Enhancement of Fear Extinction Memory and Resistance to Age-Related Cognitive Decline in Butyrylcholinesterase Knockout Mice and (R)-Bambuterol Treated Mice

Abstract

Butyrylcholinesterase (BChE) is detected in plaques preferentially in Alzheimer’s disease (AD) and may be associated with stress disorders. However, the physiological function of BChE in the central nervous system remains to be further investigated. BChE knockout (KO) mice and wild-type (WT) mice with orally or intranasal administration of (R)-bambuterol were used to explore the effect of BChE on behavior changes. (R)-bambuterol is a specific and reversible inhibitor of BChE. The behavior changes were evaluated and compared among 3–10 month old mice. Our finding showed that BChE KO and (R)-bambuterol administration enhanced episodic memory, including fear conditioning memory and fear extinction memory in fear conditioning and fear extinction test. BChE KO and (R)-bambuterol administered mice rescued age-related spatial memory and general activity in the water maze test and open field test. The brain metabolomics were imaged using a desorption electrospray ionization mass spectrometry imaging (DESI-MSI). The image of DESI-MS demonstrated that glutamine content increased in the brain of BChE KO mice. In conclusion, this study found that inhibition of BChE ameliorated episodic and spatial memories. This study also suggested that (R)-bambuterol as a BChE inhibitor has the potential application in the treatment of post-traumatic stress disorder (PTSD) and early cognitive decline.

Emerging significance of butyrylcholinesterase

“…Altered cognitive functions were associated with normal nicotinic receptor function, though the muscarinic receptor function was altered in the knockout model. Preliminary studies on the effect of (R)-bambuterol, a specific and reversible inhibitor of BChE, suggested that it may be used in the treatment of early cognitive decline[ 79 ].…”

Spatial Multi-Omics in Alzheimer’s Disease: A Multi-Dimensional Approach to Understanding Pathology and Progression

“…Advanced techniques like DESI and MALDI-MS imaging have detected significant changes in lipid metabolites, such as phosphatidylethanolamines, phosphatidylcholines, and glycerophospholipids, in early-stage AD mouse models [111]. These techniques have also been instrumental in observing the distribution of specific lipids like DHA in dementia mouse models [75] and studying the enzymatic activity of biomarkers like BChE in AD patients [112]. Lipid molecules, including lysophospholipids such as LPC and LPG, accumulate in Aβ plaques, affecting cell membrane functions like ion transportation [113] and signal reception [113].…”

Zinc Chloride-Catalyzed Synthesis of Carbamates: An Application for the Synthesis of the Anti-Alzheimer’s Drug Rivastigmine

“… 12 Pesticides like carbofuran are employed in the cultivation of maize, rice, and cotton crops. 13 FDA-approved carbamate-containing drug molecules, such as ( R )-bambuterol, have the potential to be used in the treatment of cognitive decline and post-traumatic stress disorder (PTSD), 14 while pyridostigmine is commonly used to treat myasthenia gravis. 15 On the other hand, rivastigmine acts as an acetylcholinesterase (AChE) inhibitor.…”