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Effects of an inhibitor of adenosine deaminase, deoxycoformycin, and of nucleoside transport, propentofylline, on post-ischemic recovery of adenine nucleotides in rat brain

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Abstract

The effects of an adenosine deaminase inhibitor (deoxycoformycin, 500 μg/kg) and of an inhibitor of nucleoside transport (propentofylline, 10 mg/kg) on adenosine and adenine nucleotide levels in the ischemic rat brain were investigated. The brains of the rats were microwaved before, at the end of a 20 min period of cerebral ischemia (4 vessel occlusion+hypotension), or after 5, 10, 45, and 90 min of reperfusion. Deoxycoformycin increased brain adenosine levels during both ischemia and the initial phases of reperfusion. AMP levels were elevated during ischemia and after 5 min of reperfusion. ATP levels were elevated above those in the non-treated animals after 10 and 45 min of reperfusion. ADP levels were elevated above the non-drug controls at 90 min. These increases in ATP, ADP and AMP resulted in significant increases in total adenylates during ischemia, and after 10 min and 90 min of reperfusion. Propentofylline administration resulted in enhanced AMP levels during ischemia but did not alter adenosine or adenine nucleotide levels during reperfusion in comparison with non-treated controls.

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References

  1. Adb-Elfattah, A. S., Ding, M., Dyke, C. M., and Wechsler, A. S. 1983. Protection of the stunned myocardium. Selective nucleoside transport blocker administered after 20 minutes of ischemia augments recovery of ventricular function. Circulation 88: (Pt. 2) 336–343.

    Google Scholar 

  2. Andine, P., Rudolphi, K. A., Fredholm, B. B., and Hagberg, H. 1990. Effect of propentofylline (HWA 285) on extracellular purines and excitatory amino acids in CA1 of rat hippocampus during transient ischaemia. Br. J. Pharmac. 100:814–818.

    CAS  Google Scholar 

  3. Arvin, B., Neville, L. F., Pan, J., and Roberts, P. J. 1989. 2-Chloroadenosine attenuates kainic acid induced toxicity within the rat striatum: relationship to release of glutamate and Ca2+ influx. Br. J. Pharmac. 98:225–235.

    CAS  Google Scholar 

  4. Ballarin, M., Fredholm, B. B., Ambrosio, S., and Mahy, N. 1991. Extracellular levels of adenosine and its metabolites in the striatum of awake rats: inhibition of uptake and metabolism. Acta Physiol. Scand. 142:97–103.

    Article  PubMed  CAS  Google Scholar 

  5. Bolling, S. F., Bies, L. E., Gallagher, K. P., and Bove, E. L. 1989. Enhanced myocardial protection with adenosine. Ann. Thorac. Surg. 47:809–815.

    Article  PubMed  CAS  Google Scholar 

  6. Bolling, S. F., Bies, L. E., Bove, E. L., and Gallagher, K. P. 1990. Augmenting intracellular adenosine improves myocardial recovery. J. Thorac. Cardiovasc. Surg. 99:469–474.

    PubMed  CAS  Google Scholar 

  7. DeWitt, D. F., Jochim, K. E., and Behrendt, D. M. 1983. Nucleoside degradation and functional impairment during cardioplegia: amelioration by inosine. Circulation 67:171–178.

    PubMed  CAS  Google Scholar 

  8. Dhasmana, J. P., Digerness, S. B., Geckle, J. M., Ng, T. C., Glickson, J. D., and Blackstone, E. H. 1983. Effect of adenosine deaminase inhibitors on the heart's functional and biochemical recovery from ischemia: a study using the isolated rat heart adapted to31P nuclear magnetic resonance. J. Cardiovasc. Pharmac. 5:1040–1047.

    Article  CAS  Google Scholar 

  9. Ely, S. W., Mentzer, R. M., Lasley, R. D., Lee, B. K., and Berne, R. M. 1985. Functional and metabolic evidence of enhanced myocardial tolerance to ischemia and reperfusion with adenosine. J. Thorac. Cardiovasc. Surg. 90:549–556.

    PubMed  CAS  Google Scholar 

  10. Evans, M. C., Swan, J. H., and Meldrum, B. S. 1987. An adenosine analogue, 2-chloroadenosine, protects against long term development of ischaemic cell loss in the rat hippocampus. Neurosci. Letts. 83:287–292.

