Abstract
Heptyl-physostigmine (Heptyl-Phy; MF-201) is a new carbamate derivative of physostigmine (Phy) with greater lipophilicity and longer inhibitory action on cholinesterase (ChE) activity than the parent compound. Following single dose administration of 5 mg/kg heptyl-Phy i.m., maximal whole brain acetylcholinesterase (AChE) inhibition (82%) if reached at 60 min. Inhibition of plasma BuChE butyrylcholinesterase (BuChE) remains close to the steady state level (60%) between 120 and 360 min. At 360 min, whole brain AChE activity is still 67% inhibited compared to controls. Inhibition of AChE activity displays brain regional differences which are more significant at 360 min. At this time point, AChe activity in cerebellum is only 40% inhibited while frontal cortex and medial septum are still 80% inhibited. Increases in acetycholine (ACh) levels also show regional differences, however, there is no direct relationship between AChE inhibition and ACh increase. The electrically evoked [3H]ACh release in cortical slices was inhibited only by the highest concentration of heptyl-Phy tested (10−4M). At this concentration ChE activity was 97% inhibited in vitro. In conclusion, our results demonstrate that heptyl-Phy compares favorably to other reversible cholinesterase inhibitors (ChEI), particularly to Phy as far as producing a more long-lasting inhibition of AChE and a more prolonged increase of ACh in brain with less severe side effects. Therefore, it represents an interesting candidate for cholinomimetic therapy of Alzheimer disease (AD).
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References
Becker, R. E., and Giacobini, E. 1988. Mechanisms of cholinesterase inhibition in senile dementia of the Alzheimer type: clinical, pharmacological and therapeutic aspects. Drug Development. Res. 12: 163–195.
Brufani, M., Marta, M., and Pomponi, M. 1986. Anticholinesterase activity of a new carbamate, heptylphysostigmine (C8) in view of its use in patients with Alzheimer-type dementia. Eur. J. Biochem. 157: 115–120.
Oliverio, A., Castellano, C., Iacopino, C., Pavone, F., Brufani, M., Marta, M., and Pomponi, M. 1986. Effects of physostigmine derivatives on cerebral cholinergic functions and their possible use in Alzheimer disease. Pages 305–309, in Biggio, G., Spano, P. F., Toffano, C. and Gessa, G. L. (eds.), Modulation of Central and Peripheral Transmitter Function, Liviana Press, Padova, Italy.
Brufani, M., Castellano, C., Marta, M., Oliverio, A., Pagella, P. G., Pavone, F., Pomponi, M., and Rugarli, P. L. 1987. A long-lasting cholinesterase inhibitor affecting neural and behavioral processes. Pharmacol. Biochem. Behav. 26: 625–629.
Hallak, M., and Giacobini, E. 1986. Relation of brain regional physostigmine concentration to cholinesterase activity and acetylcholine and choline levels in rat. Neurochem. Res. 11(7):1037–1048.
Johnson, C. D., and Russell, R. L. 1975. A rapid, simple radiometric assay for cholinesterase, suitable for multiple determination. Analyt. Biochem. 64:229–238.
McCaman, R. E., and Stetzler, J. 1977. Radiochemical assay for acetylcholine: modification for sub-picomoles measurements. J. Neurochem. 28:669–671.
Mattio, T. G., Richardson, J. S., and Giacobini, E. 1984. Effects of DFP iridic metabolism and release of acetylcholine and on pupillary function in the rat. Neuropharmacology 23:1207–1214.
Beani, L., Bianchi, C., Siniscalchi, A., Sivilotti, L., Tanganelli, S. and Veratti, E. 1984. Different approaches to study acetylcholine release: endogenous ACh versus tritium efflux. Arch. Pharmacol. 328:119–126.
Gorell, J. M., and Czarnecki, B. 1986. Pharmacologic evidence for direct dopaminergic regulation of striatal acetylcholine release. Life Sci. 38:2239–2246.
Yamamura, H. I., and Snyder, S. H. 1974. Muscarinic receptor binding in rat brain. Proc. Natl. Acad. Sci. USA, 71:1725–1729.
Schwartz, R. D., McGee, R., and Kellar, K. J. 1982. Nicotinic cholinergic receptors labeled by3H-acetylcholine in rat brain. Mol. Pharmacol. 22:56–62.
Lowry, O. H., Rosebrough, N. J., Farr, A. L., and Randall, R. J. 1951. Protein measurement with the folin phenol reagent. J. Biol. Chem. 193:265–275.
Segre, G., Pagella, P. G., Rugarli, P. L., Munari, M., Bernardi, R., Pomponi, M., and Brufani, M. 1988. MF-201 kinetics and ChE inhibition in brain after repeated treatment to rats: a comparison with THA. Pages 57–59, in Iqbal, K., Wisniewski, H. M. and Winblad, W. (eds.), Proceedings of Intl. Conf. Alzheimer Disease and Related Disorders, Alan R. Liss Inc., New York.
Hallak, M., and Giacobini, E. 1987. A comparison of the effects of two inhibitors on brain cholinesterase. Neuropharmacology 26(6):521–530.
Tang, X. C., DeSarno, P., Sugaya, K., and Giacobini, E. 1989. The effect of huperzine-A, a new cholinesterase inhibitor, on the central cholinergic system of the rat. J. Neurosci. Res. 24: (In Press).
Hadhazy, P., and Szerb, J. C. 1977. The effect of cholinergic drugs on3H-ACh release from slices of rat hippocampus, striatum and cortex. Brain Res. 123:311–322.
Kilbinger, H. 1984. Presynaptic muscarine receptors modulating acetylcholine release. Trends Pharmacological Sci. 5:103–105.
DeSarno, P., and Giacobini, E. 1989. Modulation of acetylcholine release by nicotinic receptors in the rat brain. J. Neurosci. Res. 22:194–200.
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Special issue dedicated to Dr. Paola S. Timiras
Dept. of Pharmacology, Shanghai Institute of Materia Medica Chinese Academy of Sciences Shanghai 20031 China.
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De Sarno, P., Pomponi, M., Giacobini, E. et al. The effect of heptyl-physostigmine, a new cholinesterase inhibitor, on the central cholinergic system of the rat. Neurochem Res 14, 971–977 (1989). https://doi.org/10.1007/BF00965931
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DOI: https://doi.org/10.1007/BF00965931