Acidosis-Related Brain Damage: Immediate and Delayed Events

  • Maj-Lis Smith
  • Bo K. Siesjö
Part of the Advances in Behavioral Biology book series (ABBI, volume 35)


Preischemic hyperglycemia is known to aggravate ischemic brain injury, resulting in severe morphological damage, brain edema, and generalized seizures. Tissue acidosis in form of an increased lactate formation during the period of ischemia in animals with hyperglycemia has been suggested as the cause for this increased vulnerability.

To measure the acidosis during ischemia, and to evaluate and compare the brain damage incurred after the insult in normo- and hyperglycemic animals, several series of experiments were made. The pH changes in the brain during and after ischemia were measured, and the edema formation and the evolution of morphological damage were studied after different recirculation periods following 10 min of forebrain ischemia in rats with preischemic normo- and hyperglycemia.

The decreases in extra- and intracellular pH during ischemia were more pronounced in the hyperglycemic group, which fell to a mean pHi value of 5.95, as compared to 6.35 in the normoglycemic group. Postishemic edema showed a two-phase pattern, with an initial increase in water content in the early recirculation in both groups, followed by normalization after 6 hrs. At 24 hrs a secondary edema developed, that again resolved in the normoglycemic group, but in the hyperglycemic group became severely aggravated with the onset of postischemic seizures. Morphological findings were that the brain damage occurred faster and was more severe in the hyperglycemic groups as compared to the normoglycemic ones. A unique lesion, affecting the substantia nigra pars reticulata, was also seen in the hyperglycemic animals, interpreted to be connected with the postischemic seizures.


