Abstract
Oxidative stress (OS), glial activation and formation of plaques and tangles are believed to contribute to progressive neurodegeneration in Alzheimer’s disease (AD). None of the acetylcholinesterase (AChE) inhibitors currently in clinical use are able to reduce OS and inflammatory processes at doses used to treat AD. Therefore, there is a need for a drug which inhibits AChE and butyrylcholinesterase (BuChE), has anti-oxidant and anti-inflammatory activities. Indole propionic acid (IPA) prevents oxidative stress and death of primary neurons and neuroblastoma cells exposed to H2O2 or amyloid beta. Derivatives of indoline propionic acid (InPA) were found to be more potent anti-oxidants than those of IPA in cell culture. Therefore, a series of novel carbamates was synthesized based on the structure of InPA and their AChE, BuChE, anti-oxidant and anti-inflammatory activities were evaluated. Three compounds: Indoline-4-ylethyl methyl carbamate (AN-854), 3-(2-(methoxycarbonyl) ethyl) indolin-4-ylethyl methyl carbamate (AN-827) and 3-(2-(methoxycarbonyl) ethyl)-1-indoline-6-ylethyl methyl carbamate (AN-680) prevented cytotoxicity induced by OS and the release of cytokines from activated microglial cells at concentrations at, or lower than those inhibiting AChE. They inhibited AChE in rat brain and reduced lipid peroxidation and formation of nitrites in mouse brain after injection of lipopolysaccharide (LPS). When injected together with LPS they lowered the levels of COX-2 and pro-inflammatory cytokines (IL-6, IL-1β and TNF-α) in the brain and spleen. The mechanism of anti-inflammatory activity was evaluated in BV2 cells activated with LPS and shown to occur through reduction in phosphorylation of p38 and activation of the transcription factor AP-1. Conclusion: Indoline derivatives which display anti-oxidant and anti-inflammatory and cholinesterase inhibitory activities in vitro and in vivo, may have potential use for the treatment of AD and other neurodegenerative diseases.
Published Version
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