Psychopharmacology

, Volume 101, Issue 2, pp 147–159 | Cite as

Pharmacology of nootropics and metabolically active compounds in relation to their use in dementia

  • C. D. Nicholson
Review

Abstract

The development of effective drugs for the treatment of dementia is an important therapeutic target. Drugs which stop the progression of dementia have not been developed; however, nootropics and metabolically active compounds such as the vinca alkaloids and the ergot alkaloids as well as alkylxanthines are widely used to alleviate the symptoms. This review summarises animal studies investigating the mechanism of action of these compounds and highlights gaps in our knowledge of their pharmacology. Nootropics, such as piracetam, facilitate learning and retrieval of information and protect the brain from physical and chemical intoxication. Nootropics may produce these effects via an enhancement of acetylcholine or dopamine release; however, this postulate requires further evaluation. The pharmacology of vinca alkaloids is reviewed with particular reference to vinpocetine. This compound attenuates cognitive deficits, reduces ischaemia-induced hippocampal cell loss and increases cerebral blood flow and glucose utilisation. These effects may be induced by modulation of cyclic nucleotide levels and adenosine re-uptake inhibition. An extensively examined ergot alkaloid is co-dergocrine; this compound increases both the oxygen tension and the electrical activity of the ischaemic cerebral cortex. Alkylxanthines have a wide range of pharmacological activities, and in this review the pharmacology of pentoxifylline, propentofylline and denbufylline is contrasted with that of theophylline and caffeine. In particular, the pharmacology of propentofylline and the selective lowKm cyclic AMP phosphodiesterase inhibitor denbufylline is summarised. Although more carefully controlled clinical trials in well defined patient collectives are required, present evidence suggests some therapeutic efficacy for nootropics and metabolically active compounds. Further studies to more closely evaluate their mechanism of action may lead to the development of more effective agents for the therapy of dementia.

Key words

Dementia Nootropics Vinca alkaloids Ergot alkaloids Alkylxanthines 

Preview

Unable to display preview. Download preview PDF.

Unable to display preview. Download preview PDF.

