Effects of Dichloroacetate on Survival Rate, Brain ATP, Lactate, and Water Content Following Cerebral Ischemia in Spontaneously Hypertensive Rats

  • Toshizoh Ishikawa
  • Toshiko Ueda
  • Takefumi Sakabe
  • Tsuyoshi Maekawa
  • Hiroshi Takeshita


Previous reports have demonstrated that brain acidosis associated with the accumulation of lactate may aggravate ischemic-hypoxic brain damage [1,2]. Therefore, measures preventing or attenuating lactate accumulation may be protective against the ischemic brain damage. Dichloroacetate (DCA) is known to activate the pyruvate dehydrogenase (PDH) complex in various tissues in vitro by inhibiting PDH kinase [3] and to reduce serum levels of lactate and pyruvate by its action on PDH [4]. A recent in vivo investigation revealed that DCA significantly lowered the lactate and glucose concentrations of the brain [5] and that it has therapeutic potential in brain ischemia. Subsequently, Biros and colleages [6–8] have demonstrated that the increase in brain lactate content following incomplete ischemia was reduced by both pre- and post-treatment with DCA. However, the effect of DCA on the neurological outcome of animals subjected to brain ischemia has not been investigated.


Lactic Acidosis Untreated Group Brain Water Content Neurochemical Pathology Lactate Content 


Unable to display preview. Download preview PDF.

Unable to display preview. Download preview PDF.


  1. 1.
    Myers RE (1979) Lactic acid accumulation as a cause of brain edema and cerebral necrosis resulting from oxygen deprivation. In: Korobkin R, Guilleminault G (eds) Advances in Perinatal Neuroloyy, Spectrum, New York, pp 85–114Google Scholar
  2. 2.
    Siesjö BK (1981) Cell damage in the brain: A speculative synthesis. J Cereb Blood Flow Metab 1: 155–185PubMedCrossRefGoogle Scholar
  3. 3.
    Whitehouse S, Randle PJ (1973) Activation of pyruvate dehydrogenase in perfused rat heart by dichloroacetate. Biochem J 134: 651–653PubMedGoogle Scholar
  4. 4.
    Evans OB, Stacpoole PW (1982) Prolonged hypolactatemia and increased total pyruvate dehydrogenase activity by dichloroacetate. Biochem Pharmacol 31: 1295–1300PubMedCrossRefGoogle Scholar
  5. 5.
    Kuroda Y, Toshima K, Watanabe T, Kobashi H, Ito M, Takeda E, Miyao M (1984) Effects of dichloroacetate on pyruvate metabolism in rat brain in vivo. Pediatr Res 18: 936–938PubMedGoogle Scholar
  6. 6.
    Biros MH, Dimlich RVW, Barsan WG (1986) Postinsult treatment of ischemia-induced cerebral lactic acidosis in the rat. Ann Emerg Med 15: 397–304PubMedCrossRefGoogle Scholar
  7. 7.
    Biros MH, Dimlich RVW (1987) Brain lactate during partial global ischemia and reperfusion: Effect of pretreatment with dichloroacetate in a rat model. Am J Emerg Med 5: 271–277PubMedCrossRefGoogle Scholar
  8. 8.
    Kaplan J, Dimlich RVW, Biros MH (1987) Dichloroacetate treatment of ischemic cerebral lactic acidosis in the fed rat. Ann Emerg Med 16: 298–304PubMedCrossRefGoogle Scholar
  9. 9.
    McGraw CP (1977) Experimental cerebral infarction. Effects of pentobarbital in Mongolian gerbils. Arch Neurol 34: 334–336PubMedCrossRefGoogle Scholar
  10. 10.
    Sadoshima S, Nakatomi Y, Fujii K, Oobashi H, Ishitsuka T, Ogata J, Fujishima M (1988) Mortality and histological findings of the brain during and after cerebral ischemia in male and female spontaneously hypertensive rats. Brain Res 454: 238–243PubMedCrossRefGoogle Scholar
  11. 11.
    Ishikawa T, Sano T, Kuroda Y, Soejima Y, Maekawa T, Sakabe T, Takeshita H (1987) Effects of buflomedil on survival rate, local cerebral blood flow and glucose utilization after cerebral ischemia in spontaneously hypertensive rats (abstract in English). Folia Pharmacol Jpn 90: 303–312CrossRefGoogle Scholar
  12. 12.
    Fujishima M, Omae T (1976) Cerebral lactate, pyruvate and ATP concentrations, and arterial acid-base balance at various time intervals following bilateral carotid artery occlusion in normotensive and spontaneously hypertensive rats. Acta Neurol Scand 54: 13–21PubMedCrossRefGoogle Scholar
  13. 13.
    Ogata J, Fujishima M, Tamaki K, Nakatomi Y, Omae T (1977) An ultrastructural study of developing cerebral infarction following bilateral carotid artery occlusion in spontaneously hypertensive rats. Acta Neuropathol (Berlin) 40: 171–177CrossRefGoogle Scholar
  14. 14.
    Siesjö BK (1985) Acid-base homeostasis in the brain: Physiology, chemistry, and neurochemical pathology. In: Kogure K, Hossmann K-A, Welsh FA (eds) Progress in brain research. Elsevier, Amsterdam, pp 121–153Google Scholar
  15. 15.
    Rehncrona S, Rosen I, Siesjö BK (1981) Brain lactic acidosis and ischemic cell damage: 1. Biochemistry and neurophysiology. J Cereb Blood Flow Metab 1: 297–311PubMedCrossRefGoogle Scholar

Copyright information

© Springer-Verlag Tokyo 1991

Authors and Affiliations

  • Toshizoh Ishikawa
  • Toshiko Ueda
  • Takefumi Sakabe
  • Tsuyoshi Maekawa
  • Hiroshi Takeshita
    • 1
  1. 1.Department of Anesthesiology-ResuscitologyYamaguchi University, School of MedicineUbe, 755Japan

Personalised recommendations