Role of Mediator Compounds in Secondary Brain Damage — Current Evidence

  • Andreas Unterberg
  • K. Maier-Hauff
  • C. Dautermann
  • U. Hack
  • L. Schürer
  • A. Baethmann
Part of the NATO ASI Series book series (NSSA, volume 115)


Formation or release of noxious factors in damaged brain tissue requires an ever increasing interest among the various mechanisms studied in the development of secondary brain damage (Baethmann, 1978; Baethmann et al., 1979, 1980; Siesjö, 1981). This review attempts to evaluate the current state of knowledge of this interesting subject. Mediator compounds are believed to form, or to become released in primarily damaged brain tissue areas, e.g. the focal necrosis, or to enter the brain parenchyma from the intravascular compartment. These factors spread then from the site of formation, or entrance into perifocal, edematous tissue. Toxic effects of mediator compounds are likely to occur not only in the boundary around a focal lesion, but also in perifocal tissue.


Arachidonic Acid Cerebral Ischemia Brain Edema Glutamate Concentration Cold Injury 
These keywords were added by machine and not by the authors. This process is experimental and the keywords may be updated as the learning algorithm improves.


Unable to display preview. Download preview PDF.

Unable to display preview. Download preview PDF.


  1. Agardh CD, Siesjö BK, Hypoglycemic brain injury: Phospholipids, free fatty acids and cyclic nucleotides in the cerebellum of the rat after 30 and 60 minutes of severe insulin-induced hypoglycemia, J Cereb Blood Flow Metabol 1: 267 (1981)CrossRefGoogle Scholar
  2. Ames A, Tsukada Y, Nesbett FB, Intracellular Cl_,Na+,K+,Ca++,Mg++ and P in nervous tissue; response to glutamate and to changes in extracellular calcium, J Neurochem 14: 245 (1967)CrossRefGoogle Scholar
  3. Baethmann A, Pathophysiological and pathochemical aspects of cerebral edema. Neurosurg Rev 1: 85 (1978)CrossRefGoogle Scholar
  4. Baethmann A, Oettinger W, Rothenfußer W, Geiger R, Biochemical aspects of cerebral edema, in: “Pathophysiology of cerebral energy metabolism”, Mrsulja BB, Rakic LM, Klatzo I, Spatz M, eds., Plenum Press, New York (1979)Google Scholar
  5. Baethmann A, Oettinger W, Rothenfußer W, Kempski O, Unterberg A, Geiger R, Brain edema factors: Current state with particular reference to plasma constituents and glutamate, in: “Brain edema”, Cervos-Navarro J, Ferszt R, eds., Raven Press, New York, Adv Neurol 28:171 (1980)Google Scholar
  6. Baethmann A, Maier-Hauff K, Kempski O, Activation of the kallikreinkinin system in brain tissue secondary to cerebral injury and ischemia, J Cereb Blood Flow Metabol 1 (Suppl 1): S218 (1981)Google Scholar
  7. Bazan NG, Effects of ischemia and electroconvulsive shock on free fatty acid pool in the brain, Biochim Biophys Acta 218: 1 (1970)Google Scholar
  8. Bazan NG, Changes in free fatty acids of brain by drug-induced convulsions, electroshock, and anesthesia, J Neurochem 18: 1379 (1971)CrossRefGoogle Scholar
  9. Bazan NG, Free arachidonic acid and other lipids in the nervous system during early ischemia and after electroshock, Adv Exp Med Biol 72: 317 (1976)Google Scholar
  10. Bazan NG, Rodriguez de Turco EB, Membrane lipids in the pathogenesis of brain edema. Phospholipids and arachidonic acid, the earliest membrane components changed at the onset of ischemia, in: “Brain edema”, Cervos-Navarro J, Ferszt R, eds., Raven Press, New York, Adv Neurol 28:197 (1980)Google Scholar
