Diacylglycerols and Arachidonic Acid in the Molecular Pathogenesis of Brain Injury

  • Nicolas G. Bazan
  • Dale L. Birkle
  • T. Sanjeeva Reddy
  • Robert E. Vadnal
Part of the FIDIA Research Series book series (FIDIA, volume 4)


Stimulation or injury promotes an accumulation of free fatty acids (FFA) and diacylglycerols in the central nervous system (Bazan, 1970, 1971; Bazan and Rako-wski, 1970; Bazan et al., 1971; Aveldano and Bazan 1975a, b, 1979; Bazan, 1976). The accumulated lipids are potentially harmful to excitable membranes by mechanisms such as FFA inhibition of membrane-bound enzymes (Rhoads et al., 1983) and lipid peroxidation (Yoshida et al., 1982). The accumulation of FFA following a single electroconvulsive shock (ECS) is transient, returning to normal levels within 5 min after the shock (Bazan and Rakowski, 1970). Similarly, the FFA increase in gerbil brain due to ischemia induced by bilateral carotid occlusion can be reversed to normal levels after reperfusion (Yoshida et al., 1980, Bhakoo et al., 1984). In the case of prolonged ischemia or during bicuculline-induced status epilepticus, the accumulation of FFA and DAG continues to rise and may lead to irreversible brain damage (Aveldano and Bazan, 1975a, b; DeMedio et al., 1980; Shiu et al., 1983; Tang and Sun, 1982, 1985; Rodriguez de Turco et al., 1983). Irreversible damage may occur because of selective degradation of functionally critical lipid classes or molecular species of lipids (e. g. polyphosphoinositides) in synaptic membranes and/or other cell membranes, such as mitochondria (Bazan et al., 1971; Bazan, 1976). In brain, accumulation of DAG and FFA (especially polyunsaturates) as a result of catabolism of polyphosphoinositides, may disturb interneuronal communication by altering levels of secondary messengers (DAG itself and water-soluble inositol polyphosphates) and the activity of protein kinase C. Protein kinase C in brain, which can be activated by polyunsaturated fatty acids (Murakami and Routtenberg, 1985) and unsaturated DAG (Nishizuka et al., 1984a), appears to play a critical role in stimulus-secretion coupling (Kawahara et al., 1980; Wooten and Wrenn, 1984; Putney et al., 1984).


