Effects on Cholinesterase Activity

Compared with AChE in animals such as horse and rat, HA is a weaker inhibitor of human serum BuChE. This selectivity for AChE as opposed to BuChE (similar to that of galanthamine) may suggest a better side-effects profile. However, a stronger inhibition of BuChE could be important in the later stage of AD and could offer more protection over amyloid p-peptide (Ap) plaque deposition. In contrast to isoflurophate, the AChE activity did not decrease with the prolongation of incubation with HA in vitro, and the AChE activity returned to 94% of the control after being washed five times, which indicates a reversible inhibitory action.  

Significant inhibition of AChE activity was demonstrated in the cortex, hippocampus, striatum, medial septum, medulla oblongata, cerebellum, and hypothalamus of rats that were sacrificed 30 min after the administration of HA at several dose levels compared with saline control.  

After administration of oral HA at doses of 0.12-0.5 mg/kg, a clear, dose-depen-dent inhibition of AChE was demonstrated in the brains of rats. ° In contrast to the AChE inhibition in vitro, the relative inhibitory effect of oral HA over AChE was found to be about 24- and 180-fold, on an equimolar basis, more potent than donepezil and tacrine, respectively. In rats, HA injected intraperitoneally (i.p.) exhibited similar efficacy of AChE inhibition as demonstrated after oral administration, whereas i.p. administration of tacrine and donepezil showed greater inhibition on both 

TABLE 4-3. Anti-ChE Activities of Oral HA, Donepezil, and Tacrine in Rats 

ChEI Dose mg/kg (pmol/kg) AChE Inhibition (%) (n = 6) BuChE Inhibition (%) Cortex Hippocampus Striatum Semm (n —3)  

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Routine gross and histopathological examinations revealed no treatment-related effects on the nervous system of dogs exposed to 0.03, 0.1, or 0.3 mg/kg/day methyl parathion in the diet for 1 year (Suba 1981). In addition, there were no treatment-related effects on cholinesterase activity in plasma, red blood cells, or brains in dogs under these exposure conditions. These data are in agreement with the NOAEL established above for dogs exposed to these levels for 13 weeks. 

When the specific additive is known, simpler procedures can be devised (67). Some insecticides can be detected from their effect on cholinesterase activity (68). 

In his ecotoxicological investigation of the Sk-agerrak area off the Swedish coast, Granbom (1996) reported on the placement of cages of crabs and mussels near scuttled ships. The organisms were checked for decreases in the enzyme activity of acetylcholinesterase. After a 2-3-week exposure, the retrieved animals appeared healthy and no statistically significant effect on cholinesterase activity was observed. 

Cefon, J.J., Ferrando, M.D., Sancho, E., Gutierrez-Panizo, C.,and Andreu-Moliner, E. Effects of diazinon exposure on cholinesterase activity in different tissues of European eel (Anguilla anguill, Ecotoxicol Environ. Sal, 35(3) 222-225, 1996. 

Fleisher reported that both sarin and VX increased the sensitivity of the isolated frog s rectus abdominis to external application of acetylcholine and at the same time decreased the activity of cholinesterase in the external surfaces of the muscle cells. Sarin at 5 x 10-7 M reduced the threshold concentration of acetylcholine for inducing contraction of the muscle to 8% of that required before application of sarin. The same concentration of VX reduced the threshold concentration of acetylcholine to 6.7% of that needed previously. Contemporaneously, the activity of cholinesterase in the external surfaces of the muscle cells was reduced to 8.1% and 0% of that before application of sarin and VX, respectively. Addition of 2-PAM I at 5 x 10 M to the baths in which the muscles were suspended had little effect on the activity of the enzyme in homogenates of the muscles, but restored 75% and 91%, respectively, of the activity of cholinesterase in the external surfaces of the muscles exposed to sarin and VX. At the same time, the concentration of acetylcholine required to induce contraction of the muscles was raised to 53.3% and 58.3% of the original threshold concentrations, respectively, for the muscles exposed to sarin and to VX. 

Harris LW, JH Fleisher, Innerebner, et al. 1969. The effects of atropine-oxime therapy on cholinesterase activity and the survival of animals poisoned with diethyl-0-(2-isopropyl-6-methyl-4-pyrimidinyl) phosphorothioate. Toxicol Appl Pharmacol 15 216-226. 

DM is considered less effective as a riot control or incapacitating agent than CS and CN (chloro-acetophenone), and it has been conjectured that there are greater differences in susceptibility among people to DM than to the other agents. DM, like CS, is considered to be a cholinesterase inhibitor, which may be responsible for its lacrimatory effect. DM also has a direct effect on gastric activity, but the evidence suggests that the lethal effect is respiratory related. 

Dube, S.N., Somani, S.M., and Colliver, J.A., Interactive effects of physostigmine and exercise on cholinesterase activity in RBC tissues of rat, Part-I. Arch. Int. Pharmacodyn. 

Husain, K. and Somani, S.M., Effect of exercise training and chronic ethanol ingestion on cholinesterase activity and lipid peroxidation in blood and brain regions of rat. Prog. Neuro-Psychopharmacol. Biol. Psychiat., 22, 411, 1998. 

Ko.sasa, T, Kuriya, Y., Matsui, K., and Yamanishi. Y. (2000). Inhibitory effect of orally adnnini,s tcrcd donepezil hydrochloride (E2020). a novel treatment for Alzheimer s disease, on cholinesterase activity in rats, Ettr. J. Pharmucoi. 389. I73-I79. 

Wilensky. J. G Dettbam, W.-D., and Rosenberg, P. (1967). Effect of ocular instillation of ccothiuphate iodide and isofluorophatc on cholinesterase activity of various rabbit tissues. Am. J. Ophthalmol. 64, 398-f04. 

Other Effects of Cadmium on the Central Nervous System. Cadmium may affect the activity of certain enzymes in the brain. Adenylate cyclase activity in the rat cerebrum, cerebellum, and brain stem vv as inhibited in vitro by micromolar concentrations of cadmiumMonoamine oxidase, which is involved in the catabolism of transmitter monoamines, was also lowered in activity by cadmium in vitro A comparative study of the effects of cadmium and zinc on cholinesterase activity in the brain showed that cadmium activated cholinesterase, whereas zinc reduced this enzyme after acute intoxication. Following chronic exposure to both metals, the cholinesterase activity was not significantly altered. ... 

R. S. Pangal, R. D. Rana and V. Kumar, The effect of imidocarb on cholinesterase activity and grossly observable behaviour in dogs, Haryana Vet., 2009, 48, 26-28. 

Petruccioli, L. and P. Turillazzi. 1991. Effect of methylmercury on acetylcholinesterase and serum cholinesterase activity in monkeys, Macaca fascicularis. Bull. Environ. Contam. Toxicol. 46 769-773. 

Martin, P.A., K.R. Solomon, D.J. Forsythe, H.J. Boermans, and N.D. Westcott. 1991b. Effects of exposure to carbofuran-sprayed vegetation on the behavior, cholinesterase activity and growth of mallard ducklings (Anas platyrhynchos). Environ. Toxicol. Chem. 10 901-909. 

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