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  • Gastrointestinal tone can be effectively modulated


    Gastrointestinal tone can be effectively modulated by cholinesterase inhibitors. As parasympathetic fibers release trpv1 to contract the circular and longitudinal intestinal muscles, AChE inhibition can facilitate those actions. Postoperative ileus (delayed gastric emptying after surgery) can arise from the surgical procedure itself, anesthetic agents, opioid medications and other factors. Neostigmine can accelerate gastric emptying, but some studies suggest it contributes to adverse bowel effects, e.g., serious leaks from intestinal anastomoses [64], [65]. Similarly, conditions such as functional dyspepsia, gastroparesis and colonic pseudo-obstruction may be treated with a cholinesterase inhibitor such as acotiamide [66], [67], [68]. Other prokinetic agents, e.g., metoclopramide, are used to facilitate gastric emptying and activate GI motoneurons as do cholinesterase inhibitors, but they act by increasing acetylcholine release rather than by blocking its degradation [69], [70]. As noted earlier, individuals expressing BChE variants with low or absent catalytic activity are generally symptomless, and only a limited amount of research has been conducted on the pharmacological/toxicological consequences of BChE inhibition. However, the enzyme’s putative role in ghrelin signaling is likely to be a therapeutic (or toxic) target in the future. Li and colleagues [26] reported that BChE knockout mice maintained on a high-fat diet gained considerably more weight than BChE+/+ littermates. Interestingly, in that study, the mice on a path to obesity did not seem to show increased food consumption. In fact, our later studies along the same lines suggest that this apparently negative outcome may have been an artifact of the means for measuring food intake, which is easily distorted by losses hidden in bedding material. In any case, the plasma concentration of acyl-ghrelin in BChE knockouts was almost twice as high as in wildtype littermates. Other hydrolases besides BChE, including, carboxylesterases and proteases, may cleave the acyl group from acyl-ghrelin or degrade the peptide itself [26], [71]. As rodents have much higher carboxylesterase blood levels than humans, such differences may influence the relative impact of BChE activity on ghrelin signaling in man compared to some test species. Nonetheless, recent findings by our research teams showed that a marked rise in plasma BChE activity after gene transfer was associated with drastically reduced acyl-ghrelin in plasma [72]. Interestingly, high-BChE mice were seen to exhibit lower levels of aggressive behavior (both spontaneous and intruder-provoked). A number of studies suggest a link between ghrelin and emotional/affective behaviors [73], [74], [75], [76], [77], [78]. The role trpv1 of BChE in ghrelin signaling is both intriguing and important but it remains incompletely understood [79]. Therefore, studies to evaluate the effects of BChE and its inhibitors in the complex signaling associated with ghrelin’s numerous physiological impacts appear well worthwhile. Fig. 2 illustrates the widespread potential influence of BChE on ghrelin signaling and associated functions in the brain.
    Cholinesterases and pharmacological effects of inhibition in the CNS A number of elegant morphological and immunochemical studies led to the description of six cholinergic cell nuclei in the brain, termed Ch1-Ch6 [80], [81], [82], [83]. Fig. 3 is taken from [80], showing the cholinergic nuclei and their general projections in the mammalian brain. The diffuse innervation by these different cholinergic fibers affects many physiological functions including cognition, respiration, locomotion, and others. Moreover, some brain regions (notably striatum) contain multiple networks of cholinergic interneurons [84], [85]. Thus, AChE inhibition in the CNS has the potential to influence an extremely wide array of functions, and this has been targeted in treating early-stage Alzheimer’s disease (AD). AD is a devastating neurodegenerative disorder affecting an estimated 35 million people worldwide [86]. Findings of extensive loss of cells in Ch4 (nucleus basalis) and widespread reduction of cholinergic markers in Alzheimer forebrain [87], [88], [89], [90], [91], [92] led to the cholinergic hypothesis of dementia (reviewed in [93], [94]). This hypothesis opened the door to examine potential therapeutic benefits of cholinesterase inhibitors [95], [96], [97]. Since that time, many natural and synthetic cholinesterase inhibitors that bind selectively or show multifunctional characteristics have been evaluated to treat Alzheimer’s disease (see recent reviews [98], [99], [100], [101], [102].