Dataset Information

Angiotensin receptor (AT2R) agonist C21 prevents cognitive decline after permanent stroke in aged animals-A randomized double- blind pre-clinical study.

ABSTRACT: Post stroke cognitive impairment (PSCI) is an understudied, long-term complication of stroke, impacting nearly 30-40% of all stroke survivors. No cure is available once the cognitive deterioration manifests. To our knowledge, this is the first study to investigate the long-term effects of C21 treatment on the development of PSCI in aged animals. Treatments with C21 or vehicle were administered orally, 24?h post-stroke, and continued for 30 days. Outcome measures for sensorimotor and cognitive function were performed using a sequence of tests, all blindly conducted and assessed at baseline as well as at different time points post-stroke. Our findings demonstrate that the angiotensin receptor (AT2R) agonist C21 effectively prevents the development of PSCI in aged animals.

SUBMITTER: Ahmed HA

PROVIDER: S-EPMC6371811 | biostudies-literature | 2019 Feb

REPOSITORIES: biostudies-literature

ACCESS DATA

Publications

Angiotensin receptor (AT2R) agonist C21 prevents cognitive decline after permanent stroke in aged animals-A randomized double- blind pre-clinical study.

Ahmed Heba A HA Ishrat Tauheed T Pillai Bindu B Bunting Kristopher M KM Vazdarjanova Almira A Waller Jennifer L JL Ergul Adviye A Fagan Susan C SC

Behavioural brain research 20181005

Post stroke cognitive impairment (PSCI) is an understudied, long-term complication of stroke, impacting nearly 30-40% of all stroke survivors. No cure is available once the cognitive deterioration manifests. To our knowledge, this is the first study to investigate the long-term effects of C21 treatment on the development of PSCI in aged animals. Treatments with C21 or vehicle were administered orally, 24 h post-stroke, and continued for 30 days. Outcome measures for sensorimotor and cognitive fu ...[more]

PMID: 30296528

Similar Datasets

Project description:Abstract The prohormone N-terminal pro-B-type natriuretic peptide (NT-proBNP) is released from stretched cardiac myocytes and is a diagnostic biomarker for heart failure and cardiac dysfunction as well as pulmonary embolism and pneumonia that are frequent complications to severe Coronavirus Disease 2019 (COVID-19). NT-proBNP is frequently elevated in COVID-19. In a recent publication, it was demonstrated that NT-proBNP was strongly associated with mortality in patients with COVID-19, and further investigation of its usefulness as a prognostic tool to predict disease outcomes in COVID-19 was suggested (1). In the recently completed phase 2 trial (angiotensin II type 2 receptor agonist COVID-19 trial [ATTRACT]; NCT04452435) in subjects hospitalised with COVID-19, it was investigated whether treatment with the AT2R agonist C21 for 7 days affected the release of the plasma biomarker NT-proBNP. ATTRACT was a randomised, double-blind, placebo-controlled, phase 2 trial that investigated the safety and efficacy of C21 treatment (100 mg twice daily) for 7 days in hospitalised subjects with COVID-19, not requiring mechanical ventilation. The results of the trial demonstrated that treatment with C21 on top of standard of care (vast majority of patients received glucocorticoids) significantly reduced the proportion of subjects requiring supplemental oxygen at Day 14, indicating faster recovery with C21 treatment compared to placebo. Blood samples for exploratory analysis were taken before and after 7 days of treatment with C21 or placebo. Plasma NT-proBNP was markedly elevated in both treatment groups before treatment, with average values of 357 and 438 pg/mL in the placebo and C21 groups, respectively, as compared to normal levels of approximately <100 pg/mL. After 7 days of treatment, the C21 group experienced a dramatic reduction in plasma NT-proBNP (by 259 pg/mL) as compared to the placebo group (63 pg/mL) (p=0.02). The results show that short-term C21 treatment decreased the release of NT-proBNP in subjects hospitalised with COVID-19. Further investigations are needed to elucidate whether this is related to effects on COVID-19-induced pulmonary damage or direct protective effects on the heart. We are currently conducting a global phase 3 trial (VP-C21–008) further investigating the effect of C21 in subjects hospitalised with COVID-19 including determination of NT-proBNP. Funding Acknowledgement Type of funding sources: Private company. Main funding source(s): Vicore Pharma AB

