AChE inhibition

Heptylphysostigmine (eptastigmine) (17) has been shown to be as active as physostigmine in AChE inhibition, but superior to physostigmine in terms of oral bioavadabihty and half-life (118—120). However, further clinical evaluation of this compound has been halted because of dmg-related hematological toxicity. 

Arthun DA, Chakraborti TK, Chapman JL, et al. 1991. Comparison of in vivo acetylcholinesterase (AChE) inhibition in neonatal and adult rats by three organophosphoms insecticides. Neurotoxicology 12 143. 

CBs, like OPs, act as inhibitors of ChE. They are treated as substrates by the enzyme and carbamylate the serine of the active site (Figure 10.8). Speaking generally, car-bamylated AChE reactivates more rapidly than phosphorylated AChE. After aging has occurred, phosphorylation of the enzyme is effectively irreversible (see Section 10.2.4). Carbamylated AChE reactivates when preparations are diluted with water, a process that is accelerated in the presence of acetylcholine, which competes as a substrate. Thus, the measurement of AChE inhibition is complicated by the fact that reactivation occurs during the course of the assay. Carbamylated AChE is not reactivated by PAM and related compounds that are used as antidotes to OP poisoning (see Box 10.1). 

Some of the best evidence of links between effects at different organizational levels comes from studies with OPs, where levels of AChE inhibition have been compared with associated neurophysiological and behavioral effects. In adopting this approach, however, the picture is complicated by mounting evidence for these compounds acting on target sites other than AChE, as discussed in Section 16.3. Thus, behavioral disturbances caused by an OP may be the outcome of interaction with both AChE and one or more other sites of action. The following account, however, will be concerned with situations where effects of OPs are closely related to levels of AChE inhibition. More complex scenarios will be discussed in the next section. 

Biosensors may provide the basis for in-field analyses and real-time process analysis. However, biosensors are generally limited to the determination of a limited range of analytes in defined matrices. Enzyme-based biosensors, principally acetylcholinesterase (AChE) inhibition, have been successfully used in environmental analysis for residues of dichlorvos and paraoxon, " carbaryl " and carbofuran. " Immunochemically based biosensors may be the basis for the determination of pesticide residues in liquid samples, principally water and environmental samples, but also fruit juices. The sensors can be linked to transducers, for example based on a piezo-... 

Intervention measures have been proposed, based on the relationships between ACHE inhibition levels and biological effects (ICOH, 1986 Zielhuis, 1972). An ACHE decrease of 30% or less from the baseline (or 50% or less from the average reference level) requires medical surveillance and examination of working conditions. A reduction of more than 30% from baseline (or 50% from the reference level) requires temporary removal from exposure and careful evaluation of the working conditions. 

Table 1 Severity and Prognosis of Acute OP Intoxication at Different Levels of ACHE Inhibition...

ACHE inhibition Level of poisoning Clinical symptoms Prognosis... 

Occupational exposure to carbamate insecticides may be monitored by measuring RBC-ACHE and/or PCHE. However, given the low cholinesterase inhibition levels and the short time duration of this effect, ACHE inhibition can generally be used as a biomarker of exposure only when exposure levels are high. Three sequential samples are recommended to establish an individual baseline before exposure. In exposed workers, blood sampling and analysis should be carried out soon after the end of exposure (WHO, 1986). 

Consequences of acetylcholinesterase inhibition differ with effector site. At postganglionic parasympathetic effector sites, AChE inhibition enhances or potentiates the action of administered ACh or ACh released by nerve activity. In part, this is a consequence of diffusion of... 

Dose-effect dependence is shared by many OPC in both the acute and chronic tests. The higher dose of an anti-cholinesterase substance, the higher degree of both acetyl cholinesterase (AChE) inhibition in neural tissue and intoxication evidence. 

A positive property of the most active reactivators of the second generation lies in their ability to reduce 2 to 2.5 times aging rate of AChE inhibited with soman. 

Blood AChE-inhibition The mean blood AChE-inhibition after pretreatment, measured as a percentage of the baseline value, was 20-35 % (see Table 2). The AChE-inhibition measured one hour after soman followed by a post-intoxication therapy, was significantly lower in all groups (t-test with Welch s correction, p < 0.05). The inhibition of AChE after soman was less in animals pretreated with PYR or with PHY combined with PC (resp. 85.5 1 % and 89.4 2 %). 

Fernandez- Vega, C., Sancho, E., Ferrando, M.D., and Andreu-Moliner, E. Rhiobencarb toxicity and plasma AchE inhibition in the European eel, J. Environ. Sci. Health, B34(l) 61-73, 1999. 

A second line of research in this area has demonstrated an AchE inhibitory effect of withanolides in vitro. More studies are needed to assess their exact mechanisms of action and extent of utility in AD as human trials are lacking. Nevertheless, these investigations do demonstrate the potential for a therapeutic role of withanolides/withanamides in both protecting against amyloid neuronal pathology and in AchE inhibition. ... 

Although it is comparatively easy to explain the fact that some alkaloids inhibit AChE because of their molecular features, it is not easy to correlate chemical structure and activity for some other phytochemical types for which AChE inhibition has recently been reported. 

The pX a (6.5-8.2) and nucleophilicity of MINA, 44, and of a series of aliphatic oximes derived from it, were found to be consistent with their ability to reactivate AChE inhibited by the nerve agents, sarin and VX. Yet, despite their ability to significantly reactivate AChE in the brains of sarin-intoxicated rats, these aliphatic oximes are not used as antidotes for treatment of OP poisoning in humans this is presumably due to their poor stability in aqueous solution and to their rapid clearance from the circulation. 

The first suggestion of a practical form of antidotal therapy came in 1949 from Hestrin, who found that acetylcholinesterase (AChE) catalyzed the formation of acetohydroxamlc acid when incubated with sodium acetate and hydroxylamine. Critical in vitro studies in the next decade led to the development of a practical approach to therapy. The crucial concept in these studies was the recognition that the compound formed when AChE reacted with a phosphorus ester was a covalent phosphoryl-enzyme Intermediate similar to that formed in the hydrolysis of acetylcholine. 3 Wilson and colleagues, beginning in 1951, demonstrated that AChE inhibited by alkyl phosphate esters (tetraethyl pyrophosphate, TEPP) could be reactivated by water, but that free enzyme formed much more rapidly in the presence of hydroxylamine. 0 21 Similar results... 

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