The selective butyrylcholinesterase inhibitor UW-MD-95 shows symptomatic and neuroprotective effects in a pharmacological mouse model of Alzheimer's disease.

AIMS: Alzheimer's disease (AD) is a devastating dementia characterized by extracellular amyloid-β (Aβ) protein aggregates and intracellular tau protein deposition. Clinically available drugs mainly target acetylcholinesterase (AChE) and indirectly sustain cholinergic neuronal tonus. Butyrylcholinesterase (BChE) also controls acetylcholine (ACh) turnover and is involved in the formation of Aß aggregates and senile plaques. UW-MD-95 is a novel carbamate-based compound acting as a potent pseudo-irreversible BChE inhibitor, with high selectivity versus AChE, and showing promising protective potentials in AD.

METHODS: We characterized the neuroprotective activity of UW-MD-95 in mice treated intracerebroventricularly with oligomerized Aβ25-35 peptide using behavioral, biochemical, and immunohistochemical approaches.

RESULTS: When injected acutely 30 min before the behavioral tests (spontaneous alternation in the Y-maze, object recognition, or passive avoidance), UW-MD-95 (0.3-3 mg/kg) showed anti-amnesic effects in Aβ25-35-treated mice. When injected once a day over 7 days, it prevented Aβ25-35-induced memory deficits. This effect was lost in BChE knockout mice. Moreover, the compound prevented Aβ25-35-induced oxidative stress (assessed by lipid peroxidation or cytochrome c release), neuroinflammation (IL-6 and TNFα levels or GFAP and IBA1 immunoreactivity) in the hippocampus and cortex, and apoptosis (Bax level). Moreover, UW-MD-95 significantly reduced the increase in soluble Aβ1-42 level in the hippocampus induced by Aβ25-35.

CONCLUSION: UW-MD-95 appeared as a potent neuroprotective compound in the Aβ25-35 model of AD, with potentially an impact on Aβ1-42 accumulation that could suggest a novel mechanism of neuroprotection.