Cereb Blood Flow Forebrain Ischemia Lateral Reticular Nucleus Complete Ischemia Hyperglycemic Group 
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  1. Auer RN, Ingvar M, Nevander G, Olsson Y, Siesjö BK (1986) Early axonal lesion and preserved microvasculature in epilepsy-induced hypermetabolic necrosis of the substantia nigra. Acta Neuropath. 71: 207–215CrossRefGoogle Scholar
  2. Avery S, Crockard HA, Russel RR (1984) Evolution and resolution of oedema following severe temporary cerebral ischemia in the gerbil. J Neurol Neurosurg Psych 47: 604–610CrossRefGoogle Scholar
  3. Barber AA, Bernheim F (1967) Lipid peroxidation: its measurement, occurrance, and significance in animal tissues. Adv Gerontol Res 2: 355–403Google Scholar
  4. Ben-Ari Y, Tremblay E, Riche D, Ghilini G, Naquet R (1981) Electrographic, clinical and pathological alterations following systemic administration of kainic acid, bicuculline or pentetrazole: metabolic mapping using the deoxyglucose method with special reference to the pathology of epilepsy. Neuroscience 6: 1361–1391CrossRefGoogle Scholar
  5. Brierly JB, Graham DI (1984) Hypoxia and vascular disorders of the central nervous system. In: Greenfield’s Neuropathology, 4th ed. ( JH Adams, JAN Corsellis, LW Duchen, eds.), Edward Arnold, London, pp. 125–207Google Scholar
  6. Dietrich WD, Busto R, Yoshida S, Ginsberg MD (1987)Histopathological and hemodynamic consequences of complete versus incomplete ischemia in the rat. J Cereb Blood Flow Metabol 7: 300–308Google Scholar
  7. Diemer NH, Siemkowicz E (1981) Regional neuron damage after cerebral ischaemia in the nonno-and hypoglycemic rat. Neuropathol Appl Neurobiol 7: 217–227CrossRefGoogle Scholar
  8. Eklöf B, Siesjö BK (1972) The effect of bilateral carotid ligation upon the blood flow and the energy state of the rat brain. Acta Physiol Scand 86: 155–165CrossRefGoogle Scholar
  9. Engel J Jr, Wolfson L, Brown L (1978) Anatomical correlates of electrical and behavioral events related to amygdaloid kindling. Ann Neurol 3: 538–544CrossRefGoogle Scholar
  10. Gale K (1985) Mechanisms of seizure control mediated by y -aminobutyric acid: role of the substantia nigra. Fed Proc 44: 2414–2424Google Scholar
  11. Gale K (1986) Role of the substantia nigra in GABA-mediated anticonvulsant action. In: Advances in Neurology, Vol 44 ( A.V. Delgado-Escueta, A.A. Ward Jr, D.M. Woodbury and R.J. Porter, eds.) Raven Press, New York, pp. 343–364Google Scholar
  12. Gardiner M, Smith M-L, Kâgström E, Shohami E, Siesjö BK (1982) Influence of blood glucose concentration on brain lactate accumulation during severe hypoxia and subsequent recovery of brain energy meyabolism. J Cereb Blood Flow Metabol 2: 429–438CrossRefGoogle Scholar
  13. Gebicki JM, Bielski BHJ (1981) Comparision of the capacities of the perhydroxyl and the superoxide radicals to initiate chain oxidation of linoleic acid. J Am Chem Soc 103 (23): 7020–7022CrossRefGoogle Scholar
  14. Ginsberg MD, Frank AW, Budd WW (1980) Deleterious effect of glucose pretreatment on recovery from diffuse cerebral ischemia in the cat. Stroke 11: 347–354CrossRefGoogle Scholar
  15. Halliwell B, Gutteridge JMC (1985a) Oxygen radicals and the nervous system. TINS 8: 22–26Google Scholar
  16. Halliwell B, Gutteridge JMC (1985b) The importance of free radicals and catalytic metal ions in human diseases. Molec Aspects Med 8: 89–193CrossRefGoogle Scholar
  17. von Hanwehr R, Smith M-L, Siesjö BK (1986) Extra-and intracellular pH during near-complete forebrain ischemia in the rat. J Neurochem 46: 331–339CrossRefGoogle Scholar
  18. Hillered L, Smith M-L, Siesjö BK (1985) Lactic acidosis and recovery of mitochondrial function following forebrain ischemia in the rat. J Cereb Blood Flow Metabol 5: 259–266CrossRefGoogle Scholar
  19. Hossmann K-A, Zimmermann V (1974) Resuscitation of the monkey brain after 1 hour’s complete ischemia. I. Physiological and morphological observations. Brain Res 81: 59–74Google Scholar
  20. Hossmann K-A, Sakaki S, Zimmerman V (1977) Cation activity in reversible ischemia of the brain. Stroke 8: 77–81CrossRefGoogle Scholar
  21. ladarola MJ, Gale K (1982) Substantia nigra: site of anticonvulsant activity mediated by y-aminobutyric acid. Science 218: 1237–1240CrossRefGoogle Scholar
  22. Inamura K, Olsson Y, Siesjö BK (1987) Substantia nigra damage induced by ischemia in hyperglycemic rats. A light and electron microscopic study. Acta Neuropath (in press)Google Scholar
  23. Inamura K, Smith M-L, Olsson Y, Siesjö BK (1988) Pathogenesis of substantia nigra lesions following hyperglycemic ischemia. J Cereb Blood Flow Metabol (in press)Google Scholar
  24. Ingvar M, Siesjö BK (1983) Local blood flow and glucose consumption in the rat brain during sustained bicuculline-induced seizures. Acta Neurol Scand 68: 129–144CrossRefGoogle Scholar