References

  1. Abrams TW, Kandel ER (1988) Is contiguity detection in classical conditioning a system or a cellular property? Learning in aplysia suggests a possible molecular site. Trends Neurosci 11:128–135Google Scholar
  2. American Psychiatric Association (1980) Diagnostic and statistical manual of mental disorders, 3rd edn. APA, Washington DCGoogle Scholar
  3. Anderson DM, Drummond L, McKeown P (1986) Comparative effects of vinpocetine, Hydergine, flunarizine and verapamil on blood vessels and resistance to cerebral hypoxia. In: Krieglstein J (ed) Pharmacology of cerebral ischaemia. Elsevier, Amsterdam, pp 340–344Google Scholar
  4. Angersbach D, Ochlich P (1984) The effect of 7-(2′-oxopropyl)-1,3-di-n-butyl-xanthine (BRL 30892) on ischaemic skeletal muscle\(Po_2 \), pH and contractility in cats and rats. Arzneimittelforschung 34:1274–1278Google Scholar
  5. Aviado DM, Porter JM (1984) Pentoxifylline: a new drug for the therapy of intermittent claudication. Pharmacotherapy 4:297–307Google Scholar
  6. Balestreri R, Fontana L, Astengo F (1987) A double-blind placebo controlled evaluation of the safety and efficacy of vinpocetine in the treatment of patients with chronic vascular senile cerebral dysfunction. J Am Geriat Soc 35:425–430Google Scholar
  7. Banfi S, Dorigotti L (1984) Experimental behavioral studies with oxiracetam on different types of chronic cerebral impairment. Clin Neuropharmacol [Suppl 1] 7:768–769Google Scholar
  8. Bartus RT, Dean RL, Beer B, Lippa AS (1982) The cholinergic hypothesis of geriatric memory dysfunction. Science 217:408–417Google Scholar
  9. Battig K, Buzzi R, Martin JR, Feierabend JM (1984) The effects of caffeine on physiological functions and mental performance. Experientia 40:1218–1222Google Scholar
  10. Beavo JA (1988) Multiple isoenzymes of cyclic nucleotide phosphodiesterase. In: Greengard P, Robison GA (eds) Advances in second messenger and protein phosphorylation research vol 22. Raven Press, New York, pp 1–38Google Scholar
  11. Beck T, Vogg P, Krieglstein J (1988) Uncoupling of cerebral blood flow and glucose utilization by dihydroergocristine in the conscious rat. Naunyn-Schmiedeberg's Arch Pharmacol 338:82–87Google Scholar
  12. Blaha L, Erzigkeit H, Adamczyk A, Freytag S, Schaltenbrand R (1989) Clinical evidence of the effectiveness of vinpocetine in the treatment of organic psychosyndrome. Human Psychopharmacol 4:103–111Google Scholar
  13. Bowen DM, Smith CB, White P, Davidson AW (1976) Neurotransmitter related enzymes and indices of hypoxia in senila dementia and other abiatrophies. Brain 99:459–496Google Scholar
  14. Bruns RF, Lu GH, Pugsley TA (1986) Characterisation of the A2 adenosine receptor labelled by [3H] NECA in rat cortical membranes. Mol Pharmacol 29:331–346Google Scholar
  15. Butcher RW, Sutherland EW (1962) Adenosine 3′,5′ phosphate in biological materials. J Biochem 237:1244–1250Google Scholar
  16. Butler DE, Nordin IC, L'Italien JL, Zweister L, Poschel PH, Marriot JG (1984) Amnesia-reversal activity of a series of N-[disubstituted-amino)alkyl]-2-oxo-1-pyrrolidineacetamides, including pramiracetam. Med Chem 27:684–691Google Scholar
  17. Caravaggi AM, Sardi A, Baldoli GF, De Francesco CF, Luca C (1977) Hemodynamic profile of a new cerebral vasodilator, vincamine and of one of its derivatives. Apovincaminic acid ethylester (RGH-4405). Arch Int Pharmacodyn Ther 226:139–148Google Scholar
  18. Carney JM (1982) Effects of caffeine, theophylline and theobromine on scheduled controlled responding in rats. Br J Pharmacol 75:451–454Google Scholar
  19. Cartheuser CF (1988) Slow channel inhibitor effects on brain function: tolerance to severe hypoxia in the rat. Br J Pharmacol 95:903–913Google Scholar
  20. Challiss RAJ, Nicholson CD (1988) Effects of selective phosphodiesterase inhibitors on cyclic AMP hydrolysis in rat cerebral cortical slices. Br J Pharmacol 99:553PGoogle Scholar
  21. Chang KH (1985) A pharmacological study on drugs acting on cerebral circulatory dynamics — effects of vinpocetine on brain monoamines in rats a vincamine derivative. Tokyo Ika Kaigahu Zasshi 43:207–220Google Scholar