Free Fatty Acid Status Epilepticus Docosahexaenoic Acid Synaptic Plasma Membrane Free Arachidonic Acid 
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  1. Adesuyi SA, Cockrell CS, Gamache DA, Ellis EF (1985) Lipoxygenase metabolism of arachidonic acid in brain. J Neurochem 45: 770–776.PubMedCrossRefGoogle Scholar
  2. Allison JH, Blisner NW, Holland WH, Hipps PP, Sherman WR (1976) Increased brain myoinositol 1-phosphate in lithium-treated rats. Biochem Biophys Res Comm 71: 664–670.PubMedCrossRefGoogle Scholar
  3. Allison JH, Stewart MA (1971) Reduced brain inositol in lithium-treated rats. Nature 233: 267–268.CrossRefGoogle Scholar
  4. Aveldano MI, Bazan NG (1974) Free fatty acids, diacyl-and triacylglycerols and total phospholipids in vertebrate retina: Comparison with brain, choroid and plasma. J Neurochem 23: 1127–1135.PubMedCrossRefGoogle Scholar
  5. Aveldano MI, Bazan, NG (1975a) Differential lipid deacylation during brain ischemia in a homeotherm and a poikilotherm. Content and composition of free fatty acids and triacylglycerols. Brain Res 100: 99–110.PubMedCrossRefGoogle Scholar
  6. Aveldano MI, Bazan NG (1975b) Rapid production of diacylglycerols enriched in arachidonate and stearate during early brain ischemia. J Neurochem 25: 919–920.PubMedCrossRefGoogle Scholar
  7. Aveldano MI, Sprecher H (1983) Synthesis of hydroxy fatty acids from 4,7,10,13,16,19-[1-14C] docosahexaenoic acid by human platelets. J Biol Chem 258: 9339–9343.PubMedGoogle Scholar
  8. Aveldano de Caldironi MI, Bazan NG (1979) α-Methyl-p-tyrosine inhibits the production of free arachidonic acid and diacylglycerols in brain after a single electroconvulsive shock. Neurochem Res 4: 213–221.CrossRefGoogle Scholar
  9. Bazan NG (1970) Effects of ischemia and electroconvulsive shock on free fatty acid pool in the brain. Biochim Biophys Acta 218: 1–10.PubMedCrossRefGoogle Scholar
  10. Bazan NG (1971) Changes in free fatty acids of brain by drug-induced convulsions, electroshock and anesthesia. J Neurochem 18: 1379–1385.PubMedCrossRefGoogle Scholar
  11. Bazan NG (1976) Free arachidonic acid and other lipids in the nervous system during early ischemia and after electroshock. Adv Exp Med Biol 72: 317–335.PubMedCrossRefGoogle Scholar
  12. Bazan NG, Bazan HEP (1975) Analysis of free and esterified fatty acids in neural tissues using gradient-thickness thin-layer chromatography. In: Marks N and Rodnight R (eds): Research Methods in Neurochemistry, Vol III, Plenum Press, New York, pp. 309–324.CrossRefGoogle Scholar
  13. Bazan NG, Giusto NM (1983) Anoxia-induced production of methylated and free fatty acids in retina, cerebral cortex, and white matter. Comparison with triglycerides and with other tissues. Neurochem Pathol 1: 17–41.CrossRefGoogle Scholar
  14. Bazan NG, Joel CD (1970) Gradient-thickness thin-layer chromatography for the isolation and analysis of trace amounts of free fatty acids in large lipid samples. J Lipid Res 11: 42–47.PubMedGoogle Scholar
  15. Bazan NG, Rakowski H (1970) Increased levels of brain free fatty acids after electroconvulsive shock. Life Sci 9: 501–507.PubMedCrossRefGoogle Scholar
  16. Bazan NG, Bazan HEP, Kennedy WG, Joel CD (1971) Regional distribution and rate of production of free fatty acids in rat brain. J Neurochem 18: 1387–1393.PubMedCrossRefGoogle Scholar
  17. Bazan NG, Politi E, Rodriguez de Turco EB (1984a) Endogenous pools of arachidonic acid-enriched membrane lipids in cryogenic brain edema. In: Go KG, Baethmann A (eds): Recent Progress in the Study of Brain Edema, Plenum Press, New York, pp. 203–212.CrossRefGoogle Scholar
  18. Bazan NG, Birkle DL, Reddy TS (1984b) Docosahexaenoic acid (22:6, n-3) is metabolized to lipoxygenase reaction products in the retina. Biochem Biophys Res Commun 125: 741–747.PubMedCrossRefGoogle Scholar
  19. Berridge MJ (1984) Inositol trisphosphate and diacylglycerol as second messengers. Biochem J 220: 345–360.PubMedGoogle Scholar
  20. Berridge MJ, Downes CP, Hanley MR (1982) Lithium amplifies agonist-dependent phosphatidylinositol responses in brain and salivary glands. Biochem J 206: 587–595.PubMedGoogle Scholar
  21. Bhakoo KK, Crockard HA, Lascelles PT (1984) Regional studies of changes in brain fatty acids following experimental ischemia and reperfusion in the gerbil. J Neurochem 43: 1025–1031.PubMedCrossRefGoogle Scholar
