Bis(9)-(−)-nor-meptazinol as a novel dual-binding AChEI potently ameliorates scopolamine-induced cognitive deficits in mice

Liu, Ting; Zheng, Xiaoli; Zhang, Weiwei; Xu, Jianrong; Ge, Xinxing; Li, Juan; Cui, Yong-Yao; Qiu, Zhuibai; Xu, Jing; Xie, Qiong; Wang, Hao; Chen, Hongzhuan

doi:10.1016/j.pbb.2012.11.009

Cited by 24 publications

(18 citation statements)

References 26 publications

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“…After releasing from the presynaptic neuron, Ach, the neurotransmitter, was gathered into the synaptic cleft, followed by binding to the Ach receptors on the postsynaptic membrane, and the signal from the nerve was relayed during the process [ 67 ]. The termination of the signal transmission was conducted by hydrolyzation of ACh located on the postsynaptic membrane [ 68 ]. AChE, one of the most important enzyme in the family serine hydrolase involved in the hydrolytic cleavage of Ach, depletes the levels of ACh involved in memory and learning [ 69 ].…”

Section: Discussionmentioning

confidence: 99%

Jiao-Tai-Wan Improves Cognitive Dysfunctions through Cholinergic Pathway in Scopolamine-Treated Mice

Wang

et al. 2018

BioMed Research International

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Cognitive dysfunction is characterized as the gradual loss of learning ability and cognitive function, as well as memory impairment. Jiao-tai-wan (JTW), a Chinese medicine prescription including Coptis chinensis and cinnamon, is mainly used for the treatment of insomnia, while the effect of JTW in improving cognitive function has not been reported. In this study, we employed a scopolamine- (SCOP-) treated learning and memory deficit model to explore whether JTW could alleviate cognitive dysfunction. In behavioral experiments, Morris water maze, Y-maze, fearing condition test, and novel object discrimination test were conducted. Results showed that oral administration of JTW (2.1 g/kg, 4.2 g/kg, and 8.4 g/kg) can effectively promote the ability of spatial recognition, learning and memory, and the memory ability of fresh things of SCOP-treated mice. In addition, the activity of acetylcholinesterase (AChE) was effectively decreased; the activity of choline acetyltransferase (ChAT) and concentration of acetylcholine (Ach) were improved after JTW treatment in both hippocampus and cortex of SCOP-treated mice. JTW effectively ameliorated oxidative stress because of decreased the levels of malondialdehyde (MDA) and reactive oxygen species (ROS) and increased the activities of superoxide dismutase (SOD) and catalase (CAT) in hippocampus and cortex. Furthermore, JTW promotes the expressions of neurotrophic factors including postsynaptic density protein 95 (PSD95) and synaptophysin (SYN) and brain-derived neurotrophic factor (BDNF) in both hippocampus and cortex. Nissl's staining shows that the neuroprotective effect of JTW was very effective. To sum up, JTW might be a promising candidate for the treatment of cognitive dysfunction.

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Section: Discussionmentioning

confidence: 99%

Jiao-Tai-Wan Improves Cognitive Dysfunctions through Cholinergic Pathway in Scopolamine-Treated Mice

Wang

et al. 2018

BioMed Research International

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“…B9M also inhibited AChE induced Aβ aggregation, indicating its potential for AD treatment [ 14 ]. Furthermore, B9M showed memory ameliorating effects at the dose of 1 μg/kg in scopolamine-induced mice model [ 27 ]. Thus, based on our previous results, three doses of B9M (0.1, 0.3, 1 μg/kg) were administrated to APP/PS1 mice and three behavioral tests were conducted to evaluate learning and memory ability in the present study.…”

Section: Discussionmentioning

confidence: 99%

Bis(9)-(−)-Meptazinol, a novel dual-binding AChE inhibitor, rescues cognitive deficits and pathological changes in APP/PS1 transgenic mice