  22. Chouinard G, Annable L, Ross-Chouinard A, Oliver M, Fontaine F (1983) Piracetam in elderly psychiatric patients with mild diffuse cerebral impairment. Psychopharmacology 81:100–106Google Scholar
  23. Cotman CW, Iversen LL (1987) Excitatory amino acids in the brain — focus on NMDA receptors. Trends Neurosci 10:263–265Google Scholar
  24. Collingridge GL, Bliss TVP (1987) NMDA receptors — their role in long term potentiation. Trends Neurosci 10:288–293Google Scholar
  25. Cumin R, Bandle EF, Gamzu E, Haefely WE (1982) Effects of the novel compound aniracetum (Ro 13-5057) upon impaired learning and memory in rodents. Psychopharmacology 78:104–111Google Scholar
  26. Daly JW, Bruns RF, Snyder SH (1981) Adenosine receptors in the central nervous system: relationship to the central actions of methylxanthines. Life Sci 28:2083–2097Google Scholar
  27. Davis CW (1984) Assessment of selective inhibition of rat cerebral cortical calcium-independent and calcium-dependent phosphodiesterase in crude extracts using deoxycyclic AMP and potassium ions. Biochem Biophys Acta 797:354–362Google Scholar
  28. De Leo J, Toth L, Schubert P, Rudolphi K, Kreutzberg GW (1987) Ischaemia-induced neuronal cell death, calcium accumulation and glial response in the hippocampus of the mongolian gerbil and protection by propentofylline (HWA 285). J Cereb Blood Flow Metabol 7:745–751Google Scholar
  29. De Noble V, Repetti SJ, Gelpke LW, Wood LM, Keim KL (1986) Vinpocetine: Nootropic effects on scopolamine-induced and hypoxia-induced retrieval deficits of a step-through passive avoidance response in rats. Pharmacol Biochem Behav 24:1123–1128Google Scholar
  30. Dragunow M (1986) Adenosine: the brain's natural anticonvulsant. TIPS 128–130Google Scholar
  31. Drugan RC, Maier SF, Skolnick P, Paul SM, Crawley JN (1985) An anxiogenic benzodiazipine receptor ligand induces learned helplessness. Eur J Pharmacol 113:453–457Google Scholar
  32. Duckles SP, Bevan JA (1976) Pharmacological characterization of adrenergic receptors of a rabbit cerebral artery in vivo. J Pharmacol Exp Ther 197:371–378Google Scholar
  33. Dunwiddie TV, Hoffer BJ, Fredholm BB (1981) Alkylxanthines elevate hippocampal excitability. Naunyn-Schmiedeberg's Arch Pharmacol 316:326–330Google Scholar
  34. Dutow AA, Tolpyschew BA, Karpow WN, Petrow AP (1986) The influence of Cavinton on drug-induced convulsions. Farmakol Toksikol 49:22–24Google Scholar
  35. Eckmann F, Fichte R, Meya U, Sastre-Y-Hernandez (1988) Rolipram in major depression: results of a double-blind comparison study with amityptiline. Curr Ther Res 43:291–295Google Scholar
  36. Edvinsson L, Owman C (1974) Pharmacological characterization of adrenergic alpha and beta receptors mediating the vasomotor responses of cerebral arteries in vitro. Circ Res 35:835–849Google Scholar
  37. Erren RA, Groswald DE, Luttges MW (1976) Triethyl-tin toxicity as a model for degenerative disorders. Pharmacol Biochem Behav 5:299–307Google Scholar
  38. Enz A, Iwangoff P, Chappuis A (1978) The influence of dihydroergotoxine mesylate on the low-K m phosphodiesterase of cat and rat brain in vitro. Gerontology [Suppl 1] 24:115–125Google Scholar
  39. Erzigkeit H (1977) Manual zum Syndrom-Kurztest, Formen A-E, Vless Verlags Gesellschaft VatersbettenGoogle Scholar
  40. Fenzyl E, Apecechea R, Schaltenbrand R, Friedel R (1986) Long-term study concerning tolerance and efficacy of vinpocetine in elderly patients suffering from a mild to moderate organic psychosyndrome. In: Bes A (ed) Senile dementias: early detection. Libbey Eurotext, pp 580–585Google Scholar
  41. Francis SH, Noblett BD, Todd BW, Wells JN, Corbin JD (1988) Relaxation of vascular and tracheal smooth muscle by cyclic nucleotide analogs that preferentially activate purified cGMP-dependent protein kinase. Mol Pharmacol 34:506–519Google Scholar
  42. Fredholm BB, Lindgren E, Lindstrom L, Vernet L (1983) The effects of some drugs with purported antianoxic effect in veratridine-induced purine release from isolated rat hypothalamic synaptasomes. Acta Pharmacol Toxicol 52:236–244Google Scholar
  43. Funk KF, Schmidt J (1984) Changes of dopamine metabolism by hypoxia and effect of nootropic drugs. Biomed Biochem Acta 11:1301–1304Google Scholar
