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Protective effects of cyclosporine and allopurinol on transient global cerebral ischemia in gerbils

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Abstract

The effects of cyclosporine and allopurinol on neuronal death following global cerebral ischemia were evaluated in Mongolian gerbils. The animals were randomly divided into four groups of 12 each: (1) sham operation as control, (2) occlusion of the bilateral common carotid arteries for 12 min and treatment with physiological saline, (3) occlusion plus treatment with 5 mg/kg of cyclosporine, and (4) occlusion plus treatment with 100 mg/kg of allopurinol 30 min before cerebral ischemia and daily thereafter for 6 days. On the 7th day after ischemia or sham operation, the gerbils' brains were removed. The number of necrotic pyramidal cells in the cortex and hippocampal CA1 was evaluated and tissue chemiluminescence (reflecting the presence of superoxide radicals) and lipid peroxides were examined. The number of necrotic pyramidal cells in each field of view (×100) of the cortex was 115±79 after ischemia, which was significantly larger than 14±8 in the control group, and was 45±33 and 60±49 after treatment with cyclosporine and allopurinol, respectively. The number of surviving pyramidal cells per mm length after ischemia in CA1 was 37±14, which was significantly smaller than 174±30 in the control group, but 78±31 following treatment with was cyclosporine, and 108±53 with allopurinol. A reduced number of necrotic pyramidal cells was associated with lower tissue chemiluminescence and lipid peroxides. The results suggest that both cyclosporine and allopurinol can inhibit neuronal death after global cerebral ischemia, and that autoimmunization and superoxide radicals are partially responsible for neuronal death.

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References

  1. Barone FC, Hillegass LM, Price WJ, White RF, Lee EV, Feuerstein GZ, Sarau HM, Clark RK, Griswold DE (1991) Polymorphonuclear leukocyte infiltration into cerebral focal ischemic tissue: myeloperoxidase activity assay and histologic verification. J Neurosci Res 29: 336–345

    Article  PubMed  CAS  Google Scholar 

  2. Wang PY, Kao CH, Mui MY, Wang SJ (1993) Leukocyte infiltration in acute hemispheric ischemic stroke. Stroke 24: 236–240

    PubMed  CAS  Google Scholar 

  3. Mori E, del Zoppo GJ, Chamber JD, Copeland BR, Arfors KE (1992) Inhibition of polymorphonuclear leukocyte adherence suppresses no-reflow after focal cerebral ischemia in baboons. Stroke 23: 712–718

    PubMed  CAS  Google Scholar 

  4. Vasthare US, Heinel LA, Rosenwasser RH, Tuma RF (1990) Leukocyte involvement in cerebral ischemia and reperfusion injury. Surg Neurol 33: 261–265

    Article  PubMed  CAS  Google Scholar 

  5. Mink RB, Dutka AJ, Hallenbeck JM (1991) Allopurinol pretreatment improves evoked response recovery following global cerebral ischemia in dogs. Stroke 22: 660–665

    PubMed  CAS  Google Scholar 

  6. Uyama O, Matsuyama T, Michishita H, Nakamura H, Sugita M (1992) Protective effects of human recombinant superoxide dismutase on transient ischemic injury of CA1 in gerbils. Stroke 23:75–81

    PubMed  CAS  Google Scholar 

  7. Kirino T (1982) Delayed neuronal death in the gerbil hippocampus following ischemia. Brain Res 239:57–69

    Article  PubMed  CAS  Google Scholar 

  8. Hayashi N, Prado R, More J, Bunge B, Green AB (1991) Regional changes of free radicals in photochemically induced ischemic injury in the central nervous system. Laser Life Sci 4: 153–159

    Google Scholar 

  9. Nakano M, Sugioka K, Ushijima Y, Goto T (1986) Chemiluminescence probe with cypridin luciferin analog, 2-methyl-6-phenyl-3,7-dihydroimidazo[1,2a] prazin-3-one, for estimating the ability of human granulocytes to generate superoxide. Anal Biochem 159: 363–369

    Article  PubMed  CAS  Google Scholar 

  10. Ohkawa H, Ohishi N, Yaki K (1979) Assay for lipid peroxides in animal tissues by thiobarbituric acid reaction. Anal Biochem 95: 351–358

    Article  PubMed  CAS  Google Scholar 

  11. Ames A III, Wright RL, Kowada M, Thurston JM, Majno G (1968) Cerebral ischemia. II. The non-flow phenomenon. Am J Pathol 52: 455–476

    PubMed  Google Scholar 

  12. Hossmann KA, Lechtape-Gruter H, Hossmann V (1973) The role of cerebral blood flow for the recovery of the brain after prolonged ischemia. Z Neurol 204:281–299

    Article  PubMed  CAS  Google Scholar 

  13. Fischer EG (1973) Impaired perfusion following cerebrovascular stasis. Arch Neurol 29: 361–366

    PubMed  CAS  Google Scholar 

  14. Chiang J, Kowada M, Ames A III, Wright RL, Majno G (1968) Cerebral ischemia. III. Vascular changes. Am J Pathol 52: 455–476

    PubMed  CAS  Google Scholar 

  15. Arsenio-Nunes ML, Hossmann K-A, Farkas-Bargeton E (1973) Ultrastructural and histochemical investigation of the cerebral cortex of cat during and after complete ischemia. Acta Neuropathol 26: 329–344