  11. Bingham WG, Paul SG, Sastry KSS, Effects of cold injury of six enzymes in rat brain, Neurology 21: 649 (1969)Google Scholar
  12. Bulle HP, Effects of reserpine and chlorpromazin in prevention of cerebral edema and reversible cell damage, Proc Soc Exp Biol Med 94: 553 (1957)Google Scholar
  13. Chan PH, Fishman RA, Brain edema: Induction in cortical slices by polyunsaturated fatty acids, Science 201: 358 (1978)CrossRefGoogle Scholar
  14. Chan PH, Fishman RA, Transient formation of superoxide radicals in polyunsaturated fatty acid-induced brain swelling, J Neurochem 35: 1004 (1980)CrossRefGoogle Scholar
  15. Chan PH, Fishman RA, Alterations of membrane integrity and cellular constituents by arachidonic acid in neuroblastoma and glioma cells, Brain Res 248: 151 (1982)CrossRefGoogle Scholar
  16. Chan PH, Yurko M, Fishman RA, Phospholipid degradation and cellular edema induced by free radicals in brain cortical slices, J Neurochem 38: 525 (1982)CrossRefGoogle Scholar
  17. Chan PH, Kerlan R, Fishman RAP, Reduction of y-aminobutyric acid and glutamate uptake and (Na -K)-ATPase activity in brain slices and synaptosomes by arachidonic acid, J Neurochem 40: 309 (1983)CrossRefGoogle Scholar
  18. Clendendon NR, Allen N, Ito T, Gordon MT, Yashan D, Response of lysosomal hydrolases of dog spinal cord and cerebrospinal fluid to experimental trauma, Neurology 28: 78 (1978)CrossRefGoogle Scholar
  19. Erdös EG, The kinins. A status report, Biochem Pharmacol 25: 1563 (1976)CrossRefGoogle Scholar
  20. Erdös EG, ed., “Bradykinin, kallidin and kallikrein”, Handbook of Experimental Pharmacology, Vol XXV ( Suppl), Springer, Berlin, Heidelberg, New York (1979)Google Scholar
  21. Fenske A, Sinterhauf K, Reulen HJ, The role of monoamines in the development of cold induced edema, in: “Dynamics of brain edema”, Pappius HM, Feindel W, eds., Springer, Berlin, Heidelberg, New York (1976)Google Scholar
  22. Frey EK, Kraut H, Werle E, Vogel R, Zickgraf G, Trautschold I, Das Kallikrein-Kinin-System und seine Inhibitoren, F. Enke, Stuttgart (1968)Google Scholar
  23. Gardiner M, Nilsson B, Rehncrona S, Siesjö BK, Free fatty acids in the rat brain in moderate and severe hypoxia, J Neurochem 36: 1500 (1981)CrossRefGoogle Scholar
  24. Gazendam J, Go KG, Van Zanten AK, Composition of isolated edema fluid in cold-induced brain edema, J Neurosurg 51: 70 (1979)CrossRefGoogle Scholar
  25. Gross PM, Cerebral histamine: Indications for neuronal and vascular regulation, J Cereb Blood Flow Metabol 2: 3 (1982)CrossRefGoogle Scholar
  26. Harvey JA, Mcllwain H, Excitatory acidic amino acids and the cation content and sodium ion flux of isolated tissues from the brain, J Biochem 108: 269 (1968)Google Scholar
  27. Joo F, Significance of adenylate cyclase in the regulation of the perme- ability of brain capillaries, in: “Pathophysiology of cerebral energy metabolism”, Mrsulja BB, Rakic CM, Klatzo I, Spatz M, eds., Plenum Press, New York (1979)Google Scholar
  28. Jorgensen MB, Diemer NH, Selective neuron loss after cerebral ischemia in the rat: Possible role of transmitter glutamate, Acta Neurol Scandinav 66: 536 (1982)CrossRefGoogle Scholar
  29. Kempski O, Die Lokalisation des Glutamat-induzierten Hirnödems, Inauguraldissertation, München (1982)Google Scholar