  44. Gaitz CM, Varner RV, Overall JT (1977) Pharmacotherapy for organic brain syndrome in late life. Evaluation of an ergot derivative versus placebo. Arch Int Gen Psychiatry 34:839–845Google Scholar
  45. Giurgea CE (1982) The nootropic concept and its prospective implications. Drug Dev Res 2:441–446Google Scholar
  46. Giurgea CE, Moyersoons FE (1972) On the pharmacology of cortical evoked potentials. Arch Int Pharmacodyn 199:67–78Google Scholar
  47. Giurgea CE, Salama M (1977) Nootropic drugs. Prog Neuro-Psychopharmacol 1:235–247Google Scholar
  48. Goelet P, Castellucci UF, Schacher SG, Kandel ER (1986) The long and the short of long term memory — a molecular framework. Nature 322:419–422Google Scholar
  49. Gottstein U, Paulson OB (1972) The effect of intra carotid aminophylline infusion on the cerebral circulation. Stroke 3:560–565Google Scholar
  50. Grome JJ, Stefanovich V (1986) Differential effects of methylxanthines on local cerebral blood flow and glucose utilization in the conscious rat. Naunyn-Schmiedeberg's Arch Pharmacol 333:172–177Google Scholar
  51. Gray R, Johnston D (1987) Noradrenaline andβ-adrenoceptor agonists increase activity of voltage-dependent calcium channels in hippocampal neurons. Nature 327:620–622Google Scholar
  52. Gygax P, Wiensperger N (1983) Hypotension induced changes in cerebral microflow and EEG and their pharmacological alteration. Acta Med Scand [Suppl 678]:29–36Google Scholar
  53. Gygax P, Meier-Ruge W, Schulz U, Enz A (1976) Experimental studies on the action of metabolic and vasoactive substances in the obligaemically disturbed brain. Arzneimittelforschung 26:1245–1246Google Scholar
  54. Hachinski VC, Lassen NA, Marshall J (1974) Multi-infarct dementia: a cause of mental deterioration in the elderly. Lancet II:207–210Google Scholar
  55. Hachinski VC, Iliff LD, Zilhka E, Du Boulay GM, McAllister VL, Marshall J, Ross-Russell RW, Symon L (1975) Cerebral blood flow in dementia. Arch Neurol 32:632–637Google Scholar
  56. Hagan JJ, Morris RGM (1988) The cholinergic hypothesis of memory: a review of animal experiments. In: Iversen LL, Iversen SD, Snyder SH (eds) Handbook of psychopharmacology, vol 20. Plenum Press, New YorkGoogle Scholar
  57. Hagiwara M, Endo T, Hidaka H (1984) Effects of vinpocetine on cyclic nucleotide metabolism in vascular smooth muscle. Biochem Pharmacol 33:453–457Google Scholar
  58. Hasegawa K, Homma A, Imai Y (1986) An epidemiological study of age-related dementia in the community. Int J Geriat Psychiatry 1:45–55Google Scholar
  59. Heiss WD, Podreka I (1981) Die Wirkung von Vinpocetin auf die regionale Hirndurchblutung bei Patienten mit chronisch-Zerebrova skulaffen Erkrankungen mit der intravenosen Xenon-clearance-methode. Report for Thiemann PharmaceuticalsGoogle Scholar
  60. Hidaka H, Endo T (1984) Selective inhibitors of three forms of cyclic nucleotide phosphodiesterase — basic and potential clinical applications. Advances in Cyclic Nucleotide and Protein Phosphorylation Research 16:245–259Google Scholar
  61. Hinze H-J (1972) Zur Pharmakokinetik von 3,7-dimethyl-1-(5-oxo-hexyl)-xanthine (BRL 191) am Menschen. Arzneimittelforschung 22:1492–1495Google Scholar
  62. Hollander E, Mohs RC, Davis KL (1986) Cholinergic approaches to the treatment of Alzheimer's disease. Br Med Bull 42:97–100Google Scholar
  63. Hollister LE (1985) Alzheimer's disease is it worth treating? Drugs 29:483–488Google Scholar
  64. Hossmann KA (1982) Treatment of experimental cerebral ischemia. J Cerebral Blood Flow Metabol 2:275–297Google Scholar
  65. Hudlicka O, Komarek J, Wright AJA (1981) The effect of an xanthine derivative, 1-(5-oxohexyl)-3-methyl-7-propylxanthine (HWA 285), on heart performance and regional blood flow in dogs and rabbits. Br J Pharmacol 72:723–730Google Scholar
  66. Imamoto T, Tanabe M, Shimamoto N, Kawazoe K, Hirata M (1984) Cerebral circulatory and cardiac effects of vinpocetine and its metabolite, apovincaminic acid, in anaesthetized dogs. Arzneimittelforschung 34:161–169Google Scholar
  67. Ineichen B (1987) Measuring the rising tide — how many dementia cases will there be by 2001. Br J Psychiatry 150:193–200Google Scholar