    Article  PubMed  CAS  Google Scholar 

  16. Hossmann KA, Hossmann V (1977) Coagulopathy following experimental cerebral ischemia. Stroke 8: 249–254

    PubMed  CAS  Google Scholar 

  17. Kagstrom E, Smith ML, Siesjo BK (1983) Local cerebral blood flow in the recovery period following complete ischemia in the rat. J Cereb Blood Flow Metabol 3: 170–182

    CAS  Google Scholar 

  18. Cantu RC, Ames A III, DiGiacinto G, Dixon J (1969) Hypotension: a major factor limiting recovery from cerebral ischemia. J Surg Res 9: 525–529

    Article  PubMed  CAS  Google Scholar 

  19. Hossmann KA, zimmermann V (1974) Resuscitation of the monkey brain after one hour complete ischemia. I. Physiological and morphological observations. Brain Res 81: 59–74

    Article  PubMed  CAS  Google Scholar 

  20. Hossmann KA, Schmidt-Kastner R, Grosse OB (1978) Recovery of integrative central nervous function after one hour global cerebro-circulatory arrest in normothermic cat. J Neurol Sci 77: 305–320

    Article  Google Scholar 

  21. Behar KL, Rothman DL, Hossman KA (1989) NMR spectroscopic investigation of the recovery of energy and acid-base homeostasis in the cat brain after prolonged ischemia. J Cereb Blood Flow Metabol 9: 655–665

    CAS  Google Scholar 

  22. Oehmichen M (1983) Inflammatory cells in the central nervous system. Prog Neuropathol 5: 277–335

    Google Scholar 

  23. Giulian D (1987) Ameboid microglia as effectors of inflammation in the central nervous system. J Neurosci Res 18: 155–171

    Article  PubMed  CAS  Google Scholar 

  24. Hallenbeck J, Dutka A, Tanishima T, Kochanek PM, Kumaroo KK, Thompson CB, Obrenovich TP, Contreras TJ (1986) Polymorphonuclear leukocyte accumulation in brain region with low blood flow during early postischemic period. Stroke 17: 246–253

    PubMed  CAS  Google Scholar 

  25. Gliulian D, Robertson C (1990) Inhibition of mononuclear phagocytes reduces ischemic injury in the spinal cord. Ann Neurol 27: 33–42

    Article  Google Scholar 

  26. Pozzilli C, Lenzi G, Argentino C, Carolei A, Rasura M, Signore A, Bozzao L, Pozzilli P (1985) Imaging of leukocyte infiltration in human cerebral infarcts. Stroke 16: 251–256

    PubMed  CAS  Google Scholar 

  27. Clark WM, Madden KP, Rothlein R, Zivin JA (1991) Reduction of central nervous system ischemic injury in rabbits using leukocyte adhesion antibody treatment. Stroke 22: 877–883

    PubMed  CAS  Google Scholar 

  28. Raichle ME (1983) The pathophysiology of brain ischemia. Ann Neurol 13: 2–10

    Article  PubMed  CAS  Google Scholar 

  29. Chen ST, Hsu CY, Hogan EL, Halushika PV, Linet OI, Yatsu FM (1986) Thromboxane, prostacyclin, and leukotrienes in cerebral ischemia. Neurology 36: 466–470

    PubMed  CAS  Google Scholar 

  30. Andrus L, Lafferty KL (1981) Inhibition of T-cell activity by cyclosporin A. Scand J Immunol 15: 449–458

    Article  PubMed  CAS  Google Scholar 

  31. Ryba M, Grieb P, Bidzinski J, Pastuszko M, Dziewiecki C, Iwanska K (1990) Cyclosporine for the prevention of neurological deficit following subarachnoid hemorrhage. Stroke 21: 133–137

    Google Scholar 

  32. Handa Y, Hayashi M, Takeuchi H, Kobayashi H, Kawano H, Kabuto M (1991) Effect of cyclosporine on the development of cerebral vasospasm in a primate model. Neurosurgery 28: 380–385

    Article  PubMed  CAS  Google Scholar 

  33. Ogawa N, Tanaka KI, Kondo Y, Asanuma M, Mizukawa K, Mori A (1993) The preventive effect of cyclosporin A, an immunosup-pressant, on the late onset reduction of muscarinic acetylcholine receptors in gerbil hippocampus after transient forebrain ischemia. Neurosci Lett 152: 173–176

    Article  PubMed  CAS  Google Scholar 

  34. McCord JM (1985) Oxygen-derived free radicals in postischemic tissue injury. N Engl J Med 312: 159–163

    Article  PubMed  CAS  Google Scholar 

  35. Palmer C, Vannucci RC, Towfighi J (1990) Reduction of perinatal hypoxicischemic brain damage with allopurinol. Pediatr Res 27: 332–336

    PubMed  CAS  Google Scholar 

  36. Lindsay S, Liu TH, Xu JA, Marshall PA, Thompson JK, Parks DA, Freeman BA, Hsu CY, Beckman JS (1991) Role of xanthine dehydrogenase and oxidase in focal cerebral ischemic injury to rat. Am J Physiol 261: H2051–2057

    PubMed  CAS  Google Scholar 

  37. Betz AL, Randall J, Martz D (1991) Xanthine oxidase is not a major source of free radicals in focal cerebral ischemia. Am J Physiol 260: H563–568.

    PubMed  CAS  Google Scholar 

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Xu, X., Ogata, H. & Luo, X.X. Protective effects of cyclosporine and allopurinol on transient global cerebral ischemia in gerbils. J Anesth 9, 170–175 (1995). https://doi.org/10.1007/BF02479851

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