TY - JOUR
T1 - Dose-limiting inhibition of acetylcholinesterase by ladostigil results from the rapid formation and fast hydrolysis of the drug-enzyme complex formed by its major metabolite, R-MCPAI
AU - Moradov, Dorit
AU - Finkin-Groner, Efrat
AU - Bejar, Corina
AU - Sunita, Priyashree
AU - Schorer-Apelbaum, Donna
AU - Barasch, Dinorah
AU - Nemirovski, Alina
AU - Cohen, Marganit
AU - Weinstock, Marta
N1 - Publisher Copyright:
© 2015 Elsevier Inc.
PY - 2015/3/15
Y1 - 2015/3/15
N2 - Ladostigil is a pseudo reversible inhibitor of acetylcholinesterase (AChE) that differs from other carbamates in that the maximal enzyme inhibition obtainable does not exceed 50-55%. This could explain the low incidence of cholinergic adverse effects induced by ladostigil in rats and human subjects. The major metabolite, R-MCPAI is believed to be responsible for AChE inhibition by ladostigil in vivo. Therefore we determined whether the ceiling in AChE inhibition resulted from a limit in the metabolism of ladostigil to R-MCPAI by liver microsomal enzymes, or from the kinetics of enzyme inhibition by R-MCPAI. Ladostigil reduces TNF-α in lipopolysaccharide-activated microglia. In vivo, it may also reduce pro-inflammatory cytokines by inhibiting AChE and increasing the action of ACh on macrophages and splenic lymphocytes. We also assessed the contribution of AChE inhibition in the spleen of LPS-injected mice to the anti-inflammatory effect of ladostigil. As in other species, AChE inhibition by ladostigil in spleen, brain and plasma did not exceed 50-55%. Since levels of R-MCPAI increased with increasing doses of ladostigil we concluded that there was no dose or rate limitation of metabolism. The kinetics of enzyme inhibition by R-MCPAI are characterized by a rapid formation of the drug-enzyme complex and fast hydrolysis which limits the attainable degree of AChE inhibition. Ladostigil and its metabolites (1-100 nM) decreased TNF-α in lipopolysaccharide-activated macrophages. Ladostigil (5 and 10 mg/kg) also reduced TNF-α in the spleen after injection of lipopolysaccharide in mice. However, AChE inhibition contributed to the anti-inflammatory effect only at a dose of 10 mg/kg.
AB - Ladostigil is a pseudo reversible inhibitor of acetylcholinesterase (AChE) that differs from other carbamates in that the maximal enzyme inhibition obtainable does not exceed 50-55%. This could explain the low incidence of cholinergic adverse effects induced by ladostigil in rats and human subjects. The major metabolite, R-MCPAI is believed to be responsible for AChE inhibition by ladostigil in vivo. Therefore we determined whether the ceiling in AChE inhibition resulted from a limit in the metabolism of ladostigil to R-MCPAI by liver microsomal enzymes, or from the kinetics of enzyme inhibition by R-MCPAI. Ladostigil reduces TNF-α in lipopolysaccharide-activated microglia. In vivo, it may also reduce pro-inflammatory cytokines by inhibiting AChE and increasing the action of ACh on macrophages and splenic lymphocytes. We also assessed the contribution of AChE inhibition in the spleen of LPS-injected mice to the anti-inflammatory effect of ladostigil. As in other species, AChE inhibition by ladostigil in spleen, brain and plasma did not exceed 50-55%. Since levels of R-MCPAI increased with increasing doses of ladostigil we concluded that there was no dose or rate limitation of metabolism. The kinetics of enzyme inhibition by R-MCPAI are characterized by a rapid formation of the drug-enzyme complex and fast hydrolysis which limits the attainable degree of AChE inhibition. Ladostigil and its metabolites (1-100 nM) decreased TNF-α in lipopolysaccharide-activated macrophages. Ladostigil (5 and 10 mg/kg) also reduced TNF-α in the spleen after injection of lipopolysaccharide in mice. However, AChE inhibition contributed to the anti-inflammatory effect only at a dose of 10 mg/kg.
KW - Acetylcholinesterase inhibition, Brain
KW - Kinetics of enzyme inhibition
KW - Ladostigil metabolites
KW - LCMS
KW - Spleen
UR - http://www.scopus.com/inward/record.url?scp=84923932439&partnerID=8YFLogxK
U2 - 10.1016/j.bcp.2015.01.017
DO - 10.1016/j.bcp.2015.01.017
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C2 - 25662585
AN - SCOPUS:84923932439
SN - 0006-2952
VL - 94
SP - 164
EP - 172
JO - Biochemical Pharmacology
JF - Biochemical Pharmacology
IS - 2
ER -