  25. Ito U, Spatz M, Walker JT, Klatzo I (1975) Experimental cerebral ischemia in mongolian gerbils. I. Light microscopic observations. Acta Neuropathol (Berl.) 32: 209–223Google Scholar
  26. Kagström E, Smith M-L, Siesjö BK (1983) Recirculation in the rat brain following incomplete ischemia. J Cereb Blood Flow Metabol 3: 183–192CrossRefGoogle Scholar
  27. Kalimo H, Rehncrona S, Söderfeldt B, Olsson Y, Siesjö BK (1981) Brain lactic acidosis and ischemic cell damage: 2. Histopathology. J Cereb Blood Flow Metabol 1: 313–327Google Scholar
  28. Katzman R, Clasen R, Klatzo I, Meyer JS, Pappius HM, Waltz AG (1977) IV. Brain Edema in Stroke: Study group on brain edema in stroke. Stroke 8: 512–540Google Scholar
  29. Kirino T (1982) Delayed neuronal death in the gerbil hippocampus following ischemia. Brain Res 239: 57–69CrossRefGoogle Scholar
  30. Kirino T, Sano K (1984) Selective vulnerability in the gerbil hippocampus following transient ischemia. Acta Neutopathol (Berl.) 62: 201–208CrossRefGoogle Scholar
  31. Klatzo I (1985) Brain oedema following brain ischaemia and the influence of therapy. Br JAnaesth 57: 18–22CrossRefGoogle Scholar
  32. Komara JS, Nayini NR, Bialick HA, Indrieri RI, Evans AT, Garritano AM, White BC, Aust SD (1986) Brain iron delocalization and lipid peroxidation following cardiac arrest. Ann Emerg Med 15:384–389Google Scholar
  33. Kraig RP, Pulsinelli WA, Plum F (1985) Heterogeneous distribution of hydrogen and bicarbonate ions during complelte brain ischemia. In: Progress in Brain Research.(K Kogure, K-A Hossmann, BK Siesjö and FA Welsh, eds.) Elsevier, Amsterdam. 63: 155–166Google Scholar
  34. Kraig RP, Pulsinelli WA, Plum F (1986) Carbonic acid buffer changes during complete brain ischemia. Am J Physiol. 250: R348 - R357Google Scholar
  35. Ljunggren B, Norberg K, Siesjö BK (1974) Influence of tissue acidosis upon restitution of brain energy metabolism following total ischemia. Brain Res 77: 173–186CrossRefGoogle Scholar
  36. McNamara JO, Galloway MT, Rigsbee LC, Shin C (1984) Evidence implicating substantia nigra in regulation of kindled seizure threshold. J Neurosci 4: 2410–2417Google Scholar
  37. Myers RE (1976) Anoxic brain pathology and blood glucose Neurology 26: 345Google Scholar
  38. Myers RE (1979a) A unitary theory of causation of anoxic and hypoxic brain pathology. In: Cerebral hypoxia and its consequences (S Fahn, JN Davis, LP Rowland, eds.). Adv Neurol 26. Raven Press, New YorkGoogle Scholar
  39. Myers RE (1979b) Lactic acid accumulation as a cause of brain edema and cerebral necrosis resulting from oxygen deprivation. In: Advances in Perinatal Neurology ( R. Korobkin, G. Guilleminault, eds.) New York, Spectrum, pp. 85–114Google Scholar
  40. Myers RE, Yamaguchi S (1976) Effects of serum glucose concentration on brain response to circulatory arrest. J Neuropath Exp Neurol 35: 301CrossRefGoogle Scholar
  41. Myers RE, Yamaguchi S (1977) Nervous system effects of cardiac arrest in monkeys. Arch Neurol 34: 65–74CrossRefGoogle Scholar
  42. Nemoto EM, Frinak S (1981) Brain tissue pH after global brain ischemia and barbiturate loading in rats. Stroke 12 (1): 77–84CrossRefGoogle Scholar
  43. Nevander G, Ingvar M, Auer R, Siesjö BK (1985) Status epilepticus in well-oxygenated rats causes neuronal necrosis. Ann Neurol 18: 281–290CrossRefGoogle Scholar
  44. Nordström CH, Rehncrona S, Siesjö BK (1976) Restitution of cerebral energy state after complete and incomplete ischemia of 30 min duration. Acta Physiol Scand 97: 270–272CrossRefGoogle Scholar
  45. Nordström CH, Siesjö BK (1978) Effects of phenobarbital in cerebral ischemia. Part I: Cerebral energy metabolism during incomplete ischemia. Stroke 9: 327–335Google Scholar
  46. Nordström CH, Rehncrona S, Siesjö BK (1978) Effects of phenobarbital in cerebral ischemia. Part II: Restitution of cerebral energy state, as well as of glycolytic metabolites, citric acid cycle intermediates and associated amino acids after pronounced incomplete ischemia. Stroke 9: 335–343Google Scholar
  47. Pulsinelli WA, Waldman S, Rawlinson D, Plum F (1982a) Moderate hyperglycemia augments ischemic brain damage: A neuropathologic study in the rat. Neurology 32: 1239–1246Google Scholar
  48. Pulsinelli WA, Brierley IB, Plum F (1982b) Temporal profile of neuronal damage in a model of transient forebrain ischemia. Ann Neurol 11: 491–498CrossRefGoogle Scholar
  49. Rehncrona S, Mela L, Siesjö BK (1979) Recovery of brain mitochondrial function in the rat after complete and incomplete cerebral ischemia. Stroke 10: 437–446CrossRefGoogle Scholar
  50. Rehncrona S, Rosén I, Siesjö BK (1980) Excessive cellular acidosis: an important mechanism of neuronal damage in the brain. Acta Physiol Scand 110: 435–437CrossRefGoogle Scholar
  51. Rehncrona S, Rosén I, Siesjö BK (1981) Brain lactic acidosis and ischemic cell damage: 1. Biochemistry and neurophysiology. J Cereb Blood Flow Metabol 1: 297–311Google Scholar