  68. Iversen SD (1977) Brain dopamine systems and behaviour. Handbook of Psychopharmacology vol 8. Plenum Press, New York, pp 333–385Google Scholar
  69. Jordan R, Souness JE (1989) Comparison of the relaxant actions of MCB 229 48 MY-5445, vinpocetine and 1-methyl-3, isobutyl-8-(methylamino) xanthine. Br J Pharmacol 96:227PGoogle Scholar
  70. Jukna JJ, Nicholson CD (1987) The effect of denbufylline on the viscosity of rat whole blood and on the deformability (filterability) of rat blood cell suspensions. Naunyn-Schmiedeberg's Arch Pharmacol 335:445–448Google Scholar
  71. Karpati E, Szporny L (1976) General and cerebral haemodynamic activity of ethyl apovincaminate. Arzneimittelforschung 26:1908–1911Google Scholar
  72. Kehr W, Debus G, Neumeister R (1985) Effects of rolipram, a novel antidepressant on monoamine metabolism in rat brain. J Neurol Transm 63:1–12Google Scholar
  73. Keim KL, Hall PC (1987) General neuropharmacology of vinpocetine: a putative cerebral activator. Drug Dev Res 11:107–115Google Scholar
  74. King GA (1987a) Protection against hypoxia-induced lethality in mice: comparison of the effects of hypothermia and drugs. Arch Int Pharmacodyn Ther 286:282–298Google Scholar
  75. King GA (1987b) Protective effects of vinpocetine and structurally related drugs on the lethal consequences of hypoxia in mice. Arch Int Pharmacodyn Ther 286:299–307Google Scholar
  76. Kiss B, Lapis E, Palosi E, Groo D, Szporny L (1982) Biochemical and pharmacological observations with vinpocetine, a cerebral oxygenator. In: Wauquier A, Borgers M, Amery WK (eds) Protection of tissues against hypoxia vol 7: International Symposium on protection of tissues against hypoxia. Elsevier, Amsterdam, pp 305–309Google Scholar
  77. Kopelman MD, Lishman WA (1986) Pharmacological treatments of dementia (non-cholinergic). Br Med Bull 42:101–105Google Scholar
  78. Lacroix P, Quiniou MJ, Linee P, Le Polles JB (1979) Cerebral metabolic and haemodynamic activities ofl-eburnamonine in the anesthetized dog. Arzneimittelforschung 29:94–101Google Scholar
  79. Lamar J-C, Beaughard M, Bromont C, Poignet H (1986) Effects of vinpocetine in four pharmacological models of cerebral ischaemia. In: Krieglstein J (ed) Pharmacology of cerebral ischaemia. Elsevier, Amsterdam, pp 334–339Google Scholar
  80. Lapis E, Balazs ZM, Rosdy B (1979) Biochemical effects of semisynthetic vinca alkaloids on the cyclic AMP system. Third Congress Hungarian Pharmacol Soc, pp 429–433Google Scholar
  81. Lemmer B, Ohm T, Bohl J (1989) Reduced basal and stimulated adenylate cyclase activity in post-mortem hippocampus of Alzheimer patients. Naunyn-Schmiedeberg's Arch Pharmacol 339:R108Google Scholar
  82. MacKenzie ET, Gotti B, Nowicki JP, Young AR (1984) Adrenergic blockers as cerebral antiischaemic agents. In: MacKenzie ET (ed) LERS, vol 2. Raven Press, New York, pp 219–243Google Scholar
  83. McDonald RJ (1979) Hydergine: a review of 26 clinical studies. Pharmakopsychiatr Neuropsychopharmakol 12:407–422Google Scholar
  84. Madison DV, Nicoll RA (1982) Noradrenaline blocks accommodation of pyramidal cell discharge in the hippocampus. Nature 299:636–638Google Scholar
  85. Markstein R (1983) Dopamine receptor profile of co-dergocrine (hydergine) and its components. Eur J Pharmacol 86:145–155Google Scholar
  86. Markstein R, Wagner H (1978) Effect of dihydroergotoxine on cyclic AMP-generating systems in rat cerebral cortex slices. Gerontology [Suppl 1] 24:94–105Google Scholar
  87. Maragos WF, Greenamyre T, Penney JB, Young AB (1987) Glutamate dysfunction in Alzheimer's disease: an hypothesis. Trends Neurosci 10:65–68Google Scholar
  88. Marriott JG, Poschel BPH, Voigtman RE, Abelson JS, Butler DE (1984) Cognition actuating properties of dihydro-pyrrolizine 3,5 (2H, 6H)-dione (Cl-911) in animal models. Soc Neurosci Abstr 10:252Google Scholar
  89. Matejeck M, Devos JE (1976) Selected methods of quantitative EEG analysis and their applications in psychotropic drug research. In: Kellaway P, Peterson I (eds) Quantitative analytic studies in epilepsy. Raven Press, New York, pp 183–205Google Scholar
