CZ-7, a new derivative of Claulansine F, ameliorates 2VO-induced vascular dementia in rats through a Nrf2-mediated antioxidant responses

Liu, Dandan; Yuan, Xia; Chu, Shifeng; Chen, Chen; Ren, Qian; Luo, Piao; Lin, Ming-Hsiu; Wang, Shasha; Zhu, Tian-Bi; Ai, Qidi; Zang, Yingda; Zhang, Dongming; He, Xin; Huang, Zhihua; Sun, Hong‐Shuo; Feng, Zhong‐Ping; Chen, Nai‐Hong

doi:10.1038/s41401-018-0078-7

Cited by 33 publications

(24 citation statements)

References 48 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…Bilateral common carotid artery occlusion (BCCAO) was established to study the cognitive dysfunction and neurodegeneration caused by chronic cerebral hypoperfusion (CCH). The BCCAO surgery was performed as previously conducted in our laboratory [ 1 ]. Thirty-two Sprague-Dawley rats were randomly divided into 2 groups, namely, the sham group ( n = 8) and the BCCAO group ( n = 24).…”

Section: Methodsmentioning

confidence: 99%

See 1 more Smart Citation

Donepezil attenuates vascular dementia in rats through increasing BDNF induced by reducing HDAC6 nuclear translocation

et al. 2020

Self Cite

View full text Add to dashboard Cite

Vascular dementia (VD) is the second most common dementia disease after Alzheimer’s diseases (AD) in the world. Donepezil is used to treat mild to moderate AD, and it has been shown to treat cognitive impairment and memory deficits caused by VD. However, the action mechanism of donepezil against VD has not been clarified. In this study, a bilateral common carotid artery occlusion (BCCAO) model was established in rats to simulate the pathology of VD. Two weeks after the surgery, the rats were administered donepezil (10 mg · kg −1 · d −1 , ig) for 3 weeks, and then subjected to behavioral tests. We showed that donepezil treatment significantly improved the performance of BCCAO rats in Morris Water Mazes test and Step-down test. Furthermore, we showed that donepezil treatment significantly attenuated neurodegeneration and restored the synapse dendritic spines density in cortex and hippocampus. We revealed that donepezil treatment significantly increased BDNF expression in cortex and hippocampus. Interestingly, donepezil treatment significantly decreased nuclear translocation of HDAC6 and the binding between HDAC6 and BDNF promoter IV in cortex, but not in the hippocampus. The attenuated neurodegeneration by donepezil in cortex and hippocampus might due to the reduced ROS levels and increased phosphorylation of AMPK, whereas increased phosphorylation of AKT was only detected in cortex. In conclusion, our results demonstrate that donepezil attenuates neurodegeneration in cortex and hippocampus via increasing BDNF expression; the regulation of donepezil on HDAC6 occurred in cortex, but not in the hippocampus. This study further clarifies the pharmacological mechanism of donepezil, while also emphasizes the promising epigenetic regulation of HDAC6.

show abstract

Section: Methodsmentioning

confidence: 99%

“…Vascular dementia (VD) is the second most common dementia-related disease in the world after Alzheimer’s disease (AD) [ 1 , 2 ]. The risks of VD increase with age, and the severity of VD depends on injury to vessels and cerebral regions.…”

Section: Introductionmentioning

confidence: 99%

Donepezil attenuates vascular dementia in rats through increasing BDNF induced by reducing HDAC6 nuclear translocation

et al. 2020

Self Cite

View full text Add to dashboard Cite

show abstract

“…The molecular mechanism of oxidative stress-induced cognitive deficits has been investigated in animal models. In occlusion rat models (BCAO), it was shown that oxidative stress is characterized by the increased production of reactive oxygen species (ROS) [58,59] which are responsible for both cardiovascular pathophysiology and neurodegeneration [60,61]. In fact, ROS and reduced antioxidant defense may directly affect synaptic activity and neurotransmission in neurons, leading to cognitive dysfunction [62].…”

Section: Molecular Mechanism Of Vcimentioning

confidence: 99%

“…In fact, ROS and reduced antioxidant defense may directly affect synaptic activity and neurotransmission in neurons, leading to cognitive dysfunction [62]. In the same models, it was also shown that the negative effects of ROS on memory processes could be counteracted by substances able to increase the gene expression of antioxidant proteins, such as nuclear factor erythroid 2 like 2 (NFE2L2), alcohol dehydrogenase 7 (ADH7), and glutathione peroxidase 2 (GPX2) and 3 (GPX3) [58,59].…”