  22. Cenedella RJ, Galli C, Paoletti R (1975) Brain free fatty acid levels in rats sacrificed by decapitation versus focused microwave irradiation. Lipids 10: 290–293.PubMedCrossRefGoogle Scholar
  23. Chapman AG, Meldrum BS, Siesjo B (1977) Cerebral metabolic changes during prolonged epileptic seizures in rats. J Neurochem 28: 1025–1035.PubMedCrossRefGoogle Scholar
  24. DeMedio GE, Goracci G, Horrocks LA, Lazarewicz JW, Mazzari S, Porcellati G, Strosznajder J, Trovarelli G (1980) The effect of transient ischemia on fatty acid and lipid metabolism in the gerbil brain. Ital J Biochem 29: 412–432.Google Scholar
  25. Fischer S, Schacky CV, Siess W, Shasser T, Weber PC (1984) Uptake, release and metabolism of docosahexaenoic acid in human platelets and neutrophils. Biochem Biophys Res Comm 120: 907–918.PubMedCrossRefGoogle Scholar
  26. Forstermann U, Seregi A, Hertting G (1984) Anticonvulsive effects of endogenous prostaglan-dins formed in brain of spontaneously convulsing gerbils. Prostaglandins 27: 913–923.PubMedCrossRefGoogle Scholar
  27. Fujiwara M, Watanabe Y, Katayama Y, Shirakabe Y (1978) Application of high-powered microwave irradiation for acetylcholine analysis in mouse brain. Eur J Pharmacol 51: 299–301.PubMedCrossRefGoogle Scholar
  28. Galli C, Spagnuolo C (1976) The release of brain free fatty acids during ischemia in essential fatty acid-deficient rats. J Neurochem 26: 401–404.PubMedCrossRefGoogle Scholar
  29. Hallcher LM, Sherman WR (1980) The effects of lithium ion and other agents on the activity of myo-inositol-1-phosphatase from bovine brain. J Biol Chem 225: 10896–10901.Google Scholar
  30. Hauser G, Eichberg J (1973) Improved conditions for the preservation and extraction of polyphosphoinositides. Biochim Biophys Acta 326:201–6.PubMedCrossRefGoogle Scholar
  31. Irvine RF, Letcher AJ, Lander DJ, Downes CP (1984) Inositol trisphosphates in carbachol-stimulated rat parotid glands. Biochem J 223: 237–243.PubMedGoogle Scholar
  32. Kawahara Y, Takai Y, Minakuchi R, Sano K, Nishizuka Y (1980) Phospholipid turnover as a possible transmembrane signal for protein phosphorylation during human platelet activation by thrombin. Biochem Biophys Res Comm 97: 309–317.PubMedCrossRefGoogle Scholar
  33. Lysz TW, Centra M, Keeting P (1985) Increased brain fatty acid cyclooxygenase activity is associated with drug induced clonic convulsions. Soc Neurosci Abstr, Vol II, part 1, pp 748.Google Scholar
  34. Moskowitz MA, Kiwak KJ, Hekimian K, Levine L (1984) Synthesis of compounds with properties of leukotrienes C4 and D4 in gerbil brains after ischemia and reperfusion. Science 224: 886–889.PubMedCrossRefGoogle Scholar
  35. Murakami K, Routtenberg A (1985) Direct activation of purified protein kinase C by unsaturated fatty acids (oleate and arachidonate) in the absence of phospholipids and Ca2+. FEBS Lett 192: 189–193.PubMedCrossRefGoogle Scholar
  36. Nishizuka Y (1984) Turnover of inositol phospholipids and signal transduction. Science 225: 1365–1370.PubMedCrossRefGoogle Scholar
  37. Politi LE, Rodriguez de Turco EB, Bazan NG (1985) Dexamethasone effect on free fatty acid and diacylglycerol accumulation during experimentally-induced vasogenic brain edema. Neurochem Pathol 3: 253–274.Google Scholar
  38. Ponten U, Ratcheson RA, Salford LG, Siesjo BK (1973) Optimal freezing conditions for cerebral metabolites in rats. J Neurochem 21: 1127–1138.PubMedCrossRefGoogle Scholar
  39. Putney JW Jr, McKinney JS, Aub DL, Leslie BA (1984) Phorbol ester-induced protein secretion in rat parotid gland: Relationship to the role of inositol lipid breakdown and protein kinase C activation in stimulus-secretion coupling. Molec Pharmacol 26: 261–266.Google Scholar
  40. Reddy TS, Bazan NG (1985) Synthesis of arachidonoyl coenzyme A and docosahexaenoyl coen zyme A in synaptic plasma membranes of cerebrum and microsomes of cerebrum, cerebellum, and brain stem of rat brain. J Neurosci Res 13: 381–390.PubMedCrossRefGoogle Scholar
  41. Reddy TS, Birkle DL, Armstrong D, Bazan NG (1985) Change in content, incorporation and lipoxygenation of docosahexaenoic acid in retina and retinal pigment epithelium in canine ceroid lipofuscinosis. Neurosci Lett 59: 67–72.PubMedCrossRefGoogle Scholar
  42. Rhoads DE, Osburn LD, Peterson NA, Raghupathy E (1983) Release of neurotransmitter amino acids from synaptosomes: Enhancement of calcium-independent efflux by oleic and arachidonic acids. J Neurochem 41: 531–537.PubMedCrossRefGoogle Scholar
