N-salicyloyl tryptamine derivatives as potential therapeutic agents for Alzheimer's disease with neuroprotective effects

Bai, Yinliang; Liú, Dan; Zhang, Honghua; Wang, Yuying; Wang, Degui; Cai, Hongbin; Wen, Huaixiu; Yuan, Guoqiang; An, Hee-Jung; Wang, Yali; Shi, Tao; Wang, Zhen

doi:10.1016/j.bioorg.2021.105255

Cited by 23 publications

(17 citation statements)

References 45 publications

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“…Melatonin also inhibits the NF-κB pathway in OGD/R or H 2 O 2 -treated SH-SY5Y cells and shows anti-inflammatory and neuroprotective effects. , However, the poor pharmacokinetic properties of melatonin, such as the short plasma half-life (∼30 min), limit its use in neurological disorders; thus, rational modifications based on the template of melatonin have been conducted. Wang et al found that the N -salicyl tryptamine derivative LZWL02003 outperformed all other compounds in terms of its anti-inflammatory, free radical scavenging, and neuroprotective capabilities. , Neuroprotective effects of LZWL02003 were also shown in in vivo and in vitro models of Alzheimer’s disease conferred by Aβ . Therefore, LZWL02003 could also be neuroprotective in the case of cerebral I/R.…”

Section: Discussionmentioning

confidence: 99%

“…10,25 Neuroprotective effects of LZWL02003 were also shown in in vivo and in vitro models of Alzheimer's disease conferred by Aβ. 13 Therefore, LZWL02003 could also be neuroprotective in the case of cerebral I/R. In this study, cerebral I/R injuries were established with two common models: the OGD/R model in HT22 cells and the MCAO/R model in C57BL/6 mice.…”

Section: ■ Discussionmentioning

confidence: 99%

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Neuroprotective Effects of an N-Salicyloyl Tryptamine Derivative against Cerebral Ischemia/Reperfusion Injury

Peng

et al. 2023

ACS Chem. Neurosci.

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Cerebral ischemia/reperfusion (I/R) injury is a key reason for the poor prognosis of ischemic stroke. As only a few neuroprotective medications for cerebral I/R injury have been applied in the clinic, it is necessary to design a new therapeutic strategy to treat cerebral I/R injury. The N-salicyloyl tryptamine derivative LZWL02003, synthesized from melatonin and salicylic acid, exhibits a wide range of biological properties. In this study, we assessed the neuroprotective capabilities of LZWL02003 in vivo and in vitro and investigated its possible mechanisms. Oxygen-glucose deprivation/reoxygenation was utilized to create an in vitro model of cerebral I/R damage. Middle cerebral artery occlusion/reperfusion was employed to imitate cerebral I/R injury in vivo. Neuronal apoptosis, oxidative stress, mitochondrial dysfunction, and neuroinflammation are associated with the pathogenesis of cerebral I/R injury. Our findings demonstrated that LZWL02003 upregulated the expression of Bcl-2 and downregulated the expression of Bax, thus maintaining the homeostasis of Bcl-2/Bax proteins and preventing apoptosis. LZWL02003 also reduced oxidative stress by reducing malondialdehyde and reactive oxygen species levels, increasing the superoxide dismutase activity, and resolving mitochondrial malfunction. LZWL02003 can lower interleukin (IL)-1β, tumor necrosis factor (TNF)-α, and IL-6 levels, which in turn suppress neuroinflammation. Activation of the nuclear factor-kappa B (NF-κB) pathway is involved in various pathophysiologies, including cerebral I/R injury. We discovered that LZWL02003 suppressed the phosphorylation activation of NF-κB pathway-related proteins and decreased the nuclear translocation of NF-κB p65 subunits. Taken together, our results suggest that LZWL02003 is a neuroprotective drug with pleiotropic effects and may be a candidate for treating cerebral I/R injury.

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Section: Discussionmentioning

confidence: 99%

Section: ■ Discussionmentioning

confidence: 99%

Neuroprotective Effects of an N-Salicyloyl Tryptamine Derivative against Cerebral Ischemia/Reperfusion Injury

Peng

et al. 2023

ACS Chem. Neurosci.

