Effects of cholinesterase inhibitor metrifonate on naive rats and rats with a model of hypoxia-induced impaired memory
Cholinesterase inhibitors are currently used in the therapy of different kind of dementia to improve brain memory functions. The acetylcholinesterase inhibitor metrifonate was studied in naive rats and in rats with a model of sodium nitrite-induced hypoxia. One active avoidance test and in two passive avoidance tests were used. In the active avoidance test metrifonate increased the number of avoidances during the learning session only. In both passive avoidance tests, metrifonate prolonged latency differently during the learning session and in short-term or in long-term memory retention. Hypoxic rats showed lower numbers of avoidances in learning and memory retention sessions. Metrifonate increased the number of avoidances during the learning session for hypoxic rats. In the step-through passive avoidance test, metrifonate increased the latency of reactions in the learning session and in long-term memory retention tests. In the step-down passive avoidance test, the groups with hypoxia and metrifonate did not change the latency of reaction in the learning and long-term memory retention sessions, but increased the latency of reactions in the short-term memory retention test. Morphological data showed a significant impaired neuronal structure in a CA1 zone of the hippocampus in hypoxic rats and a tendency to preserving in rats treated with metrifonate. Our results suggest that metrifonate improves cognitive functions in naive and in hypoxic rats.
- Department of Pharmacology, Clinical Pharmacology and Drug Toxicology, Medical University, 15A V. Aprilov str, 4002, Plovdiv, Bulgaria
- Department of Pharmacology, Clinical Pharmacology and Drug Toxicology, Medical University, 15A V. Aprilov str, 4002, Plovdiv, Bulgaria, email@example.com
- Department of Pathology, Medical University, 15A V. Aprilov str, 4002, Plovdiv, Bulgaria
-  A.J. Lerner and P.J. Whitehouse: “Primary dementias”, In: Clinical Neurology of Aging, 2nd ed, M.L. Albert and J.E. Knoefel (Eds.), New York, Oxford Press, 1994.
-  I. Gelinas and S. Auer: “Functional autonomy”, In: Clinical Diagnosis and Management of Alzheimer’s disease S. Gauthier (Ed.); Martin Dunitz Ltd, London, 1996.
-  J.M. Lopez-Arrieta and L. Schneider: “Metrifonate for Alzheimer’s disease”, Cochrane Database Syst. Rev., Vol. 19, (2006). [Crossref]
-  P.J. Whitehouse, D.L. Price, A.W. Clark, J.T. Coyle and M.R. DeLong: “Alzheimer’s disease: Evidence for selective loss of cholinergic neurons in the nucleus basalis”, Ann. Neurol., Vol. 10, (1981) pp. 122–126. http://dx.doi.org/10.1002/ana.410100203[Crossref]
-  R.T. Bartus, R.L. III Dean, B. Beer and A.S. Lippa. “The cholinergic hypothesis of geriatric memory dysfunction”, Science, Vol. 217, (1992), pp. 408–417. http://dx.doi.org/10.1126/science.7046051[Crossref]
-  J. Cerf, A. Lebrun and J. Dierichx: “A new approach in helminthiasis control: The use of an organophosphors compound”, Am. J. Trop. Med. Hyg., Vol. 11, (1962), pp. 514–517.
-  J.M. Ringman and J.L. Kummings: “Metrifonate: update on a new antidementia agent”, J. Clin. Psychiatry, Vol. 60, (1999), pp. 776–782. http://dx.doi.org/10.4088/JCP.v60n1111[Crossref]
-  M.W. Jann: “Preclinical pharmacology of metrifonate”, Pharmacotherapy, Vol. 18, (1998), pp. 55–67, pp.79–82.
-  C. Scali, F. Casamenti, A. Belluci, C. Costagli, B. Schmidt and G. Pepeu: “Effect of subchronic administration of metrifonate, rivastigmine and donepezil on brain acetylcholine in aged F344 rats”, J. Neural. Transm., Vol. 109, (2002), pp. 1067–1080. http://dx.doi.org/10.1007/s007020200090[Crossref]
-  Z. Hlinak and I. Krejci: “Long-term behavior consequences of sodium nitrite hypoxia: an animal model”, Acta Nerv. Super., Vol. 32, (1990), pp. 48–53.
