Central and peripheral anti-inflammatory effects of acetylcholinesterase inhibitors.

Acetylcholinesterase (AChE) inhibitors modulate acetylcholine hydrolysis and hence play a key role in determining the cholinergic tone and in implementing its impact on the cholinergic blockade of inflammatory processes. Such inhibitors may include rapidly acting small molecule AChE-blocking drugs and poisonous anti-AChE insecticides or war agent inhibitors which penetrate both body and brain. Notably, traumatized patients may be hyper-sensitized to anti-AChEs due to their impaired cholinergic tone, higher levels of circulation pro-inflammatory cytokines and exacerbated peripheral inflammatory responses. Those largely depend on the innate-immune system yet reach the brain via vagus pathways and/or disrupted blood-brain-barrier. Other regulators of the neuro-inflammatory cascade are AChE-targeted microRNAs (miRs) and synthetic chemically protected oligonucleotide blockers thereof, whose size prevents direct brain penetrance. Nevertheless, these larger molecules may exert parallel albeit slower inflammatory regulating effects on brain and body tissues. Additionally, oligonucleotide aptamers interacting with innate immune Toll-Like Receptors (TLRs) may control inflammation through diverse routes and in different rates. Such aptamers may compete with the action of both small molecule inhibitors and AChE-inhibiting miRs in peripheral tissues including muscle and intestine. However, rapid adaptation processes, visualized in neuromuscular junctions enable murine survival under otherwise lethal anti-cholinesterase exposure; and both miR inhibitors and TLR-modulating aptamers may exert body-brain signals protecting experimental mice from acute inflammation. The complex variety of AChE inhibiting molecules identifies diverse body-brain communication pathways which may rapidly induce long-lasting central reactions to peripheral stressful and inflammatory insults in both mice and men. This article is part of the special issue entitled 'Acetylcholinesterase Inhibitors: From Bench to Bedside to Battlefield'.