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“…Previous studies have shown that compound LZWL 02003 has definite anti-neuroinflammatory activity, good blood–brain barrier permeability, and low toxicity . Another study showed that LZWL 02003 had a good therapeutic effect on the mouse AD model . Therefore, the cell experiment of compound LZWL 02003 on anti-neuroinflammatory activity was not repeated in this paper, and we mainly focused on the detection of the neuroprotective effect.…”

Section: Discussionmentioning

confidence: 99%

Exploring the Therapeutic Effects of Multifunctional N-Salicylic Acid Tryptamine Derivative against Parkinson’s Disease

Wang

Duan

et al. 2023

ACS Omega

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Parkinson's disease (PD) is the second most common neurodegenerative disease worldwide. Neuroinflammation and oxidative stress play an important role in the whole course of PD, which have been the focus of PD drug development. In our previous research, a series of N-salicylic acid tryptamine derivatives were synthesized, and the biological evaluation showed that the compound LZWL02003 has good anti-neuroinflammatory activity and displayed great therapeutic potency for neurodegenerative disease models. In this work, the neuroprotective efficiency of LZWL02003 against PD in vitro and in vivo has been explored. It was found that LZWL02003 could protect human neuron cells SH-SY5Y from MPP + -induced neuronal damage by inhibiting ROS generation, mitochondrial dysfunction, and cellular apoptosis. Moreover, LZWL02003 could improve cognition, memory, learning, and athletic ability in a rotenone-induced PD rat model. In general, our study has demonstrated that LZWL02003 has good activity against PD in in vitro and in vivo experiments, which can potentially be developed into a therapeutic candidate for PD.

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“…Aβ1-42 induces pyroptosis in mice cortical neurons (MCNs), increases cell permeability and promotes lactate dehydrogenase (LDH) release ( Han et al, 2020b ). It has been shown that Aβ activates the NLRP3-caspase-1-GSDMD axis to induce neuronal pyroptosis, thereby promoting neuroinflammatory responses and neuronal damage, and ultimately leading to accelerated progression of AD ( Bai et al, 2021 ). In APPswe/PS1dE9 transgenic mice, NLRP1 levels were found to be upregulated in the brain.…”

Section: Research Progress In Relationship Between Pyroptosis and Alz...mentioning

confidence: 99%

“…In mouse and cellular models, AF (amentoflavone) downregulated NLRP3 and other pyroptosis-related protein levels through activation of AMP-activated protein kinase (AMPK)/Glycogen synthase kinase-3beta (GSK3β) signaling pathway, ultimately inhibiting Aβ1-42-induced hippocampal neuronal pyroptosis ( Zhao et al, 2019 ). L7 (N-salicyloyl tryptamine derivatives) antagonizes Aβ-induced pyroptosis in BV2 cells by inhibiting NLRP3-Caspase-1 signaling pathway and thus exerts neuroprotective effects by down-regulating GSDMD expression ( Bai et al, 2021 ). In the Amyloid precursor protein (APP)/presenilin-1 (PS1) mouse model, U50488H (κ-opioid receptor agonist) ameliorated synaptic plasticity and AD-related symptoms by inhibiting NLRP3-induced hippocampal microglia pyroptosis ( Song et al, 2021 ).…”

Section: Research Progress In Relationship Between Pyroptosis and Alz...mentioning

confidence: 99%

Pyroptosis as a candidate therapeutic target for Alzheimer’s disease

Huang

Li²,

Luo³

et al. 2022

Front. Aging Neurosci.

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Pyroptosis is a form of cell death mediated by inflammasomes and gasdermins, and the relevance of pyroptosis to neurodegenerative diseases is currently receiving increasing attention. Alzheimer’s disease (AD) is a chronic progressive neurodegenerative disease that is closely associated with neuroinflammation. Its main pathological features include β-amyloid (Aβ) deposition, Tau protein hyperphosphorylation and neuronal loss. Aβ, tau-induced microglia pyroptosis and polarization leading to neuroinflammation play an important role in the pathogenesis of AD. Studying the pathogenesis and treatment of AD based on cellular pyroptosis has become a new direction in AD research. In this paper, we review the research progress of pyroptosis and will focus on the pathogenic roles of pyroptosis in AD and the role of targeted inhibition of inflammasome-dependent pyroptosis in AD treatment. These results deepen our understanding of the pathogenesis of AD and provide ideas for the development of new drugs based on the regulation of pyroptosis in AD patients.

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N-salicyloyl tryptamine derivatives as potential therapeutic agents for Alzheimer's disease with neuroprotective effects

Cited by 23 publications

References 45 publications

Neuroprotective Effects of an N-Salicyloyl Tryptamine Derivative against Cerebral Ischemia/Reperfusion Injury

Neuroprotective Effects of an N-Salicyloyl Tryptamine Derivative against Cerebral Ischemia/Reperfusion Injury

Exploring the Therapeutic Effects of Multifunctional N-Salicylic Acid Tryptamine Derivative against Parkinson’s Disease

Pyroptosis as a candidate therapeutic target for Alzheimer’s disease

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