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Role of vinpocetine in cerebrovascular diseases

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Abstract

A cerebrovascular accident, or stroke, is defined as the abrupt onset of a neurological deficit, which can be due to ischemia. Cerebral ischemia is caused by a reduction in blood flow that thereby decreases cerebral metabolism. Chronic cerebral hypoperfusion leads to irreversible brain damage and plays an important role in the development of certain types of dementia. Vinpocetine, chemically known as ethyl apovincaminate, is a vinca alkaloid that exhibits cerebral blood-flow enhancing and neuroprotective effects. Nonclinical and clinical studies have suggested multiple mechanisms responsible for the beneficial neuroprotective effects of vinpocetine. As no significant side effects related to vinpocetine treatment have been reported, it is considered to be safe for long-term use. This vasoactive alkaloid is widely marketed as a supplement for vasodilation and as a nootropic for the improvement of memory. The present review focuses on studies investigating the role of vinpocetine in cerebrovascular diseases.

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Abbreviations

Aβ:

amyloid β-peptides

AD:

Alzheimer’s disease

AEDs:

antiepileptic drugs

AICVD:

asymptomatic ischemic cerebrovascular disorders

ATP:

adenosine triphosphate

CGI:

Clinical Global Impression

cGMP:

cyclic guanosine monophosphate

DOPAC:

3,4-dihydroxyphenylacetic acid

DPG:

2,3-diphosphoglycerate

GABA:

γ-aminobutyric acid

LC:

locus coeruleus

MMSQ:

mini-mental status questionnaire

NMDA:

N-methyl-D-aspartic acid

PET:

positron emission tomography

PSNHL:

progressive sensorineural hearing loss

PTZ:

pentylenetetrazole

RBC:

red blood cell

rCBF:

regional cerebral blood flow

ROS:

reactive oxygen species

RR:

relative risk

SCAG:

Sandoz clinical assessment geriatric scale

References

  1. Adám-Vizi V: Neuroprotective effect of sodium channel blockers in ischemia: the pathomechanism of early ischemic dysfunction (Hungarian). Orv Hetil, 2000, 141, 1279–1286.

    PubMed  Google Scholar 

  2. Balestreri R, Fontana L, Astengo F: 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 Geriatr Soc, 1987, 35, 425–430.

    Article  CAS  PubMed  Google Scholar 

  3. Bereczki D, Fekete I: A systematic review of vinpocetine therapy in acute ischaemic stroke. Eur J Clin Pharmacol, 1999, 55, 349–352.

    Article  CAS  PubMed  Google Scholar 

  4. Bereczki D, Fekete I: Vinpocetine for acute ischemic stroke. Stroke, 2008, 39, 2404–2405.

    Article  Google Scholar 

  5. Bonoczk P, Gulyas B, Adam-Vizi V, Nemes A, Karpati E, Kiss B, Kapas M et al.: Role of sodium channel inhibition in neuroprotection: effect of vinpocetine. Brain Res Bull, 2000, 53, 245–254.

    Article  CAS  PubMed  Google Scholar 

  6. Burtsev EM, Savkov VS, Shprakh VV, Burtsev ME: 10-years experience with using Cavinton in cerebrovascular disorders (Russian). Zh Nevropatol Psikhiatr Im S S Korsakova, 1992, 92, 56–60.

    CAS  PubMed  Google Scholar 

  7. Csillik B, Mihály A, Knyihár-Csillik E: Antinociceptive effect of vinpocetine - a comprehensive survey. Ideggyogy Sz, 2010, 63, 185–192.

    PubMed  Google Scholar 

  8. DeNoble VJ, Repetti SJ, Gelpke LW, Wood LM, Keim KL: Vinpocetine: nootropic effects on scopolamine-induced and hypoxia- induced retrieval deficits of a step-through passive avoidance response in rats. Pharmacol Biochem Behav, 1986, 24, 1123–1128.

    Article  CAS  PubMed  Google Scholar 

  9. Deshmukh R, Sharma V, Mehan S, Sharma N, Bedi KL: Amelioration of intracerebroventricular streptozotocin induced cognitive dysfunction and oxidative stress by vinpocetine - a PDE1 inhibitor. Eur J Pharmacol, 2009, 620, 49–56.

