Hyperoside ameliorates cerebral ischaemic–reperfusion injury by opening the TRPV4 channel <i>in vivo</i> through the IP <sub>3</sub>-PKC signalling pathway

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Abstract

Context

Hyperoside (Hyp), one of the active flavones from Rhododendron (Ericaceae), has beneficial effects against cerebrovascular disease. However, the effect of Hyp on vasodilatation has not been elucidated.

Objective

To explore the effect of Hyp on vasodilatation in the cerebral basilar artery (CBA) of Sprague-Dawley (SD) rats suffering with ischaemic–reperfusion (IR) injury.

Materials and methods

Sprague-Dawley rats were randomly divided into sham, model, Hyp, Hyp + channel blocker and channel blocker groups. Hyp (50 mg/kg, IC ₅₀ = 18.3 μg/mL) and channel blocker were administered via tail vein injection 30 min before ischaemic, followed by 20 min of ischaemic and 2 h of reperfusion. The vasodilation, hyperpolarization, ELISA assay, haematoxylin–eosin (HE), Nissl staining and channel-associated proteins and qPCR were analysed. Rat CBA smooth muscle cells were isolated to detect the Ca ²⁺ concentration and endothelial cells were isolated to detect apoptosis rate.

Results

Hyp treatment significantly ameliorated the brain damage induced by IR and evoked endothelium-dependent vasodilation rate (47.93 ± 3.09% vs. 2.99 ± 1.53%) and hyperpolarization (–8.15 ± 1.87 mV vs. −0.55 ± 0.42 mV) by increasing the expression of IP3R, PKC, transient receptor potential vanilloid channel 4 (TRPV4), IK _Ca and SK _Ca in the CBA. Moreover, Hyp administration significantly reduced the concentration of Ca ²⁺ (49.08 ± 7.74% vs. 83.52 ± 6.93%) and apoptosis rate (11.27 ± 1.89% vs. 23.44 ± 2.19%) in CBA. Furthermore, these beneficial effects of Hyp were blocked by channel blocker.

Discussion and conclusions

Although Hyp showed protective effect in ischaemic stroke, more clinical trial certification is needed due to the difference between animals and humans.

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Most cited references 40

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Global, regional, and national burden of stroke and its risk factors, 1990–2019: a systematic analysis for the Global Burden of Disease Study 2019

Fakher Rahim, Yasir Waheed (2022)

Summary Background Regularly updated data on stroke and its pathological types, including data on their incidence, prevalence, mortality, disability, risk factors, and epidemiological trends, are important for evidence-based stroke care planning and resource allocation. The Global Burden of Diseases, Injuries, and Risk Factors Study (GBD) aims to provide a standardised and comprehensive measurement of these metrics at global, regional, and national levels. Methods We applied GBD 2019 analytical tools to calculate stroke incidence, prevalence, mortality, disability-adjusted life-years (DALYs), and the population attributable fraction (PAF) of DALYs (with corresponding 95% uncertainty intervals [UIs]) associated with 19 risk factors, for 204 countries and territories from 1990 to 2019. These estimates were provided for ischaemic stroke, intracerebral haemorrhage, subarachnoid haemorrhage, and all strokes combined, and stratified by sex, age group, and World Bank country income level. Findings In 2019, there were 12·2 million (95% UI 11·0–13·6) incident cases of stroke, 101 million (93·2–111) prevalent cases of stroke, 143 million (133–153) DALYs due to stroke, and 6·55 million (6·00–7·02) deaths from stroke. Globally, stroke remained the second-leading cause of death (11·6% [10·8–12·2] of total deaths) and the third-leading cause of death and disability combined (5·7% [5·1–6·2] of total DALYs) in 2019. From 1990 to 2019, the absolute number of incident strokes increased by 70·0% (67·0–73·0), prevalent strokes increased by 85·0% (83·0–88·0), deaths from stroke increased by 43·0% (31·0–55·0), and DALYs due to stroke increased by 32·0% (22·0–42·0). During the same period, age-standardised rates of stroke incidence decreased by 17·0% (15·0–18·0), mortality decreased by 36·0% (31·0–42·0), prevalence decreased by 6·0% (5·0–7·0), and DALYs decreased by 36·0% (31·0–42·0). However, among people younger than 70 years, prevalence rates increased by 22·0% (21·0–24·0) and incidence rates increased by 15·0% (12·0–18·0). In 2019, the age-standardised stroke-related mortality rate was 3·6 (3·5–3·8) times higher in the World Bank low-income group than in the World Bank high-income group, and the age-standardised stroke-related DALY rate was 3·7 (3·5–3·9) times higher in the low-income group than the high-income group. Ischaemic stroke constituted 62·4% of all incident strokes in 2019 (7·63 million [6·57–8·96]), while intracerebral haemorrhage constituted 27·9% (3·41 million [2·97–3·91]) and subarachnoid haemorrhage constituted 9·7% (1·18 million [1·01–1·39]). In 2019, the five leading risk factors for stroke were high systolic blood pressure (contributing to 79·6 million [67·7–90·8] DALYs or 55·5% [48·2–62·0] of total stroke DALYs), high body-mass index (34·9 million [22·3–48·6] DALYs or 24·3% [15·7–33·2]), high fasting plasma glucose (28·9 million [19·8–41·5] DALYs or 20·2% [13·8–29·1]), ambient particulate matter pollution (28·7 million [23·4–33·4] DALYs or 20·1% [16·6–23·0]), and smoking (25·3 million [22·6–28·2] DALYs or 17·6% [16·4–19·0]). Interpretation The annual number of strokes and deaths due to stroke increased substantially from 1990 to 2019, despite substantial reductions in age-standardised rates, particularly among people older than 70 years. The highest age-standardised stroke-related mortality and DALY rates were in the World Bank low-income group. The fastest-growing risk factor for stroke between 1990 and 2019 was high body-mass index. Without urgent implementation of effective primary prevention strategies, the stroke burden will probably continue to grow across the world, particularly in low-income countries. Funding Bill & Melinda Gates Foundation.