    Article  CAS  Google Scholar 

  11. Fredholm, B. B., and Lindstrom, K. 1986. The xanthine derivative 1-(5′-oxohexyl)-3-methyl-7-propylxanthine (HWA 285) enhances the actions of adenosine. Acta Pharmacol. Toxicol. 58:187–192.

    Article  CAS  Google Scholar 

  12. Fredholm, B. B., Lindstrom, K., and Wallman-Johansson, A. 1994. Propentofylline and other adenosine transport inhibitors increase the efflux of adenosine following electrical or metabolic stimulation of rat hippocampal slices. J. Neurochem. 62:563–573.

    Article  PubMed  CAS  Google Scholar 

  13. Geiger, J. D., Lewis, J. L., MacIntyre, C. J., and Nagy, J. I. 1987. Pharmacokinetics of 2′-deoxycoformycin, an inhibitor of adenosine deaminase, in the rat. Neuropharmacol. 26:1383–1387.

    Article  CAS  Google Scholar 

  14. Grome, J. J., and Stefanovich, V. 1985. Differential effects of xanthine derivatives on local cerebral blood flow and glucose utilization in the conscious rat. Pages 453–457,in Stefanovich, V., Rudolphi, K. and Schubert, P., (eds.) Receptors and Modulation of Cell Function, IRL Press, Oxford.

    Google Scholar 

  15. Humphrey, S. M., and Seelye, R. N. 1982. Improved functional recovery of ischemic myocardium by suppression of adenosine catabolism. J. Thorac. Cardiovasc. Surg. 84:16–22.

    PubMed  CAS  Google Scholar 

  16. Kano, T., Katayama, Y., Kawamata, T., Hirota, H., and Tsubokawa, T. 1994. Propentofylline administered by microdialysis attenuates ischemia-induced hippocampal damage but not excitatory amino acid release in gerbils. Brain Res. 641:149–154.

    Article  PubMed  CAS  Google Scholar 

  17. Lin, Y., and Phillis, J. W. 1992. Deoxycoformycin and oxypurinol: protection against focal ischemic brain injury in the rat. Brain Res. 571:272–280.

    Article  PubMed  CAS  Google Scholar 

  18. Lloyd, H. G. E., and Fredholm, B. B. 1995. Involvement of adenosine deaminase and adenosine kinase in regulating extracellular adenosine concentration in rat hippocampal slices. Neurochem. Int. 26:387–395.

    Article  PubMed  CAS  Google Scholar 

  19. Lowry, O. H., Rosebrough, N. J., Farr, A. L., and Randall, R. J. 1951. Protein measurements with the Folin phenol reagent. J. Biol. Chem. 193:265–275.

    PubMed  CAS  Google Scholar 

  20. Nordstrom, C.-H., Rehncrona, S., and Siesjo, B. K. 1978. Restitution of cerebral energy state, as well as of glycolytic metabolites, citric acid cycle intermediates and associated amino acids after 30 minutes of complete ischemia in rats anaesthetized with nitrous oxide or phenobarbital. J. Neurochem. 30:479–486.

    Article  PubMed  CAS  Google Scholar 

  21. Parkinson, F. E., and Fredholm, B. B. 1991. Effects of propentofylline on adenosine A1 and A2 receptors and nitrobenzylthioinosine-sensitive nucleoside transporters: quantitative autoradiographic analysis. Europ. J. Pharmac. 202:361–366.

    Article  CAS  Google Scholar 

  22. Phillis, J. W. 1989. Adenosine in the control of the cerebral circulation. Cerebrovasc. Brain Metab. Rev. 1:26–54.

    PubMed  CAS  Google Scholar 

  23. Phillis, J. W., and O'Regan, M. H. 1989. Deoxycoformycin antagonizes ischemia-induced neuronal degeneration. Brain Res. Bull. 22:537–540.

    Article  PubMed  CAS  Google Scholar 

  24. Phillis, J. W., O'Regan, M. H., and Walter, G. A. 1989. Effect of two nucleoside transport inhibitors, dipyridamole and soluflazine, on purine release from the rat cerebral cortex. Brain Res. 481: 309–316.

    Article  PubMed  CAS  Google Scholar 

  25. Phillis, J. W., Perkins, L. M., Smith-Barbour, M., and O'Regan, M. H. 1995. Oxypurinol-enhanced post-ischemic recovery of the rat brain involves preservation of adenine nucleotides. J. Neurochem. 64:2177–2184.