    Article  CAS  PubMed  Google Scholar 

  10. Dézsi L, Kis-Varga I, Nagy J, Komlódi Z, Kárpáti E: Neuroprotective effects of vinpocetine in vivo and in vitro. Apovincaminic acid derivatives as potential therapeutic tools in ischemic stroke (Hungarian). Acta Pharm Hung, 2002, 72, 84–91.

    PubMed  Google Scholar 

  11. Dutov AA, Tolpyshev BA, Karpov VN, Petrov AP: Effect of Cavinton on convulsions caused by chemical substances (Russian). Farmakol Tbksikol, 1986, 49, 22–25.

    CAS  Google Scholar 

  12. Dutov AA, Gal’tvanitsa GA, Volkova VA, Sukhanova ON, Lavrishcheva TG, Petrov AP: Cavinton in the prevention of the convulsive syndrome in children after birth injury (Russian). Zh Nevropatol Psikhiatr Im S S Korsakova, 1991, 91, 21–22.

    CAS  PubMed  Google Scholar 

  13. Dutov AA, Tolpyshev BA, Petrov AP, Gladun VN: Use of cavinton in epilepsy (Russian). Zh Nevropatol Psikhiatr Im S S Korsakova, 1986, 86, 850–855.

    CAS  PubMed  Google Scholar 

  14. Feher G, Koltai K, Kesmarky G, Horvath B, Toth K, Komoly S, Szapary L: Effect of parenteral or oral vinpocetine on the hemorheological parameters of patients with chronic cerebrovascular diseases. Phytomedicine, 2009, 16, 111–117.

    Article  CAS  PubMed  Google Scholar 

  15. Feigin VL, Doronin BM, Popova TF, Gribatcheva EV, Tchervov DV: Vinpocetine treatment in acute ischaemic stroke: a pilot single-blind randomized clinical trial. Eur J Neurol, 2001, 8, 81–85.

    Article  CAS  PubMed  Google Scholar 

  16. Grandt R, Braun W, Schulz HU, Lührmann B, Frercks HJ: Glibenclamide steady state plasma levels during concomitant vinpocetine administration in type II diabetic patients. Arzneimittelforschung, 1989, 39, 1451–1454.

    CAS  PubMed  Google Scholar 

  17. Gurkovskaia AV, Gokina NI, Buryi VA, Shuba MF: Electrophysiological analysis of the action of cavinton on the smooth muscles (Russian). Biull Eksp Biol Med, 1987, 103, 68–71.

    CAS  PubMed  Google Scholar 

  18. Hadjiev D: Asymptomatic ischemic cerebrovascular disorders and neuroprotection with vinpocetine. Ideggyogy Sz, 2003, 56, 166–172.

    PubMed  Google Scholar 

  19. Hadjiev D, Yancheva S: Rheoencephalographic and psychological studies with ethyl apovincaminate in cerebral vascular insufficiency. Arzneimittelforschung, 1976, 26, 1947–1950.

    CAS  PubMed  Google Scholar 

  20. Hagiwara M, Endo T, Hidaka H: Effects of vinpocetine on cyclic nucleotide metabolism in vascular smooth muscle. Biochem Pharmacol, 1984, 33, 453–457.

    Article  CAS  PubMed  Google Scholar 

  21. Hayakawa M: Effect of vinpocetine on red blood cell de-formability in stroke patients. Arzneimittelforschung, 1992, 42, 425–427.

    CAS  PubMed  Google Scholar 

  22. Hayakawa M: Comparative efficacy of vinpocetine, pentoxifylline and nicergoline on red blood cell deformabil-ity. Arzneimittelforschung, 1992, 42, 108–110.

    CAS  PubMed  Google Scholar 

  23. Hindmarch I, Fuchs HH, Erzigkeit H: Efficacy and tolerance of vinpocetine in ambulant patients suffering from mild to moderate organic psychosyndromes. Int Clin Psychopharmacol, 1991, 6, 31–43.

