Calmodulin inhibitor ameliorates cognitive dysfunction via inhibiting nitrosative stress and <scp>NLRP</scp>3 signaling in mice with bilateral carotid artery stenosis

Wang, Rui; Yin, Yixuan; Mahmood, Qaisar; Wang, Xiao-Juan; Gao, Yinping; Gou, Guojing; Ahmed, Muhammad Masood; Kohji, Fukunag; Du, Yong‐Zhong; Han, Feng

doi:10.1111/cns.12726

Cited by 28 publications

(17 citation statements)

References 44 publications

(84 reference statements)

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“…The macrophage content of the atherosclerotic vessel depends on the extent of the inflammatory reaction [41, 42]. Notably, several recent studies suggested that nitrosative stress is a key trigger of inflammasome activation [14, 43]. In the present study, an elevation in NLRP3 in the aortic sinus of atherosclerosis mice was observed, and a further dramatic increase was evidenced in atherosclerotic mice with GPR124 overexpression.…”

Section: Discussionsupporting

confidence: 61%

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Endothelial GPR124 Exaggerates the Pathogenesis of Atherosclerosis by Activating Inflammation

Gong

Chen

Hong

et al. 2018

Cell Physiol Biochem

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Background/Aims: Endothelial cell dysfunction is the principal pathological process underlying atherosclerotic cardiovascular disease. G protein-coupled receptor 124 (GPR124), an orphan receptor in the adhesion GPCR subfamily, promotes angiogenesis in the brain. In the present study, we explored the role of endothelial GPR124 in the development and progression of atherosclerosis in adult mice. Methods: Using tetracycline-inducible transgenic systems, we generated mice expressing GPR124 specifically under control of the Tie-2 promoter. The animal model of atherosclerosis was constructed by intravenously injecting AAV-PCSK9^DY into tetracycline-regulated mice and feeding the mice a high-fat diet for 16 consecutive weeks. Biochemical analysis and immunohistochemistry methods were used to address the role and mechanism of GPR124 in the pathological process of atherosclerosis. Results: Higher TC (total cholesterol) and LDL-C (low density lipoprotein cholesterol) levels in serum and greater lipid deposition in the aortic sinus were found in atherosclerotic mice with GPR124 overexpression, coincident with the elevated proliferation of smooth muscle cells. We observed an elevation of ONOO^- in the aortic sinus in this model by using immunofluorescence, and the experiments showed that the specific overexpression of GPR124 in the endothelium induced the up-regulation of CD68, NLRP3 and caspase-1 levels in the aortic sinus. Conclusion: The above results indicate that manipulating GPR124 in the endothelium may contribute to delayed pathological progression of atherosclerosis.

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Section: Discussionsupporting

confidence: 61%

“…Accumulating evidence indicates that the molecular and cellular mechanisms associated with inflammasome signaling are potentially important during pathological disease processes [14-16]. Importantly, NLRP3 inflammasomes are required for atherogenesis and are activated by cholesterol crystals is an early event of inflammation [17].…”

Section: Introductionmentioning

confidence: 99%

Endothelial GPR124 Exaggerates the Pathogenesis of Atherosclerosis by Activating Inflammation

Gong

Chen

Hong

et al. 2018

Cell Physiol Biochem

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“…Similarly, immunohistochemical results confirmed that GAS decreased the expression of LC3 compared with VD rats, especially in the CA1 regions of the hippocampus (Fig. 2c-d) .Calcium/calmodulin-dependent protein kinase II (CaMKII) belonging to the CaMK familyis a serine/threonine protein kinase as an pivotal calcium signal molecule, which is the main mediator of physiologically excitatory glutamate signal [22,28,32]. CaMKII has demonstrated a critical role in autophagy regulation [29].…”

Section: Gas Reverses Suppression Of Autophagy Flux and Hyper-phosphosupporting

confidence: 53%

Protection effect of gastrodin on learning and memory ability in vascular dementia by promoting autophagy flux via Ca2+/CaMKII signal pathway