  90. Mathew RJ, Wilson WH (1985) Caffeine induced changes in cerebral circulation. Stroke 16:814–817Google Scholar
  91. Meier-Ruge W, Enz A, Gygax P, Iwangoff P, Wiensperger N (1978) Pharmacological aspects of dihydrogenated ergot alkaloids in experimental brain research. Pharmacology [Suppl 1] 16:45–62Google Scholar
  92. Meldrum BS (1983) Metabolic effects of prolonged epileptic seizures and causation of epileptic seizures and causation of epileptic brain damage. In: Rose FC (ed) Metabolic disorders of the nervous system. Pitman, London, pp 175–187Google Scholar
  93. Milanova D, Nikolov R, Nikolova M (1983) Study on the antihypoxic effect of some drugs used in the pharmacotherapy of cerebrovascular disease. Methods Find Exp Clin Pharmacol 5:407–422Google Scholar
  94. Mohs RC, Davis KL (1987) The experimental pharmacology of Alzheimer's and related dementias. In: Meltzer H (ed) Psychopharmacology, the third generation of progress. Raven Press, New York, pp 921–928Google Scholar
  95. Moos WH, Davis RE, Schwarz RD, Gamzu ER (1988) Cognition activators. In: Medical research reviews, vol 8. Wiley, New York, pp 353–391Google Scholar
  96. Morris RGM, Anderson E, Lynch GS, Baudry M (1986) Selective impairment of learning and blockade of long term potentiation by an N-methyl-d-aspartate receptor antagonist, APS. Nature 319:774–776Google Scholar
  97. Moyersoons F, Giurgea CE (1974) Protective effect of piracetam in experimental barbiturate intoxication: EEG and behavioural studies. Arch Int Pharmacodyn Ther 210:38–48Google Scholar
  98. Mrsulja BB, Micic DV, Djuricic BM (1983) Gerbil stroke model: an approach to the study of therapeutic aspects of post-ischemic brain odema. In: Stefanovich V (ed) “Stroke” animal models. Oxford, Pergamon Press, pp 45–60Google Scholar
  99. Muller R (1981) Hemorheology and peripheral vascular disease a new therapeutic approach. J Med 12:209–236Google Scholar
  100. Muller R, Lehrach F (1981) Haemorheology and cerebrovascular disease: multifunctional approach with pentoxifylline. Curr Med Res Opin 7:253–263Google Scholar
  101. Murray CL, Fibiger HC (1986) The effect of pramiracetam (CI-879) on the acquisition of a radial arm maze task. Psychopharmacology 89:378–381Google Scholar
  102. Nagata K, Ogawa T, Osmosu M, Fujimoto K, Hayashi S (1985) In vitro and in vivo inhibitory effects of propentofylline on cyclic AMP phosphodiesterase activity. Arzneimittelforschung 30:1034–1037Google Scholar
  103. Nehlig A, Lucignani G, Kadekaro M, Porrino LJ, Sokoloff L (1984) Effects of acute administration of caffeine on local cerebral glucose utilization in the rat. Eur J Pharmacol 101:91–100Google Scholar
  104. Nicholson CD, Angersbach D (1986) Denbufylline (BRL 30892) — a novel drug to alleviate the consequences of cerebral ischaemia. In: Krieglstein (ed) Pharmacology of cerebral ischaemia. Elsevier, Amsterdam, pp 371–396Google Scholar
  105. Nicholson CD, Jackman SA, Wilke R (1989) The ability of denbufylline to inhibit cyclic nucleotide phosphodiesterase and its affinity for adenosine receptors and the adenosine re-uptake site. Br J Pharmacol 97:889–897Google Scholar
  106. Nicholson CD, Jukna JJ, Wilke R, Angersbach D (1989) Effect of denbufylline in passive avoidance trials in gerbils, following transient forebrain ischaemia, and in mice. Drug Dev Res 14:349–352Google Scholar
  107. Nickolson VJ, Wolthuis OL (1976) Effect of the acquisition-enhancing drug piracetam on rat cerebral energy metabolism. Comparison with naftidrofuryl and methamphetamine. Biochem Pharmacol 25:2241–2244Google Scholar
  108. O'Connolly MO, Mayer M-ER, Wolf D, Brett M, Greb WH (1986) Efficacy and tolerance of denbufylline (BRL 30892) in patients with cerebrovascular disease — an investigational study with a new agent. In: Krieglstein J (ed) Pharmacology of cerebral ischaemia. Elsevier, Amsterdam, pp 440–444Google Scholar
  109. Okuyama S, Aihara H (1988) Action of nootropic drugs on transcallosal responses in rats. Neuropharmacology 27:67–72Google Scholar
  110. Pearson RC, Esiri MM, Hiorns RW, Wilcock GH, Powell TP (1985) Anatomical correlates of the distribution of the pathological changes in the neocortex in Alzheimer disease. Proc Natl Acad Sci USA 82:4531–4534Google Scholar
