Abstract
Phenserine ((−)-N-phenylcarbamoyl eseroline), a carbamate analog of physostigmine (Phy), is a long-acting inhibitor of cholinesterase. We have assessed the potential clinical value of phenserine for cholinomimetic therapy of cognitive impairments associated with aging and Alzheimer's disease by evaluating its duration of in vivo activity against rat plasma acetylcholinesterase (AChE) and its effect on attenuating a scopolamine-induced impairment in learning performance of young rats in a shock-motivated 14-unit T-maze. Phenserine achieved maximum AChE inhibition of 73.5% at 5 min and maintained a high and relatively constant inhibition for more than 8 h. For analysis of effects on learning performance, 69, 3-month-old male Fischer-344 rats were pretrained in a straight runway to avoid electric footshock. On the following day, each animal received 15 trials in the 14-unit T-maze. Sixty minutes prior to the maze training, each rat received the first IP injection of either vehicle (Tween 80, ethanol and 0.9% NaCl) or phenserine at 1.5, 3.0, 4.0, 5.0, 7.5, or 10.0 mg/kg. Then 30 min prior to the training, each animal received a second IP injection of either 0.9% NaCl or scopolamine hydrochloride (0.75 mg/kg; SCOP). Compared to the vehicle-SCOP group, all but the 7.5 mg/kg dose of phenserine significantly ameliorated error performance, runtime, shock frequency and shock duration in SCOP-treated rats at the final block of three trials. Appearing to have a long effect and a wide therapeutic window, phenserine deserves further study as a cognitive enhancer.
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References
Atack JR, Yu S-Q, Soncrant TT, Brossi A, Rapoport SI (1989) Comparative inhibitory effects of various physostigmine analogs against acetyl-and butylrylcholinesterases. J Pharmacol Exp Ther 249:194–202
Bartus RT, Dean RL III, Beer B, Lippa AS (1982) The cholinergic hypothesis of geriatric memory dysfunction. Science 217:408–417
Beilstein E (1954) Handbuch der Organischen Chemie, 4th edn, vol. 23. Springer Verlag, Berlin, pp 333
Bresnahan EL, Kametani H, Spangler EL, Chachich ME, Wiser PR, Ingram DK (1988) Fimbria-fornix lesions in young rats impair acquisition in a 14-unit T-maze similar to prior observed performance deficits in aged rats. Psychobiology 16:243–250
Brozostowska M, He X-S, Greig NH, Rapoport SI, Brossi A (1992) Phenylcarbamates of (−)-eseroline, (−)-N1-noreseroline and (−)-physovenol: selective inhibitors of acetyl and, or butyrylcholinesterase. Med Chem Res 2:238–246
Brufani M, Castellano C, Marta M, Oliverio A, Pagella PG, Pavone F, Pomponi M, Rugarli PL (1987) A long-lasting cholinesterase inhibitor affecting neural and behavioral processes. Pharmacol Biochem Behav 26:625–629
Dawson GR, Bentley G, Draper F, Rycroft W, Iversen SD, Pagella PG (1991) The behavioral effects of heptyl physostigmine, a new cholinesterase inhibitor, in tests of long-term and working memory in rodents. Pharmacol Biochem Behav 39:865–871
Decker MW, McGaugh JL (1991) The role of interactions between the cholinergic system and other neuromodulatory systems in learning and memory. Synapse 7:151–168
De Sarno P, Pomponi M, Giacobini E, Tang XC, Williams E (1989) The effect of heptyl-physostigmine, a new cholinesterase inhibitor, on the central cholinergic system of the rat. Neurochem Res 14:971–977
Dunnett SB, Everitt BJ, Robbins TW (1991) The basal forebrain-cortical cholinergic system: interpreting the functional consequences of excitotoxic lesions. TINS 14:494–501
Ellman GL, Courtney KD, Andres V Jr., Featherstone RM (1961) A new and rapid colorimetric determination of acetylcholinesterase activity. Biochem Pharmacol 7:88–95
Fibiger HC (1991) Cholinergic mechanisms in learning, memory and dementia: a review of recent evidence. TINS 14:220–223
Fischer W, Chen KS, Gage FH, Björklund A (1992) Progressive decline in spatial learning and integrity of forebrain cholinergic neurons in rats during aging. Neurobiol Aging 13:9–23
Gauthier S, Bouchard R, Lamontagne A, Bailey P, Bergman H, Ratner J, Tesfaye Y, Saint-Martin M, Bacher Y, Carrier L, Charbonneau R, Clarfield AM, Collier B, Dastoor D, Gauthier L, Germain M, Kissel C, Krieger M, Kushnir S, Masson H, Morin J, Nair V, Neirinck L, Suissa S (1990) Tetrahydroaminoacridine-lecithin combination treatment in patients with intermediate-stage Alzheimer's disease. N Engl J Med 322:1272–1276