    Article  CAS  PubMed  Google Scholar 

  24. Hitzenberger G, Schmid R, Braun W, Grandt R: Vinpocetine therapy does not change imipramine pharmacokinetics in man. Int J Clin Pharmacol Ther Toxicol, 1990, 28, 99–104.

    CAS  PubMed  Google Scholar 

  25. Jeon KI, Xu X, Aizawa T, Lim JH, Jono H, Kwon DS, Abe J et al.: Vinpocetine inhibits NF-кB dependent inflammation via an IKK-dependent but PDE-independent mechanism. Proc Natl Acad Sci USA, 2010, 107, 9795–9800.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  26. Kaham A, Olah M: Use of ethyl apovincaminate in oph-thalmological therapy. Arzneimittelforschung, 1976, 26, 1969–1972.

    Google Scholar 

  27. Karpati E, Szporny L: General and cerebral haemody-namic activity of ethyl apovincaminate. Arzneimittelforschung, 1976, 26, 1908–1912.

    CAS  PubMed  Google Scholar 

  28. Katsuta K, Umemura K, Ueyama N, Matsuoka N: Pharmacological evidence for a correlation between hippo-campal CA1 cell damage and hyperlocomotion following global cerebral ischemia in gerbils. Eur J Pharmacol, 2003, 467, 103–109.

    Article  CAS  PubMed  Google Scholar 

  29. Kiss B, Karpati E: Mechanism of action of vinpocetine (Hungarian). Acta Pharm Hung, 1996, 66, 213–224.

    CAS  PubMed  Google Scholar 

  30. Krieglstein J, Rischke R: Vinpocetine increases the neuroprotective effect of adenosine in vitro. Eur J Pharmacol, 1991, 205, 7–10.

    Article  CAS  PubMed  Google Scholar 

  31. Kuzuya F, Osawa M, Maruyama S: Effects of vinpocetine on blood viscosity and platelet aggregability. Today’s Therapy Trends, 1985, 1, 21–29.

    Google Scholar 

  32. Lakics V, Sebestyén MG, Erdö SL: Vinpocetine is a highly potent neuroprotectant against veratridine-induced cell death in primary cultures of rat cerebral cortex. Neurosci Lett, 1995, 185, 127–130.

    Article  CAS  PubMed  Google Scholar 

  33. Lamar JC, Poignet H, Beaughard M: Calcium antagonist activity of vinpocetine and vincamine in several models of cerebral ischemia. Drug Develop Res, 1988, 14, 297–304.

    Article  Google Scholar 

  34. Lohmann A, Dingier E, Sommer W, Schaffler K, Wober W, Schmidt W: Bioavailability of vinpocetine and interference of the time of application with food intake. Arzneimittelforschung, 1992, 42, 914–917.

    CAS  PubMed  Google Scholar 

  35. Lorincz C, Szasz K, Kisfaludy L: The synthesis of ethyl apovincaminate. Arzneimittelforschung, 1976, 26, 1907.

    CAS  PubMed  Google Scholar 

  36. Maslarova J, Nikolov R: Antihypoxic effect of vinpocetine. Works of the Chemical Pharmaceutical Research Institute, 1999, XIX, 175–182.

    Google Scholar 

  37. Matsukawa M, Ogawa M, Nakadate K, Maeshima T, Ichitani Y, Kawai N: Serotonin and acetylcholine are crucial to maintain hippocampal synapses and memory acquisition in rats. Neurosci Lett, 1997, 230, 13–16.

    Article  CAS  PubMed  Google Scholar 

  38. McDaniel MA, Maier SF, Einstein GO: Brain-specific nutrients: a memory cure? Nutrition, 2003, 19, 957–975.

    Article  CAS  PubMed  Google Scholar 

  39. Milusheva E, Sperlagh B, Kiss B, Szporny L, Pásztor E, Papasova M, Vizi ES: Inhibitory effect of hypoxic condition on acetylcholine release is partly due to the effect of adenosine released from the tissue. Brain Res Bull, 1990, 24, 369–373.