  52. Salford LG, Plum F, Siesjö BK (1973) Graded hypoxia-oligemia in rat brain. Biochemical alterations and their implications. Arch Neurol 29: 227Google Scholar
  53. Salford LG, Siesjö BK (1974) The influence of arterial hypoxia and unilateral carotid artery occlusion upon regional blood flow and metabolism in the rat brain Acta Physiol Scand 92: 130Google Scholar
  54. Schwartzkroin PA and Wyler AR (1980) Mechanisms underlying epileptiform burst discharge. Ann Neurol 7: 95–107CrossRefGoogle Scholar
  55. Siemkowicz E (1981) Brain uptake of mannitol and sucrose after cerebral ischemia: Effect of hyperglycemia. Acta Physiol Scand 112: 359–363CrossRefGoogle Scholar
  56. Siemkowicz E, Hansen M (1981) Brain extracellular ion composition and EEG activity following 10 minutes ischemia in normo-and hyperglycemic rats. Stroke 12: 236–240CrossRefGoogle Scholar
  57. Siesjö BK, von Hanwehr R, Nergelius G, Nevander G, Ingvar M (1985a) Extra-and intracellular pH in the brain during seizures and in the recovery period following arrest of seizure activity. J Cereb Blood Flow Metabol 5: 47–57CrossRefGoogle Scholar
  58. Siesjö BK, Bendek G, Koide T, Westerberg E, Wieloch T (1985b) Influence of acidosis on lipid peroxidation in brain tissues in vitro. Cereb Blood Flow Metabol 5: 253–258CrossRefGoogle Scholar
  59. Siesjö BK (1985) Acid-base homeostasis in the brain: Physiology, chemistry, and neurochemical pathology. In: Progress in Brain Research (K. Kogure, K.-A. Hossmann, B.K. Siesjö, F.A. Welsh, eds.) Elsevier, Amsterdam. 63: 121–154Google Scholar
  60. Siesjö BK (1988) Historical overview: calcium, ischemia and death of brain cells. Ann NY Acad Sci (in press)Google Scholar
  61. Sloper JJ, Johnson P, Powell TPS (1980) Selective degeneration of intemeurons in the motor cortex of infant monkeys following controled hypoxia: a possible cause of epilepsy. Brian Res 198: 204–209CrossRefGoogle Scholar
  62. Smith M-L, Bendek G, Dahlgren N, Rosén I, Wieloch T, Siesjö BK (1984 a) Models for studying long-term recovery following forebrain ischemia in the rat. 2. A 2-vessel occlusion model. Acta Neurol Scand 69: 385–401Google Scholar
  63. Smith M-L, Auer RN, Siesjö BK (1984 b) The density and distribution of ischemic brain injury in the rat following 2–10 min of forebrain ischemia. Acta Neuropathol.(Berl) 64: 319–332Google Scholar
  64. Smith M-L, von Hanwehr R, Siesjö BK (1986) Changes in extra-and intracellular pH in the brain during and following ischemia in hyperglycemic and in moderately hypoglycemic rats. Cereb Blood Flow Metabol 6: 574–583CrossRefGoogle Scholar
  65. Smith M-L, Kalimo H, Warner DS, Siesjö BK (1987) Glucose treatment preceding forebrain ischemia causes subs tantia nigra damage. J Cereb Blood Flow Metabol 7,Suppl 1: S73Google Scholar
  66. Smith M-L, Kalimo H, Warner DS, Siesjö BK (1988) Morphological lesions in the brain preceding the development of postischemic seizures. Acta Neuropathol (in press)Google Scholar
  67. Thom W, Heitman R (1954) pH der Gehimrinde vom Kaninchen in situ während perakuter, totaler Ischämie, reiner Anoxie and in der Erholung. Pfluegers Arch. Ges. Physiol. 258: 501–510Google Scholar
  68. Turski L, Cavalheiro EA, Turski WA, Meldrum BS (1986) Excitatory neurotransmission within substantia nigra pars reticulata regulates treshold for seizures produced by pilocarpine in rats: Effects of intranigral 2-amino-7-phosphonoheptanoate and N- methyl-D-aspartate. Neuroscience 18: 61–77CrossRefGoogle Scholar
  69. Warner DS, Smith M-L, Siesjö BK (1987) Ischemia in normo-and hyperglycemic rats: effects on brain water and electrolytes Stroke 18: 464–471Google Scholar
  70. Welsh FA, Ginsberg MD, Rieder W, Budd WW (1980) Deleterious effect of glucose pretreatment on recovery from diffuse cerebral ischemia in the cat. II. Regional metabolite levels. Stroke 11 (4): 355–365CrossRefGoogle Scholar
  71. Welsh FA, Sims RE, Mc Kee AG (1983) Effect of glucose on recovery of energy metabolism following hypoxia-oligemia in mouse brain: dose-dependence and carbohydrate specificity. J Cereb Blood Flow Metabol 3: 486–492CrossRefGoogle Scholar
  72. Wong RKS, Prince DA (1978) Participation of calcium spikes during intrinsic burst firing in hippocampal neurons. Brain Res 159: 385–390CrossRefGoogle Scholar
  73. Yoshida Y, Busto R, Martinez E, Scheinberg P, Ginsberg MD (1985) Regional brain energy metabolism after complete versus incomplete ischemia in the rat in the absence of severe lactic acidosis. Cereb Blood Flow Metabol 5: 490–501CrossRefGoogle Scholar

Copyright information

© Plenum Press, New York 1988

Authors and Affiliations

  • Maj-Lis Smith
    • 1
  • Bo K. Siesjö
    • 1
  1. 1.Laboratory for Experimental Brain ResearchLund University Lund HospitalLundSweden

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