-  B.H. Schmidt and M. De Jonge: “Behavioral and biochemical studies on metrifonate: a novel putative Alzheimer therapeutic”, Biol. Psychiatry, Vol. 29, (1991), p. 486S.
-  J. Prickaerts, A. Sik, F.J. van der Staay, J. de Vente and A. Blokland: “Dissociable effects of acethylcholinesterase inhibitors and phosphodiesterase type 5 inhibitors on object recognition memory: acquisition versus consolidation”, Psychopharmacology, Vol. 177, (2005), pp. 381–390. http://dx.doi.org/10.1007/s00213-004-1967-7[Crossref]
-  C.L. Liu, B.K. Siesjo and B.R. Hu: “Pathogenesis of hippocampal neuronal death after hypoxia-ischemia changes during brain development”, Neuroscience, Vol. 127, (2004), pp. 113–123. http://dx.doi.org/10.1016/j.neuroscience.2004.03.062[Crossref]
-  V.S. Koziar, S.S. Trofimov, R.U. Ostrovskaia, A.K. Sariev and V.P. Zherdev. “Prenatal exposure to sodium oxybutirate prevents a disorder of general behaviour, learning and memory in the progeny of rats subjected to chronic haemic hypoxia”, Eksp. Klin. Farmakol., Vol. 57, (1994), pp. 8–11.
-  Z. Hlinak, I. Krejci,.J. Hondlik and A. Yamamoto: “Behavioral consequences of sodium nitrite in male rats: amelioration with alaptide treatment”, Methods. Find. Exp. Clin. Pharmacol., Vol. 12, (1990), pp. 385–393.
-  G.M. Govannini, C. Scali, L. Bartolini, B. Schmidt and G. Pepeu. “Effect of subchronic treatment with metrifonate and tacrine on brain cholinergic function in aged F344 rats”, Eur. J. Pharmacol., Vol. 354, (1998), pp. 17–24. http://dx.doi.org/10.1016/S0014-2999(98)00429-4[Crossref]
-  B.H. Schmidt, V.C. Hinz and F.J. van der Staay: “The preclinical pharmacology of metrifonate, a long-acting and well tolerated cholinesterase inhibitor for Alzheimer therapy”, In: Progress in Alzheimer and Parkinson’s Disease, A. Fisher, M. Yoshida, I. Hanin (Eds.), Plenum, New York, 1997.
-  M. Riekkinen, B.H. Schmidt and P.J. Riekkinen: “Subchronic treatment increases the duration of the cognitive enhancement induced by metrifonate”, Eur. J. Pharmacol., Vol. 338, (1997), pp. 105–110. http://dx.doi.org/10.1016/S0014-2999(97)81936-X[Crossref]
-  C. Nyakas, B. Buwalda, R.J. Kramers, J. Traber and P.G. Luiten: “Postnatal development of hyppocampal and neocortical cholinergic and serotonergic innervation in rat: effects of nitrite-induced prenatal hypoxia and nimodipine treatment”, Neuroscience, Vol. 59, (1994), pp. 541–559. http://dx.doi.org/10.1016/0306-4522(94)90176-7[Crossref]
-  J.F. Disterhoft and M.M. Oh: “Pharmacological and molecular enhancement of learning in aging and Alzheimer’s disease”, J. Physiol. Paris, Vol. 99, (2006), pp. 180–192. http://dx.doi.org/10.1016/j.jphysparis.2005.12.079[Crossref]
-  J.F. Disterhoft and M.M. Oh: “Modulation of cholinergic transmission enhances excitability of hippocampal pyramidal neurons and ameliorates learning impairments in aging animals”, Neurobiol. Learn. Mem., Vol. 80, (2003), pp. 223–233. http://dx.doi.org/10.1016/j.nlm.2003.08.004[Crossref]