  111. Perry E (1986) The cholinergic hypothesis — ten years on. Br Med Bull 42:63–69Google Scholar
  112. Popendiker R, Bohsay I, Bollmann V (1971) Zur Pharmakologie des neuen peripheren Gefässdilatators 3,7-Dimethyl-1-(5-oxohexyl)-xanthin. Arzneimittelforschung 21:1160–1171Google Scholar
  113. Pugliese AM, Corradetti R, Pepeu G (1989) Effect of the cognition enhancing agent oxiracetam on electrical activity of hippocampal slices. Br J Pharmacol 96:80PGoogle Scholar
  114. Rogers RL, Meyer JS, Mortel KF, Mahurin RK, Judd BW (1986) Decreased cerebral blood flow precedes multi-infarct dementia, but follows senile dementia of Alzheimer type. Neurology 36:1–6Google Scholar
  115. Rosdy B, Balazs M, Szporny L (1976) Biochemical effects of ethyl apovincaminate. Arzneimittelforschung 26:1973–1976Google Scholar
  116. Rothman SM, Olney JW (1987) Excitotoxicity and the NMDA receptor. Trends Neurosci 10:299–302Google Scholar
  117. Rubieck J, Geiger C, Abt K (1972) An ergot alkaloid preparation (Hydergine) in geriatric therapy. J Am Geriat Soc 20:222–229Google Scholar
  118. Rudolphi KA, Keil M, Hinze HJ (1987) Effect of theophylline on ischemically induced hippocampal damage in mongolian gerbils: a behavioural and histopathological study. J Cereb Blood Flow Metabol 7:74–81Google Scholar
  119. Sansone M, Castellano C, Ammassari-Teule M (1985) Improvement of avoidance acquisition by the nootropic drug oxiracetam in mice. Arch Int Pharmacodyn Ther 275:86–92Google Scholar
  120. Sara SJ (1980) Memory retrieval deficits: alleviation by etiracetam, a nootropic drug. Psychopharmacology 68:235–241Google Scholar
  121. Sara SJ, David-Remacle M, Weyers M, Giurgea CE (1979) Piracetam facilitates retrieval but does not impair extinction of barpressing in rats. Psychopharmacology 61:71–75Google Scholar
  122. Sarter M, Schneider HH, Stephens DN (1988) Treatment strategies for senile dementia: antagonistβ-carbolines. Trends Neurosci 11:13–17Google Scholar
  123. Satoh M, Ishihara K, Iwana T, Takagy H (1986) Aniracetam augments, and midazolam inhibits, the long-term potentiation in guinea-pig hippocampal slices. Neurosci Lett 68:216–220Google Scholar
  124. Sauer D, Rischke R, Beck T, Rossberg C, Mennel H-D, Bielenberg CW, Krieglstein J (1988) Vinpocetine prevents ischemic cell damage in rat hippocampus. Life Sci 43:1733–1739Google Scholar
  125. Schindler U, Rush D, Fielding S (1984) Nootropic drugs: animal modes for studying effect on cognition. Drug Dev Res 4:567–576Google Scholar
  126. Schmid-Schonbein H (1976) Microrheology of erythrocytes blood viscosity and the distribution of blood flow in the microcirculation. In: Guyten AC, Cowley AW (eds) Rev Physiol 9, University Park Press, Baltimore, pp 1–61Google Scholar
  127. Schmid-Schonbein H (1989) Influence of vinpocetine on microsieve filterability and membrane curvature of red cells after exposure to hypersomalality and lactacidosis. Drug Dev Res (in press)Google Scholar
  128. Schoffelmeer ANM, Wardeh G, Mulder AH (1985) Cyclic AMP facilitates the electrically evoked release of radiolabelled noradrenaline, dopamine and 5-hydroxytryptamine from rat brain slices. Naunyn-Schmiedeberg's Arch Pharmacol 330:74–76Google Scholar
  129. Schubert P, Kreutzberg GW (1987) Pre- versus postsynaptic effects of adenosine on neuronal calcium fluxes. In: Gerlach E, Becker BF (eds) Topics and perspectives in adenosine research. Springer, Berlin Heidelberg New York, pp 521–532Google Scholar
  130. Shibota M, Kakihana M, Nagaoka A (1982) The effect of vinpocetine on brain glucose uptake in mice. Folia Pharmacol Japan 80:221–224Google Scholar
  131. Silver PJ, Hamel LT, Perrone MH, Bentley RG, Bushover CR, Evans DB (1988) Differential pharmacologic sensitivity of cyclic nucleotide phosphodiesterase isoenzymes isolated from cardiac muscle arterial and airways smooth muscle. Eur J Pharmacol 150:85–94Google Scholar
  132. Simon RP, Griffiths T, Evans MC, Swan JH, Meldrum BS (1984) Calcium overload in selectively vulnerable neurons of the hippocampus during and after ischemia: an electron microscopy study in the rat. J Cereb Blood Flow Metabol 4:350–361Google Scholar
