Tacrine(10)-Hupyridone Prevents Post-operative Cognitive Dysfunction via the Activation of BDNF Pathway and the Inhibition of AChE in Aged Mice

Chen, Huixin; Wu, Xiang; Gu, Xinmei; Zhou, Yiying; Ye, Luying; Zhang, Ke; Pan, Hanbo; Wang, Jialing; Hua, Wei; Zhu, Binbin; Naman, C. Benjamin; Mak, Shinghung; Carlier, Paul R.; Cui, Wei; Han, Yifan

doi:10.3389/fncel.2018.00396

Cited by 17 publications

(27 citation statements)

References 30 publications

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“…It is because that long-term treatment of A10E might cause the accumulation of A10E in the brain of mice. A10E could elevate the expression of BDNF and activate the TrkB/Akt pathway, the downstream pathway of BDNF, which is consistent to our previous study [25]. BDNF was reported to produce neuroprotective effects against Aβ-induced neurotoxicity in AD.…”

Section: Discussionsupporting

confidence: 92%

“…TrkB is a main receptor of BDNF. Previously, we reported that A10E could prevent surgery-induced decrease of BDNF expression [25]. Therefore, in this study, we applied Western blotting analysis to detect the effect of A10E on the BNDF-TrkB pathway.…”

Section: A10e Attenuates Aβ Oligomers-induced Cognitive Impairments In Micementioning

confidence: 99%

“…Dimeric Tacrine(10)-hupyridone (A10E), was designed and synthesized by linking tacrine with hupyridone, a fragment of huperzine A molecule using methylene groups [24]. Previously, we have reported that A10E could inhibit AChE, attenuate scopolamine-induced cognitive impairments in mice, and prevent postoperative cognitive impairments via the enhancement of BDNF expression [25,26]. However, it is largely unknown whether A10E could act on other AD-related targets, and whether A10E could produce cognitionenhancing ability in AD animal models.…”

Section: Introductionmentioning

confidence: 99%

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Dimeric Tacrine (10)-Hupyridone Effectively Combats Alzheimer’s Disease as A Multi-Target-Directed Ligand

Xuan

Yan

et al. 2021

Preprint

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Background Alzheimer’s disease (AD) is a neurodegenerative disorder with multiple pathological features. Therefore, multi-target-directed ligands (MTDLs) strategy has been developed to combat this disease. We have previously designed and synthesized dimeric tacrine (10)-hupyridone (A10E), a novel tacrine derivative with acetylcholinesterase (AChE) inhibition and brain-derived neurotrophic factor (BDNF) activation activity, by linking tacrine and a fragment of huperzine A. However, it was largely unknown whether A10E could act on other AD targets and produce cognition-enhancing ability in AD animal models. Methods Behavioral and biochemical methods were applied to evaluate multi-target cognitive-enhancing effects and mechanisms of A10E in APP/PS1 transgenic mice and β-amyloid (Aβ) oligomers-treated mice. The neuroprotective mechanisms of A10E were explored in SH-SY5Y cells. And the anti-aggregation effects of A10E on Aβ were directly investigated in vitro. Results A10E could prevent cognitive impairments in both APP/PS1 mice and Aβ oligomers-treated mice, with higher potency than tacrine and huperzine A. Moreover, A10E could effectively inhibit Aβ production and deposition, reduce neuroinflammation, enhance brain derived brain-derived neurotrophic factor (BDNF) expression, and elevate cholinergic neurotransmission in vivo. A10E, at nanomolar concentrations, could also inhibit Aβ oligomers-induced neurotoxicity via the activation of the TrkB/Akt pathway. Furthermore, Aβ oligomerization and fibrillization could be directly disrupted by A10E. Conclusion A10E could produce anti-AD neuroprotective effects via multi-target mechanisms, including the inhibition of Aβ aggregation, the activation of the BDNF/TrkB pathway, the reduction of neuroinflammation and the decrease of AChE activity. As MTDLs could produce additional benefits, such as overcoming the deficits of drug combination and enhancing the compliance of AD patients, our results suggested that A10E might be developed as a promising MTDL lead for the treatment of AD.