  43. Rodriguez de Turco EB, Morelli de Liberti S, Bazan NG (1983) Stimulation of free fatty acid and diacylglycerol accumulation in cerebrum and cerebellum during bicuculline-induced status epilepticus. Effect of pretreatment with α-methyl-p-tyrosine and p-chlorophenylalanine. J Neurochem 40: 252–259.CrossRefGoogle Scholar
  44. Sautebin L, Spagnuolo C, Galli G (1978) A mass fragmentographic procedure for the simultaneous determination of HETE and PGF, in the central nervous system. Prostaglandins 16: 985–988.PubMedCrossRefGoogle Scholar
  45. Schneider DR, Felt BT, Goldman H (1981) Microwave radiation energy: A probe for the neurobiologist. Life Sci 29: 643–653.PubMedCrossRefGoogle Scholar
  46. Schneider HH (1984) Brain cAMP response to phosphodiesterase inhibitors in rats killed by microwave irradiation or decapitation. Biochem Pharmacol 33: 1690–1693.PubMedCrossRefGoogle Scholar
  47. Seregi A, Forstermann U, Hertting G (1984) Decreased levels of brain cyclo-oxygenase products as a possible cause of increased seizure susceptibility in convulsion-prone gerbils. Brain Res 305: 393–395.PubMedCrossRefGoogle Scholar
  48. Siesjo BK, Ingvar M, Westerberg E (1982) The influence of bicuculline-induced seizures on free fatty acid concentrations in cerebral cortex, hippocampus and cerebellum. J Neurochem 39: 796–802.PubMedCrossRefGoogle Scholar
  49. Sherman WR, Munsell LY, Gish BG, Hanchor MP (1985) Effects of systemically administered lithium on phosphoinositide metabolism in rat brain, kidney and testis. J Neurochem 44: 798–807.PubMedCrossRefGoogle Scholar
  50. Shiu GK, Nemoto EM (1981) Barbiturate attenuation of brain free fatty acid liberation during global ischemia. J Neurochem 37: 1448–1456.PubMedCrossRefGoogle Scholar
  51. Shiu GK, Nemmer P, Nemoto EM (1983) Reassessment of brain fatty acid liberation during global ischemia and its attenuation by barbiturate anesthesia. J Neurochem 40: 880–884.PubMedCrossRefGoogle Scholar
  52. Soukup JF, Friedel RO, Schanberg SM (1978) Cholinergic stimulation of polyphosphoinositide metabolism in brain in vivo. Biochem Pharmacol 27: 1239–1243.PubMedCrossRefGoogle Scholar
  53. Spagnuolo C, Sautebin L, Galli G, Racagni G, Galli C, Mazzari S, Finesso M (1979) PGF, thromboxane B2 and HETE levels in gerbil brain cortex after ligation of common carotid arteries and decapitation. Prostaglandins 18: 53–61.PubMedCrossRefGoogle Scholar
  54. Stavinova WB, Frazer J, Modak AT (1977) Microwave fixation for the study of acetylcholine metabolism. Adv Behav Biol 24: 169–179.CrossRefGoogle Scholar
  55. Suzuki N, Nakamura T, Imabayashi S, Ishikawa Y, Sasaki T, Asano T (1983) Identification of S-hydroxyeicosatetraenoic acid in cerebrospinal fluid after subarachnoid hemorrhage. J Neurochem 41: 1186–1189.PubMedCrossRefGoogle Scholar
  56. Tang W, Sun GY (1982) Factors affecting the free fatty acids in rat brain cortex. Neurochem Int 4: 269–273.PubMedCrossRefGoogle Scholar
  57. Tang W, Sun GY (1985) Effects of ischemia on free fatty acids and diacylglycerols in developing rat brain. Int J Develop Neurosci 3: 51–56.CrossRefGoogle Scholar
  58. Wolfe LS (1982) Eicosanoids: Prostaglandins, thromboxanes, leukotrienes and other derivatives of carbon-20 unsaturated fatty acids. J Neurochem 38: 1–3.PubMedCrossRefGoogle Scholar
  59. Wolfe LS, Coceani F (1979) The role of prostaglandins in the central nervous system. Ann Rev Physiol 41: 669–684.CrossRefGoogle Scholar
  60. Wooten MW, Wrenn RW (1984) Phorbol ester induces intracellular translocation of phospholipid/Ca2+-dependent protein kinase and stimulates amylase secretion in isolated pancreatic acini. FEBS Lett 171: 183–186.PubMedCrossRefGoogle Scholar
  61. Yoshida S, Inoh S, Asano T, Sano K, Kubota M, Shimazaki H, Ueta N (1980) Effect of transient ischemia on free fatty acids and phospholipids in the gerbil brain. J Neurosurg 53: 323–331.PubMedCrossRefGoogle Scholar
  62. Yoshida S, Abe K, Busto R, Watson BD, Kogure K, Ginsberg MD (1982) Influence of transient ischemia on lipid-soluble antioxidants, free fatty acids and energy metabolites in rat brain. Brain Res 245: 307–316.PubMedCrossRefGoogle Scholar

Copyright information

© Springer-Verlag Berlin Heidelberg 1986

Authors and Affiliations

  • Nicolas G. Bazan
    • 1
  • Dale L. Birkle
    • 1
  • T. Sanjeeva Reddy
    • 1
  • Robert E. Vadnal
    • 1
  1. 1.LSU Eye Center and Department of PsychiatryLouisiana State University School of MedicineNew OrleansUSA

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