Shi

Huang

Wang

et al. 2018

Transl Neurodegener

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BackgroundAlzheimer’s disease (AD) is a progressive and irreversible neurodegenerative brain disorder, which is the most common form of dementia. Intensive efforts have been made to find effective and safe treatment against AD. Acetylcholinesterase inhibitors (AChEIs) have been widely used for the treatment of mild to moderate AD. In this study, we investigated the effect of Bis(9)-(−)-Meptazinol (B9M), a novel potential dual-binding acetylcholinesterase (AChE) inhibitor, on learning and memory abilities, as well as the underlying mechanism in the APP/PS1 mouse model of AD.MethodsB9M (0.1 μg/kg, 0.3 μg/kg, and 1 μg/kg) was administered by subcutaneous injection into eight-month-old APP/PS1 transgenic mice for four weeks. Morris water maze, nest-building and novel object recognition were used to examine learning and memory ability. Aβ levels and Aβ plaque were evaluated by ELISA and immunochemistry.ResultsOur results showed that chronic treatment with B9M significantly improved the cognitive function of APP/PS1 transgenic mice in the Morris water maze test, nest-building test and novel object recognition test. Moreover, B9M improved cognitive deficits in APP/PS1 mice by a mechanism that may be associated with its inhibition of the AChE activity, Aβ plaque burden, levels of Aβ and the consequent activation of astrocytes and microglia in the brain of APP/PS1 transgenic mice. Most of important, the most effective dose of B9M in the present study is 1 μg/kg, which is one thousand of the dosage of Donepezil acted as the control treatment. Furthermore, B9M reduced Aβ plaque burden better than Donepezil.ConclusionThese results indicate that B9M appears to have potential as an effective AChE inhibitor for the treatment of AD with symptom-relieving and disease-modifying properties.

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“…The cognitive deficiency associated with AD is considered to be primarily related to disorder of cholinergic neurotransmission in the cerebral hippocampus and cortex [ 23 , 24 ]. Various factors can induce brain impairment by influencing the synthesis, release, and uptake of acetylcholine (ACh) [ 25 ]. Scopolamine, an anticholinergic drug, can block ACh receptors and lead to a significant increase of acetylcholinesterase (AChE) level in the hippocampus and cortex [ 26 ].…”

Section: Discussionmentioning

confidence: 99%

“…AChE, also located on the postsynaptic membrane, terminates the signal transmission by hydrolyzing ACh. The alterations in the membrane can be a decisive factor in changing the conformational state of the AChE molecule [ 25 ]. The results of increasing activity of AChE and decreasing activity of ChAT in the cortex and hippocampus of SCOP-treated mice were consisted with previous studies [ 26 , 27 ].…”

Section: Discussionmentioning

confidence: 99%

Sodium Tanshinone IIA Sulfonate Attenuates Scopolamine-Induced Cognitive Dysfunctions via Improving Cholinergic System

Yang

et al. 2016

BioMed Research International

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Sodium Tanshinone IIA sulfonate (STS) is a derivative of Tanshinone IIA (Tan IIA). Tan IIA has been reported to possess neuroprotective effects against Alzheimer's disease (AD). However, whether STS possesses effect on AD remains unclear. This study aims to estimate whether STS could protect against scopolamine- (SCOP-) induced learning and memory deficit in Kunming mice. Morris water maze results showed that oral administration of STS (10 mg/kg and 20 mg/kg) and Donepezil shortened escape latency, increased crossing times of the original position of the platform, and increased the time spent in the target quadrant. STS decreased the activity of acetylcholinesterase (AChE) and increased the activity of choline acetyltransferase (ChAT) in the hippocampus and cortex of SCOP-treated mice. Oxidative stress results showed that STS increased the activity of superoxide dismutase (SOD) and decreased the levels of malondialdehyde (MDA) and reactive oxygen species (ROS) in hippocampus and cortex. In addition, western blot was carried out to detect the expression of apoptosis related proteins (Bcl-2, Bax, and Caspase-3). STS upregulated the protein expression of Bcl-2 and downregulated the proteins expression of Bax and Caspase-3. These results indicated that STS might become a promising therapeutic candidate for attenuating AD-like pathological dysfunction.

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Bis(9)-(−)-nor-meptazinol as a novel dual-binding AChEI potently ameliorates scopolamine-induced cognitive deficits in mice

Cited by 24 publications

References 26 publications

Jiao-Tai-Wan Improves Cognitive Dysfunctions through Cholinergic Pathway in Scopolamine-Treated Mice

Jiao-Tai-Wan Improves Cognitive Dysfunctions through Cholinergic Pathway in Scopolamine-Treated Mice

Bis(9)-(−)-Meptazinol, a novel dual-binding AChE inhibitor, rescues cognitive deficits and pathological changes in APP/PS1 transgenic mice

Sodium Tanshinone IIA Sulfonate Attenuates Scopolamine-Induced Cognitive Dysfunctions via Improving Cholinergic System

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