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Section: Discussionsupporting

confidence: 92%

Section: A10e Attenuates Aβ Oligomers-induced Cognitive Impairments In Micementioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

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Dimeric Tacrine (10)-Hupyridone Effectively Combats Alzheimer’s Disease as A Multi-Target-Directed Ligand

Xuan

Yan

et al. 2021

Preprint

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“…Brain‐derived neurotrophic factor (BDNF) and its intra‐neuronal pathway have been implicated as mediators between neuro‐inflammation and neuronal dysfunction (e.g., decreased neurogenesis, synaptic plasticity, and LTP) (Barrientos et al., 2004; Yirmiya & Goshen, 2011). Many studies have shown that activation of BDNF signaling pathway could attenuate cognitive impairment after surgery and reduce the elevated levels of inflammatory cytokines (Chen, Wu, & Gu, 2018; Wei, Zheng, & Liu, 2018), suggesting the critical role of BDNF in the development of POCD.…”

Section: Introductionmentioning

confidence: 99%

Association between BDNF rs6265 polymorphisms and postoperative cognitive dysfunction in Chinese Han Population

Xie

Zhou

et al. 2020

Brain and Behavior

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Postoperative cognitive dysfunction (POCD), also named as postoperative neurocognitive disorder (NCD) (Evered, Silbert, & Knopman, 2018), is a highly prevalent disorder, especially in elderly patients, characterized by acute or persistent deficits in attention, concentration, learning, and memory following surgery, which can be detected by a battery of neuropsychological tests (Skvarc, Berk, & Byrne, 2018). POCD can prolong hospital stay, reduce quality of life, increase mortality, and aggravate the burden of public health, leading

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“…Morris water maze task. The Morris water maze task was used to measure the spatial learning and memory of animals (18), and performed as previously described with minor modification (19). The water maze apparatus consisted of a circular pool with a diameter of 110 cm, which was filled with water at 23±2˚C to cover a platform.…”

Section: Synthesis Of 6-bromotryptamine Amentioning

confidence: 99%

Inhibition of acetylcholinesterase activity and β‑amyloid oligomer formation by 6‑bromotryptamine�A, a multi‑target anti‑Alzheimer's molecule

et al. 2019

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Alzheimer's disease (AD) is a neurodegenerative disorder characterized by learning and memory impairments. Recent studies have suggested that AD can be induced by multiple factors, such as cholinergic system dysfunction and β-amyloid (Aβ) neurotoxicity. It was reported that 6-bromo-N-propionyltryptamine could treat neurological diseases, including AD. In the present study, 6-bromotryptamine A, a derivative of 6-bromo-N-propionyltryptamine, was synthesized by the condensation of 2-(6-bromo-1H-indol-3-yl)ethan-1-amine and 2-(4-bromophenyl)acetic acid, and was used as a potential anti-AD molecule. Furthermore, scopolamine can induce impairments of learning and memory, and was widely used to establish AD animal models. The results demonstrated that 6-bromotryptamine A significantly prevented scopolamine-induced short-term cognitive impairments, as revealed by various behavioral tests in mice. Furthermore, an acetylcholinesterase (AChE) activity assay revealed that 6-bromotryptamine A directly inhibited AChE activity. Notably, it was observed that 6-bromotryptamine A blocked the formation of Aβ oligomer, as evaluated by the dot blot assay. All these results suggested that 6-bromotryptamine A may be used to prevent impairments in short-term learning and memory ability possibly via the inhibition of AChE and the blockade of Aβ oligomer formation.

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Tacrine(10)-Hupyridone Prevents Post-operative Cognitive Dysfunction via the Activation of BDNF Pathway and the Inhibition of AChE in Aged Mice

Cited by 17 publications

References 30 publications

Dimeric Tacrine (10)-Hupyridone Effectively Combats Alzheimer’s Disease as A Multi-Target-Directed Ligand

Dimeric Tacrine (10)-Hupyridone Effectively Combats Alzheimer’s Disease as A Multi-Target-Directed Ligand

Association between BDNF rs6265 polymorphisms and postoperative cognitive dysfunction in Chinese Han Population

Inhibition of acetylcholinesterase activity and β‑amyloid oligomer formation by 6‑bromotryptamine�A, a multi‑target anti‑Alzheimer's molecule

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