  133. Smellie FW, Davis CW, Daly JW, Wells JN (1979) Alkylxanthines: inhibition of adenosine elicited accumulation of cyclic AMP in brain slices and brain phosphodiesterase activity. Life Sci 24:2474–2482Google Scholar
  134. Sonders MS, Keana JFW, Weber E (1988) Phencyclidine and psychotomimetic sigma opiates insights into their biochemical and physiological sites of action. Trends Neurosci 11:37–40Google Scholar
  135. Spignoli G, Pepeu G (1987) Interactions between oxiracetam, aniracetam and scopolamine on behavior and brain acetylcholine. Pharmacol Biochem Behav 27:491–495Google Scholar
  136. Stefanovich V (1973) Concerning specificity of the influence of pentoxifylline on various cyclic AMP phosphodiesterases. Res Commun Chem Pathol Pharmacol 5:655Google Scholar
  137. Stefanovich V (1983) Uptake of adenosine by isolated bovine cortex microvessels. Neurochem Res 11:1459–1469Google Scholar
  138. Stegink AJ (1972) The clinical use of piracetam, a new nootropic drug. Arzneimittelforschung 22:975–979Google Scholar
  139. Strada SJ, Martin MW, Thompson WJ (1984) General properties of multiple molecular forms of cyclic nucleotide phosphodiesterase in the nervous system. Adv Cyclic Nucleotide Res 16:13–29Google Scholar
  140. Subhan Z, Hindmarch I (1985) Psychopharmacological effects of vinpocetine in normal healthy volunteers. Eur J Clin Pharmacol 28:567–571Google Scholar
  141. Sutherland EW, Rall TW (1958) Fractionation and characterisation of a cyclic adenosine ribonucleotide formed by tissue particles. J Biol Chem 232:1077–1091Google Scholar
  142. Tank AW, Weiner N (1981) Effect of carbachol and 56 mM-potassium chloride on the cyclic AMP-mediated induction of tyrosine hydroxylase in neuroblastoma cells in culture. J Neurochem 36:518–531Google Scholar
  143. Tomlinson BE, Blessed G, Roth M (1970) Observations of the brains of demented old people. J Neurol Sci 11:205–242Google Scholar
  144. Venutti P, Ferretti C, Portaleone P (1982) Ergot alkaloids and phosphodiesterase: ‘in vitro’ activities in several rat brain areas. Experientia 38:601–603Google Scholar
  145. Vereczkey L, Szporny L (1976) Metabolism of ethyl apovincaminate in the rat. Arzneimittelforschung 26:1933–1938Google Scholar
  146. Vereczkey L, Czira J, Tamas J, Szentirmay ZS, Botar Z, Szporny L (1979) Pharmacokinetics of vinpocetine in humans. Arzneimittelforschung 29:957–960Google Scholar
  147. Wauquier A (1984) Effect of calcium entry blockers in models of brain hypoxia. Dev Cardiovasc Med 40:241–254Google Scholar
  148. Weishaar RE, Cain MH, Bristol JA (1985) A new generation of phosphodiesterase inhibitors: multiple forms of phosphodiesterase and its potential for drug selectivity. J Med Chem 246:3145–3150Google Scholar
  149. Weishaar RE, Kobylarz-Singer DC, Steffen RP, Kaplan MR (1987) Sublcasses of cyclic AMP-specific phosphodiesterase in left ventricular muscle and their involvement in regulating myocardial contractility. Circ Res 61:539–547Google Scholar
  150. Wieloch T, Koide T, Westerberg E (1986) Inhibitory neurotransmitters and neuromodulators as protective agents against ischemic brain damage. In: Krieglstein J (ed) Pharmacology of cerebral ischaemia. Elsevier, Amsterdam, pp 191–197Google Scholar
  151. Wilke R, Arch JRS, Nicholson CD (1989) Tissue selective inhibition of cyclic nucleotide phosphodiesterase by denbufylline. Arzneimittelforschung 39:665–667Google Scholar
  152. Wolthuis OL (1971) Experiments with UCB 6215, a drug which enhances acquisition in rats: its effects compared with those of metamphetamine. Eur J Pharmacol 16:283–297Google Scholar
  153. Wolthuis OL (1981) Behavioural effects of etiracetam in rats. Pharmacol Biochem Behav 15:247–255Google Scholar
  154. Wu PH, Phillis JW, Nye MJ (1982) Alkylxanthines as adenosine receptor antagonists and membrane phosphodiesterase inhibitors in central nervous tissue: evaluation of structure-activity relationships. Life Sci 31:2857–2862Google Scholar

Copyright information

© Springer-Verlag 1990

Authors and Affiliations

  • C. D. Nicholson
    • 1
  1. 1.Scientific Development GroupOrganon Laboratories LimitedNewhouseUK

Personalised recommendations