title: Inhibitory effect of ebselen on cerebral acetylcholinesterase activity in vitro: kinetics and reversibility of inhibition.
abstract: Ebselen is a synthetic organoselenium compound that has been considered a potential pharmacological agent with low toxicity, showing antioxidant, anti-inflammatory and neuroprotective effects. It is bioavailable, blood-brain barrier permeant and safe based on cellular toxicity and Phase I-III clinical trials. There is evidence that ebselen inhibits acetylcholinesterase (AChE) activity, an enzyme that plays a key role in the cholinergic system by hydrolyzing acetylcholine (ACh), in vitro and ex vivo. This system has a well-known relationship with cognitive process, and AChE inhibitors, such as donepezil and galantamine, have been used to treat cognitive deficits, mainly in the Alzheimer's Disease (AD). However, these drugs have poor bioavailability and a number of side effects, including gastrointestinal upsets and hepatotoxicity. In this way, this study aimed to evaluate the effect of ebselen on cerebral AChE activity in vitro and to determine the kinetic profile and the reversibility of inhibition by dialysis. Ebselen inhibited the cerebral AChE activity with an IC50 of 29 µM, similar to IC50 found with pure AChE from electric eel, demonstrating a mixed and reversible inhibition of AChE, since it increased Km and decreased Vmax. The AChE activity was recovered within 60 min of dialysis. Therefore, the use of ebselen as a therapeutic agent for treatment of AD should be considered, although memory behavior tasks are needed to support such hypothesis.
authors.forename: Franciele
authors.initials: F
authors.lastname: Martini
authors.forename: César Augusto
authors.initials: CA
authors.lastname: Bruning
authors.forename: Suelen Mendonca
authors.initials: SM
authors.lastname: Soares
authors.forename: Cristina Wayne
authors.initials: CW
authors.lastname: Nogueira
authors.affiliation: Departamento de Química, Centro de Ciências Naturais e Exatas, Universidade Federal de Santa Maria, Santa Maria, CEP 97105-900, RS, Brazil. gzeni@ufsm.br.
authors.forename: Gilson
authors.initials: G
authors.lastname: Zeni
mesh_terms: D000818:Animals; D000894:Anti-Inflammatory Agents, Non-Steroidal / Q000493:pharmacokinetics; D000975:Antioxidants / Q000493:pharmacokinetics; D001393:Azoles / Q000493:pharmacokinetics*; D001812:Blood-Brain Barrier / Q000187:drug effects / Q000201:enzymology; D002540:Cerebral Cortex / Q000187:drug effects* / Q000201:enzymology*; D002800:Cholinesterase Inhibitors / Q000493:pharmacokinetics*; D004789:Enzyme Activation / Q000187:drug effects / Q000502:physiology; D054833:Isoindoles; D008297:Male; D016566:Organoselenium Compounds / Q000493:pharmacokinetics*; D051381:Rats; D017208:Rats, Wistar
chemical_list: D000894:Anti-Inflammatory Agents, Non-Steroidal; D000975:Antioxidants; D001393:Azoles; D002800:Cholinesterase Inhibitors; D054833:Isoindoles; D016566:Organoselenium Compounds; C042986:ebselen