  30. Kempski O, Gross U, Baethmann A, An in-vitro model of cytotoxic brain edema: Cell volume and metabolism of cultivated glial and nerve cells, in: “Advances in neurosurgery, Vol 10”, Driesen W, Brock M, Klinger M, eds., Springer, Berlin, Heidelberg (1982)Google Scholar
  31. Khattab FI, Alterations in acid phosphatase bodies (lysosomes) in cat motoneurons after asphyxiation of the spinal cord, Exp Neurol 18: 133 (1967)CrossRefGoogle Scholar
  32. Kobrine AI, Doyle T, Role of histamine in posttraumatic spinal cord hyperemia and the luxury perfusion syndrome, J Neurosurg 44: 16 (1976)CrossRefGoogle Scholar
  33. Kontos HA, Wei EP, Povlishock JT, Dietrich WD, Magiera CJ, Ellis EF, Cerebral arteriolar damage by arachidonic acid and prostaglandin G2, Science 209: 1242 (1980)CrossRefGoogle Scholar
  34. Maier-Hauff K, Baethmann A, Lange M, Schürer L, Unterberg A, The kallikrein-kinin system as mediator in vasogenic brain edema. Part 2: Studies on kinin formation in focal and perifocal brain tissue, J Neurosurg 61: 97 (1984a)CrossRefGoogle Scholar
  35. Maier-Hauff K, Lange M, Schürer L, Guggenbichler C, Vogt W, Jacob K, Baethmann A, Glutamate and free fatty acid concentrations in extracellular vasogenic edema fluid, in: “Recent progress in the study and therapy of brain edema”, Go KG, Baethmann A, eds., Plenum Press, New York (1984b)Google Scholar
  36. Movat HZ, The plasma kallikrein-kinin system and its interrelationship with other components of blood, in: “Bradykinin, kallidin and kallikrein”, Handbook of Experimental Pharmacology, Vol XXV (Suppl), Erdös EG, ed., Springer, Berlin, Heidelberg, New York (1979)Google Scholar
  37. Nasjletti A, Malik KU, Relationship between the kallikrein-kinin and prostaglandin systems, Life Sci 25: 99 (1979)CrossRefGoogle Scholar
  38. Osterholm J, Bell J, Meyer R, Peyenson J, Experimental effects of free serotonin on the brain and its relation to injury. Part I-III, J Neurosurgery 31: 408 (1969)CrossRefGoogle Scholar
  39. Pappius HM, Wolfe LS, Functional disturbances in brain following injury: search for underlying mechanisms, Neurochem Res 8: 63 (1983)CrossRefGoogle Scholar
  40. Pappius HM, Wolfe LS, Effect of drugs on local cerebral glucose utilization in traumatized brain. Mechanisms of action of steroids revisited, in: “Recent progress in the study and therapy of brain edema”, Go KG, Baethmann A, eds., Plenum Press, New York (1984)Google Scholar
  41. Perry TL, Jones RT, The aminoacid content of human cerebrospinal fluid in normal individuals and mental defectives, J Clin Invest 40: 1363 (1961)CrossRefGoogle Scholar
  42. Perry TL, Hansen S, Kennedy J, CSF amino acids and plasma - CSF amino acid ratios in adults, J Neurochem 24: 587 (1975)CrossRefGoogle Scholar
  43. Pickard JD, Role of prostaglandins and arachidonic acid derivatives in the coupling of cerebral blood flow to cerebral metabolism, J Cereb Blood Flow Metabol 1: 361 (1981)CrossRefGoogle Scholar
  44. Rehncrona S, Westerberg E, Akesson B, Siesjö BK, Brain cortical fatty acids and phospholipids during and following complete and severe incomplete ischemia, J Neurochem 38: 84 (1982)CrossRefGoogle Scholar
  45. Reiser G, Hamprecht B, Bradykinin induces hyperpolarizations in rat glioma cells and in neuroblastoma x glioma hybrid cells, Brain Res 239: 191 (1982)CrossRefGoogle Scholar
  46. Rothenfußer W, Die Bedeutung von Glutamat als Hirnödemfaktor, Inauguraldissertation, München (1982)Google Scholar
  47. Shikimi T, Kema R, Matsumoto M, Yamahata Y, Miyata S, Studies on kinin-like substances in brain, Biochem Pharmacol 22: 567 (1983)Google Scholar
