Cholinesterase inhibitors can be helpful in treating glaucom

Cholinesterase inhibitors can be helpful in treating glaucoma, a leading cause of blindness worldwide [59]. Generally, increased intraocular pressure from aqueous humor accumulation leads to degeneration of the optic nerve and retinal ganglion cells. Strategies that reduce intraocular pressure are the only approaches proven to treat most forms of glaucoma [60]. Ocular administration of an anti-ChE can facilitate contraction of the ciliary muscle and increase the flow of aqueous humor through the trabecular meshwork to reduce intraocular pressure. Other drugs, e.g., sulfonamide carbonic anhydrase inhibitors such as acetazolamide and dorzolamide that decrease the formation of aqueous humor and prostaglandin F analogs (e.g., latanoprost, bimatoprost) that enhance aqueous humor outflow have largely supplanted cholinesterase inhibitors for these conditions [61]. Interestingly, the reversible cholinesterase inhibitor galantamine was recently shown to protect retinal ganglion cells and improve local blood flow in experimental models of glaucoma, but in a manner independent of intraocular pressure [62], [63]. Gastrointestinal tone can be effectively modulated by cholinesterase inhibitors. As parasympathetic fibers release 3-Deazaneplanocin synthesis 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 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.