    Article  CAS  PubMed  Google Scholar 

  40. Miskolczi P, Korma K, Polgar M, Vereczkey L: Pharmacokinetics of vinpocetine and its main metabolite apovincaminic acid before and after the chronic oral administration of vinpocetine to humans. Eur J Drug Metab Pharmacokinet, 1990, 15, 1–5.

    Article  CAS  PubMed  Google Scholar 

  41. Miyata N, Yamaura H, Tanaka M, Muramatsu M, Tsuchida K, Okuyama S, Otomo S: Effects of VA-045, a novel apovincaminic acid derivative, on isolated blood vessels: cerebroarterial selectivity. Life Sci, 1993, 52, 181–186.

    Article  Google Scholar 

  42. Miyazaki M: The effect of cerebral vasodilator, vinpocetine, on cerebral vascular resistance evaluated by the Doppler ultrasonic technique in patients with cerebrovascular diseases. Angiology, 1995, 46, 53–58.

    Article  CAS  PubMed  Google Scholar 

  43. Nosalova V, Machova J, Babulova A: Protective action of vinpocetine against experimentally induced gastric damage in rats. Arzneimittelforschung, 1993, 43, 981–985.

    CAS  PubMed  Google Scholar 

  44. Nyakas C, Felszeghy K, Szabó R, Keijser JN, Luiten PG, Szombathelyi Z, Tihanyi K: Neuroprotective effects of vinpocetine and its major metabolite cis-apovincaminic acid on NMDA-induced neurotoxicity in a rat entorhinal cortex lesion model. CNS Neurosci Ther, 2009, 15, 89–99.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  45. Olpe HR, Steinmann MW, Jones RSG: Locus coeruleus as a target for psychogeriatric agents. Ann NY Acad Sci, 1985, 444, 399–405.

    Article  Google Scholar 

  46. Ordögh B, Sárossy D, Klimstein G: Therapeutic action of cavinton in hearing defects of neurological origin. Ther Hung, 1978, 26, 16–19.

    PubMed  Google Scholar 

  47. Orosz E, Deak Gy, Benoist Gy: Effect of ethyl apovincaminate on the cerebral circulation. Arzneimittelforschung, 1976, 26, 1951–1956.

    CAS  PubMed  Google Scholar 

  48. Pálosi É, Szporny L: Effect of ethyl apovincaminate of the central nervous system. Arzneimittelforschung, 1976, 26, 1926–1929.

    PubMed  Google Scholar 

  49. Pereira C, Agostinho P, Moreira PI, Duarte AI, Santos MS, Oliveira CR: Neuroprotection strategies: effect of vinpocetine in vitro oxidative stress models (Portuguese). Acta Med Port, 2003, 16, 401–406.

    CAS  PubMed  Google Scholar 

  50. Pereira C, Agostinho P, Oliveira CR: Vinpocetine attenuates the metabolic dysfunction induced by amyloid beta-peptides in PC12 cells. Free Radic Res, 2000, 33, 497–506.

    Article  CAS  PubMed  Google Scholar 

  51. Polich J, Gloria R: Cognitive effects of a Ginkgo biloba/vinpocetine compound in normal adults: systematic assessment of perception, attention and memory. Hum Psychopharmacol, 2001, 16, 409–416.

    Article  CAS  PubMed  Google Scholar 

  52. Pudleiner P, Vereczkey L: Study on the absorption of vinpocetine and apovincaminic acid. Eur J Drug Metab Pharmacokinet, 1993, 18, 317–321.

    Article  CAS  PubMed  Google Scholar 

  53. Ribari O, Zelen B, Kollar B: Ethyl apovincaminate in the treatment of sensorineuronal impairment of hearing. Arzneimittelforschung, 1976, 26, 1977–1980.

    CAS  PubMed  Google Scholar 

  54. Rischke R, Krieglstein J: Effects of vinpocetine on local cerebral blood flow and glucose utilization seven days after forebrain ischemia in the rat. Pharmacology, 1990, 41, 153–160.

    Article  CAS  PubMed  Google Scholar 

  55. Rischke R, Krieglstein J: Protective effect of vinpocetine against brain damage caused by ischemia. Jpn J Pharmacol, 1991, 56, 349–356.