  48. Siesjö BK, Cell damage in the brain: a speculative synthesis, J Cereb Blood Flow Metabol 1: 155 (1981)CrossRefGoogle Scholar
  49. Unterberg A, Baethmann A, The kallikrein-kinin-system as mediator in vasogenic brain edema: I. Cerebral exposure to bradykinin and plasma, J Neurosurg 61: 87 (1984)CrossRefGoogle Scholar
  50. Unterberg A, Hack U, Baethmann A, Cerebral blood flow and metabolism during bradykinin exposure, in: “Cerebral blood flow, metabolism and epilepsy”, Baldy-Moulinier M, Ingvar DH, Meldrum BS, eds., John Libbey, London, Paris (1983)Google Scholar
  51. Unterberg A, Wahl M, Baethmann A, Effects of bradykinin on permeability and diameter of pial vessels in-vivo, J Cereb Blood Flow Metabol 4: 574 (1984)CrossRefGoogle Scholar
  52. Unterberg A, Hack U, Baethmann A, Blood flow, metabolism and function of the brain during cerebral administration of bradykinin, in: “Extra-intracranial vascular anastomoses. Microsurgery at the edge of the tentorium”, Advances in Neurosurgery, Vol. 13, Dietz H, Brock M, Klinger K, eds., Springer, Berlin, Heidelberg, New York (1985)Google Scholar
  53. Unterberg, A, Dautermann C, Baethmann A, Müller-Esterl W, The kallikrein-kinin system as mediator in vasogenic brain edema. III: Inhibition of the kallikrein-kinin system in traumatic brain swelling, J Neurosurg 64: 269 (1986)CrossRefGoogle Scholar
  54. Van Harreveld A, The extracellular space in the vertebrate central nervous system, in: “The structure and function of nervous tissue, IV”, Bourne HG, ed., Academic Press, New York, London (1972)Google Scholar
  55. Van Harreveld A, Fifkova E, Effects of glutamate and other amino acids on the retina, J Neurochem 18: 2145 (1971a)CrossRefGoogle Scholar
  56. Van Harreveld A, Fifkova E, Light-and electronmicroscopic changes in central nervous tissue after electrophoretic injection of glutamate, Exp Molec Pathol 15: 61 (1971b)CrossRefGoogle Scholar
  57. Vargaftig RJ, Dao Hai N, Selective inhibition by mepacrine of the release of “rabbit aorta contracting substance” evoked by the administration of bradykinin, J Pharm Pharmacol 24: 159 (1972)CrossRefGoogle Scholar
  58. Vio CP, Churchill L, Terragno A, Mc Giff JC, Terragno NA, Arachidonic acid stimulated renal kallikrein release in isolated rat kidney, Clin Sci 63: 235 (1982)Google Scholar
  59. Wahl M, Young AR, Edvinsson L, Wagner F, Effects of bradykinin on pial arteries and arterioles in vitro and in situ, J Cereb Blood Flow Metabol 3: 231 (1983)CrossRefGoogle Scholar
  60. Westergaard E, Enhanced vesicular transport of exogenous peroxidase across cerebral vessels, induced by serotonin, Acta Neuropath 32: 27 (1975)CrossRefGoogle Scholar
  61. Wieloch T, Lindvall O, Blomquist P, Gage FH, Evidence for amelioration of ischaemic neuronal damage in the hippocampal formation by lesions of the perforant path, Neurol Res 7: 24 (1985)Google Scholar
  62. Wolfe LS, Eicosanoids: Prostaglandins, thromboxanes, leukotrienes, and other derivates of carbon-20 unsaturated fatty acids, J Neurochem 38: 1 (1982)CrossRefGoogle Scholar

Copyright information

© Plenum Press, New York 1986

Authors and Affiliations

  • Andreas Unterberg
    • 1
  • K. Maier-Hauff
    • 1
  • C. Dautermann
    • 1
  • U. Hack
    • 1
  • L. Schürer
    • 1
  • A. Baethmann
    • 1
  1. 1.Institute for Surgical Research, Klinikum GroßhadernLudwig-Maximilians-UniversityMunich 70W.-Germany

Personalised recommendations