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GLOBAL, REGIONAL, AND COUNTRY-SPECIFIC LIFETIME RISK OF STROKE, 1990–2016

Valery L. Feigin, Grant Nguyen, Kelly Cercy … (2019)

Background Lifetime stroke risk has been calculated in a limited number of selected populations. We determined lifetime risk of stroke globally and at the regional and country level. Methods Using Global Burden of Disease Study estimates of stroke incidence and the competing risks of non-stroke mortality, we estimated the cumulative lifetime risk of ischemic stroke, hemorrhagic stroke, and total stroke (with 95% uncertainty intervals [UI]) for 195 countries among adults over 25 years) for the years 1990 and 2016 and according to the GBD Study Socio-Demographic Index (SDI). Results The global estimated lifetime risk of stroke from age 25 onward was 24.9% (95% UI: 23.5–26.2): 24.7% (23.3–26.0) in men and 25.1% (23.7–26.5) in women. The lifetime risk of ischemic stroke was 18.3% and of hemorrhagic stroke was 8.2%. The risk of stroke was 23.5% in high SDI countries, 31.1% in high-middle SDI countries, and 13.2% in low SDI countries with UIs not overlapping for these categories. The greatest estimated risk of stroke was in East Asia (38.8%) and Central and Eastern Europe (31.7 and 31.6 %%), and lowest in Eastern Sub-Saharan Africa (11.8%). From 1990 to 2016, there was a relative increase of 8.9% in global lifetime risk. Conclusions The global lifetime risk of stroke is approximately 25% starting at age 25 in both men and women. There is geographical variation in the lifetime risk of stroke, with particularly high risk in East Asia, Central and Eastern Europe.

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Elementary Ca2+ signals through endothelial TRPV4 channels regulate vascular function.

Swapnil Sonkusare, Wolfgang Liedtke, Thomas J. Heppner … (2012)

Major features of the transcellular signaling mechanism responsible for endothelium-dependent regulation of vascular smooth muscle tone are unresolved. We identified local calcium (Ca(2+)) signals ("sparklets") in the vascular endothelium of resistance arteries that represent Ca(2+) influx through single TRPV4 cation channels. Gating of individual TRPV4 channels within a four-channel cluster was cooperative, with activation of as few as three channels per cell causing maximal dilation through activation of endothelial cell intermediate (IK)- and small (SK)-conductance, Ca(2+)-sensitive potassium (K(+)) channels. Endothelial-dependent muscarinic receptor signaling also acted largely through TRPV4 sparklet-mediated stimulation of IK and SK channels to promote vasodilation. These results support the concept that Ca(2+) influx through single TRPV4 channels is leveraged by the amplifier effect of cooperative channel gating and the high Ca(2+) sensitivity of IK and SK channels to cause vasodilation.

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Author and article information

Journal

Journal ID (nlm-ta): Pharm Biol

Journal ID (iso-abbrev): Pharm Biol

Title: Pharmaceutical Biology

Publisher: Taylor & Francis

ISSN (Print): 1388-0209

ISSN (Electronic): 1744-5116

Publication date (Electronic, pub): 6 July 2023

Publication date (Electronic, collection): 2023

Publication date PMC-release: 6 July 2023

Volume: 61

Issue: 1

Pages: 1000-1012

Affiliations

[a ]Pharmacology 3rd Grade Laboratory of the State Administration of Traditional Chinese Medicine, Wannan Medical College , Wuhu, China

[b ]Anhui Provincial Engineering Laboratory for Screening and Re-evaluation of Active Compounds of Herbal Medicines in Southern Anhui, Wannan Medical College , Wuhu, China

[c ]Department of Pharmacology, School of Pharmacy, Wannan Medical College , Wuhu, China

[d ]Anhui Provincial Engineering Research Center for Polysaccharide Drugs, Wannan Medical College , Wuhu, China

[e ]Drug Research and Development Center, Wannan Medical College , Wuhu, China

Author notes

[*]

Both authors contributed equally to this work.

CONTACT Xuefeng Hou kaiwenhou@ 123456163.com

Jun Han hanjun@ 123456wnmc.edu.cn Department of Pharmacology, School of Pharmacy, Wannan Medical College , 22 Wenchang West Road, Wuhu, Anhui, P.R. China

Article

Publisher ID: 2228379

DOI: 10.1080/13880209.2023.2228379

PMC ID: 10327524

PubMed ID: 37410551

SO-VID: 2d31f635-0db4-48f0-9457-7bee444f1056

License:

This is an Open Access article distributed under the terms of the Creative Commons Attribution-NonCommercial License ( http://creativecommons.org/licenses/by-nc/4.0/), which permits unrestricted non-commercial use, distribution, and reproduction in any medium, provided the original work is properly cited. The terms on which this article has been published allow the posting of the Accepted Manuscript in a repository by the author(s) or with their consent.