Huff FJ, Antuono P, Murphy M, Beyer J, Dobson C (1991) Potential clinical use of an adrenergic/cholinergic agent (HP 128) in the treatment of Alzheimer's disease. In: Growdon JH, Corkin S, Ritter-Walker E, Wurtman RJ (eds) Aging and Alzheimer's disease: sensory systems, neuronal growth, and neuronal metabolism. Ann NY Acad Sci 640:263–267
Iijima S, Greig NH, Garofalo P, Spangler EL, Heller B, Brossi A, Ingram DK (1992) The long-acting cholinesterase inhibitor heptyl-physostigmine attenuates the scopolamine-induced learning impairment of rats in a 14-unit T-maze. Neurosci Lett 144:79–83
Ingram DK (1988) Complex maze learning in rodents as a model of age-related memory impairment. Neurobiol Aging 9:475–485
Ingram DK (1990) Complex maze learning in rodents: progress and potential for modeling age-related memory dysfunction. In: Goldstein A (ed) Biomedical advances in aging. Plenum, New York, pp 451–468
Jucker M, Kametani H, Bresnahan EL, Ingram DK (1990) Parietal cortex lesions do not impair retention performance of rats in a 14-unit T-maze unless hippocampal damage is present. Physiol Behav 47:207–212
Kametani H, Bresnahan EL, Chahich ME, Spangler EL, Ingram DK (1989) Comparison of retention performance between young rats with fimbria-fornix lesions and aged rats in a 14-unit T-maze. Behav Brain Res 35:253–263
Mandel RJ, Thal LJ (1988) Physostigmine improves water maze performance following nucleus basalis magnocellularis lesions in rats. Psychopharmacology 96:421–425
Marta M, Castellano C, Oliverio A, Pavone F, Pagella PG, Brufani M, Pomponi M (1988) New analogs of physostigmine: alternative drugs for Alzheimer's disease? Life Sci 43:1921–1928
Marx JL (1987) Alzheimer's drug trial put on hold. Science 238:1041–1042
Mohs RC, Davis BM, Greenwald BS, Mathé AA, Johns CA, Horvath TB, Davis KL (1985) Clinical studies of the cholinergic deficit in Alzheimer's disease, II. Psychopharmacologic studies. J Am Geriatr Soc 33:749–757
Murray TK, Cross AJ, Green AR (1991) Reversal by tetrahydroaminoacridine of scopolamine-induced memory and performance deficits in rats. Psychopharmacology 105:134–136
Palmer AM, Gershon S (1990) Is the neuronal basis of Alzheimer's disease cholinergic or glutamatergic? FASEB J 4:2745–2752
Perry EK, Irving D, Perry RH (1991) Cholinergic controversies. TINS 14:483–484
Polonovski M (1916) Alkaloids of the calabar bean. V. Action of phenyl isocyanate. Phenylic homologs of eserine and geneserine. Bull Soc Chim 19:46–59 (Translation from French)
Pomponi M, Giacobini E, Brufani M (1990) Present state and future development of the therapy of Alzheimer's disease. Aging 2:125–153
Ridley RM, Baker HF, Fine A (1991) Cholinergic controversies. TINS 14:482–483
Rupniak NMJ, Field MJ, Samson NA, Steventon MJ, Iversen SD (1990) Direct comparison of cognitive facilitation by physostigmine and tetrahydroaminoacridine in two primate models. Neurobiol Aging 11:609–613
Sarter M (1991) Taking stock of cognition enhancers. TIPS 12:456–461
Spangler EL, Rigby P, Ingram DK (1986) Scopolamine impairs learning performance of rats in a 14-unit T-maze. Pharmacol Biochem Behav 25:673–679
Spangler EL, Chachich ME, Ingram DK (1988) Scopolamine in rats impairs acquisition but not retention in a 14-unit T-maze. Pharmacol Biochem Behav 30:949–955
Spangler EL, Chachich ME, Curtis NJ, Ingram DK (1989) Age-related impairment in complex maze learning in rats: Relationship to neophobia and cholinergic antagonism. Neurobiol Aging 10:133–141
Summers WK, Majovski LV, Marsh GM, Tachiki K, Kling A (1986) Oral tetrahydroaminoacridine in long-term treatment of senile dementia, Alzheimer type. N Engl J Med 315:1241–1245
Wesnes KA, Simpson PM, White L, Pinker S, Jertz G, Murphy M, Klaudius S (1991) Cholinesterase inhibition in the scopolamine model of dementia. In: Growdon JH, Corkin S, Ritter-Walker E, Wurtman RJ (eds) Aging and Alzheimer's disease: sensory systems, neuronal growth, and neuronal metabolism. Ann NY Acad Sci 640:268–271
Yu Q-S, Atack JR, Rapoport SI, Brossi A (1988) Carbamate analogues of (−)-physostigmine, in vitro inhibition of acetyl- and butyrylcholinesterase. FEBS Lett 234:127–130
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Iijima, S., Greig, N.H., Garofalo, P. et al. Phenserine: a physostigmine derivative that is a long-acting inhibitor of cholinesterase and demonstrates a wide dose range for attenuating a scopolamine-induced learning impairment of rats in a 14-unit T-maze. Psychopharmacology 112, 415–420 (1993). https://doi.org/10.1007/BF02244888
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DOI: https://doi.org/10.1007/BF02244888