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Butyrylcholinesterase (BChE) efficiently hydrolyzes acetylcholine (ACh) at high concentrations when acetylcholinesterase (AChE) is substrate-inhibited. Recent studies have shown that BChE also has a function that is independent of ACh, but it has not been fully explored. Low BChE expression is accompanied with higher stress-induced aggression and ghrelin levels in stress models, and BChE knockout mice exhibit cognitive and memory impairments. However, the role of BChE in posttraumatic stress disorder (PTSD) remains unclear. In the present study, we investigated the role of BChE in contextual fear memory and its regulatory effect on the expression of factors related to the glutamate (Glu)-glutamine (Gln) cycle via knockdown studies. We used AAVs and lentiviruses to knockdown BChE expression in the mouse hippocampal CA1 region and C8D1A astrocytes. Our behavioral data from those mice injected with AAV-shBChE in the hippocampal CA1 region showed strengthened fear memory and increased dendritic spine density. Elevated Glu levels and glutamine synthetase (GS) enzyme activity were detected in contextual fear conditioned-BChE knockdown animals and astrocytes. We observed that an AAV-shBChE induced lowering of BChE expression in the hippocampus CA1 region enhanced contextual fear memory expression and promoted the astrocytic Glu-Gln cycle but did not elevate ACh-hydrolyzing activity. This study provides new insight into the regulatory role of BChE in cognition and suggests potential target for stressrelated psychiatric disorder such as PTSD where patients experience fear after exposure to severe life-threatening traumatic events.

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Stroke, also known as cerebral ischemia, is a common neurological disease. The therapeutic potential of MLC901 (NeuroAiD II™) has been reported in clinical trials on traumatic brain injury as well as in animal and cell models. MLC901 reduced the infarction size, ischemia-induced neurological deficits and pro-inflammatory infiltration of phagocyte. It also inhibited the ischemia-induced expression of pro-inflammatory mediators and Prx6, TLR4 signalling, and phosphorylation of NFκB. We found that the beneficial effects of MLC901 are in coherent with studies performed on the individual active ingredient. MLC901 may develop its efficacy through a synergistic effect via nine herbal extracts. MLC901 is a multifaceted traditional Chinese medicine. A cocktail of herbs provides a broader spectrum of targets. This may surpass single-target drug treatment in terms of side effect and therapeutic efficacy. MLC901 leads to various potential research directions on the development or improvement of a feasible, effective and promising herbal formulation for treating stroke patients.

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