar KJ (1985) A strong influence of serotonin axons on α-adrenergic receptors in rat brain. Science 230: 323–325.PubMedCrossRefGoogle Scholar
  28. Stone TW, Perkins MN (1981) Quinolinic acid: a potent endogenous excitant at amino receptors in CNS. Eur J Pharmacol 72: 411–412.PubMedCrossRefGoogle Scholar
  29. Van Nueten JM, Janssen AJ, Van Beek J, Xhonneux R, Verbeuren TJ, Vanhoutte PM (1981) Vascular effects of ketanserin (R 41468), a novel antagonist of 5-HT2 serotonergic receptors. J Pharm Exper Ther 218: 217–230.Google Scholar
  30. Weiner N (1980) Drugs that inhibit adrenergic nerves and block adrenergic receptors. In: Goodman LS, Gilman A (eds) The pharmacological basis of therapeutics, 6th edn. Macmillan, New York, pp 176–205.Google Scholar
  31. Wong EHF, Kemp JA, Priestley T, Knight AR, Woodruff GN, Iversen LL (1986) The anticonvulsant MK-801 is a potent N-methyl-D-aspartate antagonist. Proc Natl Acad Sci USA 83: 7104–7108.PubMedCrossRefGoogle Scholar

Copyright information

© Springer-Verlag 1990

Authors and Affiliations

  • Hanna M. Pappius
    • 1
    • 2
  1. 1.The Goad Unit of the Donner Laboratory of Experimental Neurochemistry, Montreal Neurological InstituteMcGill UniversityMontrealCanada
  2. 2.Montreal Neurological InstituteMontrealCanada

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