Acetylcholinesterase Inhibitors: Pharmacology and Toxicology

Abstract

Acetylcholinesterase is involved in the termination of impulse transmission by rapid hydrolysis of the neurotransmitter acetylcholine in numerous cholinergic pathways in the central and peripheral nervous systems. The enzyme inactivation, induced by various inhibitors, leads to acetylcholine accumulation, hyperstimulation of nicotinic and muscarinic receptors, and disrupted neurotransmission. Hence, acetylcholinesterase inhibitors, interacting with the enzyme as their primary target, are applied as relevant drugs and toxins. This review presents an overview of toxicology and pharmacology of reversible and irreversible acetylcholinesterase inactivating compounds. In the case of reversible inhibitors being commonly applied in neurodegenerative disorders treatment, special attention is paid to currently approved drugs (donepezil, rivastigmine and galantamine) in the pharmacotherapy of Alzheimer’s disease, and toxic carbamates used as pesticides. Subsequently, mechanism of irreversible acetylcholinesterase inhibition induced by organophosphorus compounds (insecticides and nerve agents), and their specific and nonspecific toxic effects are described, as well as irreversible inhibitors having pharmacological implementation. In addition, the pharmacological treatment of intoxication caused by organophosphates is presented, with emphasis on oxime reactivators of the inhibited enzyme activity administering as causal drugs after the poisoning. Besides, organophosphorus and carbamate insecticides can be detoxified in mammals through enzymatic hydrolysis before they reach targets in the nervous system. Carboxylesterases most effectively decompose carbamates, whereas the most successful route of organophosphates detoxification is their degradation by corresponding phosphotriesterases.

Self-reported Health Effects among Short and Long-term Pesticide Sprayers in Arusha, Northern Tanzania: A cross Sectional Study

“…Because the sprayers in the present study did not use eye protection, it is likely that the eyes were directly exposed to substantial concentrations of pesticides including OPs. Because exposure to OPs has been associated with loss of cholinergic neurons in the brain and ocular pathways leading to permanent damage of vision [57] it is likely that similar lesions may occur in the study participants of the present study. This suggests that, substantial unrecognized vision disorders due to pesticide exposure may exist among pesticide sprayers as well as other farm workers in the study area.…”

Evento de Intoxicación en Perros de Zona Urbana mediante Cebos Contaminados con Aldicarb

“…Los valores de referencia propios pueden aplicarse en el diagnóstico diferencial entre OF y CB. Así, una segunda determinación a las 24 h puede inferir la presencia de un OF si se mantiene el nivel de inhibición o de un CB si la actividad enzimática ha aumentado, ya que los primeros producen una inhibición irreversible de la BChe y los segundos una inhibición reversible (Colovic et al, 2013).…”

In Silico Comparison of Synthetic and Natural Molecules Bindings with Acetylcholinesterase Enzyme using Molecular Docking

“…Acetylcholinesterase inhibitors are classified as reversible, irreversible, or quasi-irreversible (also called pseudo-irreversible) [15]. Acetylcholinesterase inhibitors (tacrine, donepezil, rivastigmine, galantamine), in the cholinergenic family, act to slow acetylcholinesterase activity in order to maintain high levels of acetylcholine, which is greatly reduced in patients with cholinergenic disease.…”