Tt¹,

Zhou²,

Yn³

et al. 2020

Preprint

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Background: Vascular dementia is a common and frequently-occurring disease in the process of human aging. Although the current treatment can delay the deterioration of the disease, it has not a great breakthrough in improving cognitive impairment. Therefore, exploring the potential key molecular targets of VD provide promising strategy for prevention and treatment. Methods: vascular dementia rats were reproduced by permanent middle cerebral artery occlusion (pMCAO) and anoxic injury of HT22 cells were induced by Cobalt Chloride (CoCl 2 , 200μM). The ability of spatial learning and memory was assessed by morris water maze (MWM) test. Histological analysis was performed by HE staining and immunohistochemical staining. The effects of gastrodin on autophagy flux and calcium signal in vascular dementia rats and HT22 cells during hypoxia injury were detected by Western blotting and immunofluorescence. Furthermore, intracellular Ca 2+ levels were quantified using a Ca 2+ quantification kit and were also measured by flow cytometric estimation of Fluo-4 AM. Results: Gastrodin significantly reversed cognitive deficits in vascular dementia rats. The results of immunohistochemical analysis and western blot confirmed that gastrodin could attenuate the levels of LC3, p62 and phosphorylated CaMKII in hippocampus of VD rats. In addition, gastrodin was similar to the early autophagic inhibitor (3-BDO) ameliorating CoCl 2 -induced autophagic flux dysfunction and p62 knockdown by siRNA also promoting autophagic flux patency, but the late autophagy inhibitor (CQ) weakened the improvement effect of gastrodin. Furthermore, gastrodin markedly inhibited CoCl 2 -induced autophagic flux dysfunction by inhibiting [Ca 2+ ] i -dependent CaMKII. Conclusion: Gastrodin is a potential promising candidate for VD by improving autophagy flux dysfunction via increasing lysosome acidification and autophagosome-lysosome fusion mediated by CaMKII-regulated suppression of p62 signaling. Keywords: Gastrodin, Vascular dementia, Neuron injury, Autophagic flux, Ca 2+ , CaMKII

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“…Vascular cognitive impairment (VCI) is termed as a spectrum of cognitive dysfunction associated with vascular disease origins from mild cognitive impairment to dementia . White matter damage due to chronic cerebral hypoperfusion is involved in a variety of neurological disorders including VCI . White matter hyperintensities (WMH) are the main manifestation of white matter damage, while cognitive impairment and subjective impairment are associated with severe WMH .…”

Section: Introductionmentioning

confidence: 99%

dl‐3‐n‐butylphthalide preserves white matter integrity and alleviates cognitive impairment in mice with chronic cerebral hypoperfusion

Han

Zhang

et al. 2019

CNS Neurosci Ther

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Aims Effects of dl‐3‐n‐butylphthalide (NBP) on white matter damage and cognitive impairment in vascular cognitive impairment (VCI) have not been well studied. This study aimed to investigate the effects of NBP treatment on chronic cerebral hypoperfusion‐induced white matter lesions and cognitive dysfunction in mice. Methods Mice were subjected to bilateral common carotid artery stenosis (BCAS) for over 30 days. The cerebral blood flow was detected using a laser Doppler flowmetry. Cognitive functions were assessed by several behavioral tests. We also evaluated the effects of NBP on the blood‐brain barrier (BBB) disruption and reactive astrogliosis, using Evans Blue extravasation, Western blot, CBA, and immunofluorescence in BCAS mice and cultured astrocytes. Results The results indicated that NBP treatment attenuated spatial memory dysfunction while promoted cerebral perfusion and white matter integrity in BCAS mice. Moreover, NBP treatment prevented BBB leakage and damage of endothelial cells, as well as disruption of endothelial tight junctions. Furthermore, NBP administration effectively decreased the number of activated astrocytes and pro‐inflammatory cytokines, as well as the production of MMPs, in BCAS‐induced mice and LPS‐stimulated astrocytes. Conclusion Our results indicated that NBP represents a promising therapy for chronic cerebral hypoperfusion‐induced white matter damage and cognitive impairment.

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Calmodulin inhibitor ameliorates cognitive dysfunction via inhibiting nitrosative stress and NLRP3 signaling in mice with bilateral carotid artery stenosis

Abstract: These data disclose novel findings about the therapeutic potential of DY-9836, and its encapsulated nanodrug delivery system significantly enhanced the cognitive function via inhibitory effect on nitrosative stress and NLRP3 signaling in VaD mice.

Cited by 28 publications

References 44 publications

Endothelial GPR124 Exaggerates the Pathogenesis of Atherosclerosis by Activating Inflammation

Endothelial GPR124 Exaggerates the Pathogenesis of Atherosclerosis by Activating Inflammation

Protection effect of gastrodin on learning and memory ability in vascular dementia by promoting autophagy flux via Ca2+/CaMKII signal pathway

dl‐3‐n‐butylphthalide preserves white matter integrity and alleviates cognitive impairment in mice with chronic cerebral hypoperfusion

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