    Article  CAS  PubMed  Google Scholar 

  56. Romodanov AP, Potapov AI: The dynamic changes in the regional volumetric cerebral blood flow and local vascular reactivity in acute craniocerebral trauma in animals with alloxan diabetes (Russian). Zh Vopr Neirokhir Im N N Burdenko, 1990, 3, 19–22.

    Google Scholar 

  57. Schmidt J: Comparative studies on the anticonvulsant effectiveness of nootropic drugs in kindled rats. Biomed Biochim Acta, 1990, 49, 413–419.

    CAS  PubMed  Google Scholar 

  58. Shibuya T, Sato K: Effects of vinpocetine on experimental brain ischemia, histological study of brain monomines. IgakuNo Ayumi, 1986, 139, 217–219.

    CAS  Google Scholar 

  59. Shimizu Y, Saitoh K, Nakayama M: Agranulocytosis induced by vinpocetine. Medicine Online [serial online]. Available at: http://www.priory.com/med/vinpocetine.htm. Accessed March 08, 2008.

    Google Scholar 

  60. Sitges M, Galván E, Nekrassov V: Vinpocetine blockade of sodium channels inhibits the rise in sodium and calcium induced by 4-aminopyridine in synaptosome. Neurochem Int, 2005, 46, 533–540.

    Article  CAS  PubMed  Google Scholar 

  61. Sitges M, Guarneros A, Nekrassov V: Effects of carbamazepine, phenytoin, valproic acid, oxcarbazepine, lamotrigine, topiramate and vinpocetine on the presynaptic Ca2+ channel-mediated release of [3H]glutamate: comparison with the Na+ channel-mediated release. Neuropharmacology, 2007, 53, 854–862.

    Article  CAS  PubMed  Google Scholar 

  62. Skoromets AA, Tanashian MM, Chukanova EI, Petrova EA, Spirin NN, Nikonov AA, Peverennova IE, Levin IaI: A multicenter program on assessment of efficacy and safety of a new therapeutic scheme for patients with chronic cerebrovascular insufficiency (Russian). Zh Nevrol Psikhiatr Im S S Korsakova, 2009, 109, 44–48.

    CAS  PubMed  Google Scholar 

  63. Solntseva EI, Bukanova IuV, Skrebitskii VG: Memory and potassium channels (Russian). Usp Fiziol Nauk, 2003, 34, 16–25.

    CAS  PubMed  Google Scholar 

  64. Solti F, Iskum M, Czakó E: Effect of ethyl apovincaminate on the cerebral circulation. Studies in patients with obliterative cerebral arterial disease. Arzneimittelforschung, 1976, 26, 1945–1947.

    CAS  PubMed  Google Scholar 

  65. Stole S: Indole derivatives as neuroprotectants. Life Sci, 1999, 65, 1943–1950.

    Article  Google Scholar 

  66. Storm G, Oosterhuis B, Sollie FAE, Visscher HW, Sommer W, Beitinger H, Jonkman JHG: Lack of pharmacokinetic interaction between vinpocetine and oxazepam. Br J Clin Pharmcol, 1994, 38, 143–146.

    Article  CAS  Google Scholar 

  67. Subhan Z, Hindmarch I: Psychopharmacological effects of vinpocetine in normal healthy volunteers. Eur J Clin Pharmacol, 1985, 28, 567–571.

    Article  CAS  PubMed  Google Scholar 

  68. Szakali S, Boros I, Balkay L, Emri M, Fekete I, Kerényi L, Lehel S et al.: Cerebral effects of a single dose of intravenous vinpocetine in chronic stroke patients: A PET study. J Neuroimaging, 1998, 8, 197–204.

    Article  Google Scholar 

  69. Szapáry L, Horváth B, Alexy T, Márton Z, Késmárky G, Szóts M, Nagy F et al.: Effect of vinpocetin on the hemorheologic parameters in patients with chronic cerebrovascular disease (Hungarian). Orv Hetil, 2003, 144, 973–978.

    PubMed  Google Scholar 

  70. Szatmari SZ, Whitehouse PJ: Vinpocetine for cognitive impairment and dementia. Cochrane Database Syst Rev, 2003, 1, CD003119.