Section: Molecular Mechanism Of Vcimentioning

confidence: 99%

Vascular Cognitive Impairment: Information from Animal Models on the Pathogenic Mechanisms of Cognitive Deficits

Hort

Vališ

Kuča

et al. 2019

IJMS

View full text Add to dashboard Cite

Vascular cognitive impairment (VCI) is the second most common cause of cognitive deficit after Alzheimer’s disease. Since VCI patients represent an important target population for prevention, an ongoing effort has been made to elucidate the pathogenesis of this disorder. In this review, we summarize the information from animal models on the molecular changes that occur in the brain during a cerebral vascular insult and ultimately lead to cognitive deficits in VCI. Animal models cannot effectively represent the complex clinical picture of VCI in humans. Nonetheless, they allow some understanding of the important molecular mechanisms leading to cognitive deficits. VCI may be caused by various mechanisms and metabolic pathways. The pathological mechanisms, in terms of cognitive deficits, may span from oxidative stress to vascular clearance of toxic waste products (such as amyloid beta) and from neuroinflammation to impaired function of microglia, astrocytes, pericytes, and endothelial cells. Impaired production of elements of the immune response, such as cytokines, and vascular factors, such as insulin-like growth factor 1 (IGF-1), may also affect cognitive functions. No single event could be seen as being the unique cause of cognitive deficits in VCI. These events are interconnected, and may produce cascade effects resulting in cognitive impairment.

show abstract

“…More importantly, CZ-7 exposure in the brain was 4.3-fold higher than that in plasma, and preliminary acute toxicological test results showed that CZ-7 had no toxic side effects with an oral 1 g/kg dose in ICR (Institute of Cancer Research) mice [ 16 ]. In addition, CZ-7 has therapeutic potential for VD (vascular dementia) by alleviating oxidative stress injury through Nrf2-mediated antioxidant responses [ 17 ].…”

Section: Introductionmentioning

confidence: 99%

Claulansine F–Donepezil Hybrids as Anti-Alzheimer’s Disease Agents with Cholinergic, Free-Radical Scavenging, and Neuroprotective Activities

et al. 2021

View full text Add to dashboard Cite

The multifactorial nature of Alzheimer’s disease (AD) calls for the development of multitarget agents addressing key pathogenic processes. A total of 26 Claulansine F–donepezil hybrids were designed and synthesized as multitarget drugs. Among these compounds, six compounds exhibited excellent acetylcholinesterase (AChE) inhibitory activity (half maximal inhibitory concentration (IC50) 1.63–4.62 μM). Moreover, (E)-3-(8-(tert-Butyl)-3,3-dimethyl-3,11-dihydropyrano[3,2-a]carbazol-5-yl)-N-((1-(2-chlorobenzyl)piperidin-4-yl)methyl)acrylamide (6bd) exhibited better neuroprotective effects against OGD/R (oxygen–glucose deprivation/reoxygenation) than lead compound Claulansine F. Furthermore, 6bd could cross the blood–brain barrier in vitro. More importantly, compared to edaravone, 6bd had stronger free-radical scavenging activity. Molecular docking studies revealed that 6bd could interact with the catalytic active site of AChE. All of these outstanding in vitro results indicate 6bd as a leading structure worthy of further investigation.

show abstract

CZ-7, a new derivative of Claulansine F, ameliorates 2VO-induced vascular dementia in rats through a Nrf2-mediated antioxidant responses

Cited by 33 publications

References 48 publications

Donepezil attenuates vascular dementia in rats through increasing BDNF induced by reducing HDAC6 nuclear translocation

Donepezil attenuates vascular dementia in rats through increasing BDNF induced by reducing HDAC6 nuclear translocation

Vascular Cognitive Impairment: Information from Animal Models on the Pathogenic Mechanisms of Cognitive Deficits

Claulansine F–Donepezil Hybrids as Anti-Alzheimer’s Disease Agents with Cholinergic, Free-Radical Scavenging, and Neuroprotective Activities

Contact Info

Product

Resources

About