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

Jian, Wenxuan; Zhao, Zi‐Gang; Zhan, Jia-Hong; Chu, Shifeng; Ye, Peng; Zhao, Mingfei; Wang, Qi; Chen, Nai‐Hong

doi:10.1038/s41401-019-0334-5

Cited by 31 publications

(25 citation statements)

References 29 publications

(38 reference statements)

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“…According to a previous report, 16 a VD rat model was established by permanent occlusion of bilateral common carotid arteries (CCA). Within 12 h before the operation, all rats were fasted with free access to water.…”

Section: Methodsmentioning

confidence: 99%

Therapeutic Effect of Idebenone on Rats with Vascular Dementia via the MicroRNA-216a/RSK2/NF-κB Axis

Qian¹,

Xu²,

Li³

et al. 2021

NDT

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Background Vascular dementia (VD) is a brain disease featured by cognitive impairment and cerebrovascular pathologies. Idebenone can treat neurodegenerative diseases. This study evaluated the mechanism of Idebenone in VD. Methods The VD rat model was established by permanent occlusion of bilateral common carotid arteries, followed by intragastrical administration of Idebenone. The learning and spatial memory abilities, and the levels of MDA, SOD, IL-6 and TNF-α were measured. Histological staining was adopted to observe the damage of neurons in the hippocampal cortex and to quantitatively analyze the neuronal damage in CA1 area of hippocampus. Microarray analysis was performed to find out the effect of Idebenone treatment on microRNA (miR) expression in hippocampus of rats. The potential target genes of miR and the pathways regulated by target genes were searched by bioinformatics analysis, and verified by experiments. The mechanism of action behind Idebenone in VD rats was proved by rescue experiment. Results Idebenone treatment improved the learning and spatial memory abilities of VD rats, inhibited neuroinflammation and oxidative stress, and prevented neuronal apoptosis. Idebenone treatment elevated miR-216a expression in hippocampus of rats, but the therapeutic effect of Idebenone was averted by lentivirus inhibition of miR-216a. miR-216a targeted RSK2. Overexpression of RSK2 annulled the therapeutic effect of Idebenone on VD rats by activating the IκBα/NF-κB axis. Conclusion Idebenone inhibits the activation of RSK2/IκBα/NF-κB axis by increasing miR-216a, thus alleviating oxidative stress and neuroinflammation in VD rats.

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Section: Methodsmentioning

confidence: 99%

Therapeutic Effect of Idebenone on Rats with Vascular Dementia via the MicroRNA-216a/RSK2/NF-κB Axis

Qian¹,

Xu²,

Li³

et al. 2021

NDT

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“…Donepezil is a clinically used US FDA‐approved drug for dementia of Alzheimer’s disease. It is also clinically employed for dementia of other etiologies [31,32]. Donepezil is taken as positive standard in our study based on our previous work [33].…”

Section: Methodsmentioning

confidence: 99%

“…Therefore, the present study has been conducted to investigate the efficacy of ozagrel, a thromboxane A2 synthase inhibitor in rat model of HHcy‐induced VCID. Donepezil, a central cholinesterase inhibitor, currently being clinically used for dementia of Alzheimer’s disease [31] and other etiologies [32] has been employed as a positive standard in the present investigation.…”

Section: Introductionmentioning

confidence: 99%

Ameliorative effect of ozagrel, a thromboxane A2 synthase inhibitor, in hyperhomocysteinemia‐induced experimental vascular cognitive impairment and dementia

Bhatia

Singh

2020

Fundamemntal Clinical Pharma

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The present study investigates the effect of ozagrel, a selective thromboxane A2 (TXA2) inhibitor, in rat model of hyperhomocysteinemia (HHcy)‐induced vascular cognitive impairment and dementia (VCID). Wistar rats were administered L‐methionine (1.7 g/kg/day; p.o. × 8 weeks) to induce VCID. Morris water maze (MWM) test was employed to assess learning and memory. Endothelial dysfunction was assessed in the isolated aorta by observing endothelial‐dependent vasorelaxation and levels of serum nitrite. Various biochemical and histopathological estimations were also performed. L‐methionine produced significant impairment in endothelium‐dependent vasorelaxation and decreases serum nitrite levels indicating endothelial dysfunction. Further, these animals performed poorly on MWM, depicting impairment of learning and memory. Further, a significant rise in brain oxidative stress level (indicated by increase in brain thiobarbituric acid‐reactive species and decrease in reduced glutathione levels), brain acetylcholinesterase activity, brain myeloperoxidase activity, brain TNF‐α and IL‐6 levels, and brain leukocyte (neutrophil) infiltration was also observed. Treatment of ozagrel (10 and 20 mg/kg, p. o.)/donepezil (0.5 mg/kg, i.p., serving as standard) ameliorated L‐methionine‐induced endothelial dysfunction, memory deficits, and biochemical and histopathological changes. It may be concluded that ozagrel markedly improved endothelial dysfunction, learning and memory, and biochemical and histopathological alteration associated with L‐methionine‐induced VCID and that TXA2 can be considered as an important therapeutic target for the management of VCID.

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“…Vascular dementia (VD) is a common dementia disease, second in the world only to Alzheimer’s disease (AD) [ 43 ]. Donepezil, used to treat mild to moderate AD, has been shown to treat cognitive impairment and memory deficits caused by VD.…”

Section: Cognition Regulation and Neurodegenerationmentioning

confidence: 99%

“…Donepezil, used to treat mild to moderate AD, has been shown to treat cognitive impairment and memory deficits caused by VD. Jian et al [ 43 ] showed that donepezil treatment significantly improved cognitive performance. Furthermore, donepezil treatment significantly attenuated neurodegeneration and restored synapse dendritic spine density in the cortex and hippocampus.…”

Section: Cognition Regulation and Neurodegenerationmentioning

confidence: 99%

HDAC6 in Diseases of Cognition and of Neurons

LoPresti

2020

Cells

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Central nervous system (CNS) neurodegenerative diseases are characterized by faulty intracellular transport, cognition, and aggregate regulation. Traditionally, neuroprotection exerted by histone deacetylase (HDAC) inhibitors (HDACi) has been attributed to the ability of this drug class to promote histone acetylation. However, HDAC6 in the healthy CNS functions via distinct mechanisms, due largely to its cytoplasmic localization. Indeed, in healthy neurons, cytoplasmic HDAC6 regulates the acetylation of a variety of non-histone proteins that are linked to separate functions, i.e., intracellular transport, neurotransmitter release, and aggregate formation. These three HDAC6 activities could work independently or in synergy. Of particular interest, HDAC6 targets the synaptic protein Bruchpilot and neurotransmitter release. In pathological conditions, HDAC6 becomes abundant in the nucleus, with deleterious consequences for transcription regulation and synapses. Thus, HDAC6 plays a leading role in neuronal health or dysfunction. Here, we review recent findings and novel conclusions on the role of HDAC6 in neurodegeneration. Selective studies with pan-HDACi are also included. We propose that an early alteration of HDAC6 undermines synaptic transmission, while altering transport and aggregation, eventually leading to neurodegeneration.

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

Cited by 31 publications

References 29 publications

Therapeutic Effect of Idebenone on Rats with Vascular Dementia via the MicroRNA-216a/RSK2/NF-κB Axis

Therapeutic Effect of Idebenone on Rats with Vascular Dementia via the MicroRNA-216a/RSK2/NF-κB Axis

Ameliorative effect of ozagrel, a thromboxane A2 synthase inhibitor, in hyperhomocysteinemia‐induced experimental vascular cognitive impairment and dementia

HDAC6 in Diseases of Cognition and of Neurons

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