    Google Scholar 

  71. Szmolenszky T, Török B: Effect of ethyl apovincaminate on cerebral, carduac and renal flow rate in dogs in the course of administration. Arzneimittelforschung, 1976, 26, 1914–1917.

    CAS  PubMed  Google Scholar 

  72. Szobor A, Klein M: Ethyl apovincaminate therapy in neurovascular diseases. Arzneimittelforschung, 1976, 26, 1984–1989.

    CAS  PubMed  Google Scholar 

  73. Tamaki N, Kusunoki T, Matsumoto S: The effect of vinpocetine on cerebral blood flow in patients with cerebrovascular disorders. Ther Hungar, 1985, 33, 13–21.

    CAS  Google Scholar 

  74. Tárnok K, Kiss E, Luiten PG, Nyakas C, Tihanyi K, Schlett K, Eisel UL: Effects of Vinpocetine on mitochondrial function and neuroprotection in primary cortical neurons. Neurochem Int, 2008, 53, 289–295.

    Article  PubMed  CAS  Google Scholar 

  75. Thal LJ, Salmon DP, Lasker B, Bower D, Klauber MR: The safety and lack of efficacy of vinpocetine in Alzheimer’s disease. J Am Geriatr Soc, 1989, 37, 515–520.

    Article  CAS  PubMed  Google Scholar 

  76. Tohgi H, Sasaki K, Chiba K, Nozaki Y: Effect of vinpocetine on oxygen release of hemoglobin and erythrocyte organic polyphosphate concentrations in patients with vascular dementia of the Binswanger type. Arzneimittelforschung, 1990, 40, 640–643.

    CAS  PubMed  Google Scholar 

  77. Trejo F, Nekrassov V, Sitges M: Characterization of vinpocetine effects on DA and DOPAC release in striatal isolated nerve endings. Brain Res, 2001, 909, 59–67.

    Article  CAS  PubMed  Google Scholar 

  78. Truss MC, Uckert S, Stief CG, Forssmann WG, Jonas U: Cyclic nucleotide phosphodiesterase (PDE) isoenzymes in the human detrusor smooth muscle. II. Effect of various PDE inhibitors on smooth muscle tone and cyclic nucleotide levels in vitro. Urol Res, 1996, 24, 129–134.

    Article  CAS  PubMed  Google Scholar 

  79. Valikovics A: Investigation of the effect of vinpocetine on cerebral blood flow and cognitive functions (Hungarian). Ideggyogy Sz, 2007, 60, 301–310.

    PubMed  Google Scholar 

  80. Vaizova OE, Vengerovskii AI, Alifirova VM: An effect of vinpocetine (cavinton) on endothelium functions in patients with chronic cerebral ischemia (Russian). Zh Nevrol Psikhiatr Im S S Korsakova, 2006, 16, 46–50.

    PubMed  Google Scholar 

  81. Vereczkey L: Pharmacokinetics and metabolism of vin-camine and related compounds. Eur J Drug Metab Phar-macokinet, 1985, 10, 89–103.

    Article  CAS  Google Scholar 

  82. World Health Organization. World Health Report 2002. Reducing Risks, Promoting Healthy Life. Geneva: WHO, 2002. (www.who.int/whr).

    Google Scholar 

  83. Yao JH, Su CY, Chu XY: Pharmacokinetics and disposition of vinpocetine in rats (Chinese). Yao Xue Xue Bao, 1994, 29, 81–85.

    CAS  PubMed  Google Scholar 

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  1. Department of Pharmacology & Neurology, Postgraduate Institute of Medical Education and Research, Chandigarh, 160012, Chandigarh, India

    Sazal Patyar, Ajay Prakash, Manish Modi & Bikash Medhi

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  1. Sazal Patyar
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  2. Ajay Prakash
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Patyar, S., Prakash, A., Modi, M. et al. Role of vinpocetine in cerebrovascular diseases. Pharmacol. Rep 63, 618–628 (2011). https://doi.org/10.1016/S1734-1140(11)70574-6

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