    Article  PubMed  CAS  Google Scholar 

  26. Phillis, J. W., Walter, G. A., and Simpson, R. E. 1991. Brain adenosine and transmitter amino acid release from the ischemic rat cerebral cortex: Effects of the adenosine deaminase inhibitor deoxycoformycin. J. Neurochem. 56:644–650.

    Article  PubMed  CAS  Google Scholar 

  27. Phillis, J. W., and Sen, S. 1993. oxypurinol attenuates hydroxyl radical production during ischemia/reperfusion injury of the rat cerebral cortex: an ESR study. Brain Res. 628:309–312.

    Article  PubMed  CAS  Google Scholar 

  28. Pulsinelli, W. A., and Brierley, J. B. 1979. A new model of bilateral hemispheric ischemia in the unanesthetized rat. Stroke 10: 267–272.

    PubMed  CAS  Google Scholar 

  29. Rottenberg, H. 1983. Uncoupling of oxidative phosphorylation in rat liver mitochondria by general anesthetics. Proc. Nat. Acad. Sci. (U.S.A.) 80:3313–3317.

    Article  CAS  Google Scholar 

  30. Rudolphi, K. A., Schubert, P., Parkinson, F. E., and Fredholm, B. B. 1992. Adenosine and brain ischemia. Cerebrovasc. Brain Metabol. Rev. 4:346–369.

    CAS  Google Scholar 

  31. Sandhu, G. S., Burrier, A. C., and Janero, D. R. 1993. Adenosine deaminase inhibitors attenuate ischemic injury and preserve energy balance in isolated guinea pig heart. Am. J. Physiol. 265: H1249-H1256.

    PubMed  CAS  Google Scholar 

  32. Sciotti, V. M., and Van Wylen, D. G. L. 1993. Increases in interstitial adenosine nad cerebral blood flow with inhibition of adenosine kinase and adenosine deaminase. J. Cereb. Blood Flow Metab. 13:201–207.

    PubMed  CAS  Google Scholar 

  33. Simpson, R. E., O'Regan, M. H., Perkins, L. M., and Phillis, J. W. 1992. Excitatory transmitter amino acid release from the ischemic rat cerebral cortex: Effects of adenosine receptor agonists and antagonists. J. Neurochem. 58:1683–1690.

    Article  PubMed  CAS  Google Scholar 

  34. Von Lubitz, D. K., Dambrosia, J. M., Kempski, O., and Redmond, D. J. 1988. Cyclohexyladenosine protects against neuronal death following ischemia in the CA1 region of gerbil hippocampus. Stroke 19:1133–1139.

    Google Scholar 

  35. Ward, H. B., St. Cry, S. A., Cogordan, J. A., Alyono, D., Bianco, R. W., Kriett, J. M., and Foker, J. E. 1984. Recovery of adenosine nucleotide levels after global myocardial ischemia in dogs. Surgery 96:248–255.

    PubMed  CAS  Google Scholar 

  36. Winn, H. R., Welsh, J. E., Rubio, R., and Berne, R. M. 1980. Changes in brain adenosine during bicuculline-induced seizures in rats. Effects of hypoxia and altered systemic blood pressure. Circ. Res. 47:568–577.

    PubMed  CAS  Google Scholar 

  37. Zetterstrom, T., Vernet, L., Ungerstedt, U., Tossman, U., Jonzon, B., and Fredholm, B. B. 1982. Purine levels in the intact rat brain. Studies with an implanted perfused hollow fibre. Neurosci. Lett. 29:111–115

    Article  PubMed  CAS  Google Scholar 

  38. Zughaib, M. E., Abd-Elfattah, A. S., Jeroudi, M. O., Sun, J-Z., Sekili, S., Tang, X-L., and Bolli, R. 1993. Augmentation of endogenous adenosine attenuates myocardial ‘stunning’ independently of coronary flow or hemodynamic effects. Circulation 88: Pt. 1:2359–2369.

    PubMed  CAS  Google Scholar 

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  1. Department of Physiology, Wayne State University School of Medicine, 540 E. Canfield, 48201, Detroit, MI

    J. W. Phillis & M. H. O'Regan

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  1. J. W. Phillis
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  2. M. H. O'Regan
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Phillis, J.W., O'Regan, M.H. Effects of an inhibitor of adenosine deaminase, deoxycoformycin, and of nucleoside transport, propentofylline, on post-ischemic recovery of adenine nucleotides in rat brain. Neurochem Res 21, 347–353 (1996). https://doi.org/10.1007/BF02531651

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