Project description:BackgroundCOVID-19 morbidity and mortality remains high and the need for safe and effective drugs continues despite vaccines.MethodsDouble-blind, placebo-controlled, multi-centre, randomised, parallel group phase 2 trial to evaluate safety and efficacy of oral angiotensin II type 2 receptor agonist C21 in hospitalized patients with COVID-19 and CRP ≥ 50-150 mg/L conducted at eight sites in India (NCT04452435). Patients were randomly assigned 100 mg C21 bid or placebo for 7 days in addition to standard of care. Primary endpoint: reduction in CRP. The study period was 21 July to 13 October 2020.Findings106 patients were randomised and included in the analysis (51 C21, 55 placebo). There was no significant group difference in reduction of CRP, 81% and 78% in the C21 and placebo groups, respectively, with a treatment effect ratio of 0.85 [90% CI 0.57, 1.26]. In a secondary analysis in patients requiring supplemental oxygen at randomisation, CRP was reduced in the C21 group compared to placebo. At the end of the 7-day treatment, 37 (72.5%) and 30 (54.5%) of the patients did not require supplemental oxygen in the C21 and placebo group, respectively (OR 2.20 [90% CI 1.12, 4.41]). A post hoc analysis showed that at day 14, the proportion of patients not requiring supplemental oxygen was 98% and 80% in the C21 group compared to placebo (OR 12.5 [90% CI 2.9, 126]). Fewer patients required mechanical ventilation (one C21 patient; four placebo patients), and C21 was associated with a numerical reduction in the mortality rate (one vs three in the C21 and placebo group, respectively). Treatment with C21 was safe and well tolerated.InterpretationAmong hospitalised patients with COVID-19 receiving C21 for 7 days there was no reduction in CRP compared to placebo. However, a post-hoc analysis indicated a marked reduction of requirement for oxygen at day 14. The day 14 results from this study justify further evaluation in a Phase 3 study and such a trial is currently underway.FundingVicore Pharma AB and LifeArc, UK.

Project description:Oxidative and nitrosative stress have been implicated in high-sodium diet (HSD)-related hypertensive renal injury. In this study, we investigated angiotensin II type 2-receptor-mediated renoprotection in obese Zucker rats fed HSD. Obese Zucker rats were fed normal sodium diet or HSD 4%, for 14 days, with/without angiotensin II type 2-receptor agonist C21, delivered subcutaneously via osmotic pump, 1 mg/kg per day. Compared with normal sodium diet controls, HSD rats exhibited increase in cortical nicotinamide adenine dinucleotide phosphate oxidase activity, urinary H2O2, and 8-isoprostanes, which were associated with severe glomerulosclerosis, interstitial fibrosis, decline in estimated glomerular filtration rate, and an increase in urinary leak and activity of N-acetyl-?-D-glucosaminidase, a lysosomal enzyme and a marker of tubular damage. These changes were improved by C21 treatment. Cortical expression of endothelial nitric oxide synthase, phospho-endothelial nitric oxide synthase (Ser(1177)), and plasma nitrites were reduced after HSD intake, whereas nitrosative stress (3-nitrotyrosine) and enzymatic defense (superoxide dismutase-to-catalase activity) remained unaltered. However, C21 preserved plasma nitrites in HSD-fed obese Zucker rat. C21 treatment reduced protein-to-creatinine, albumin-to-creatinine, as well as fractional excretion of protein and albumin in HSD-fed obese Zucker rat, which is independent of changes in protein recycling receptors, megalin, and cubilin. HSD intake also altered renal excretory and reabsorptive capacity as evident by elevated plasma urea nitrogen-to-creatinine and fractional excretion of urea nitrogen, and reduced urine-to-plasma creatinine, which were modestly, but insignificantly, improved by C21 treatment. Together results demonstrate that angiotensin II type 2-receptor activation protects against HSD-induced kidney damage in obesity plausibly by reducing nicotinamide adenine dinucleotide phosphate oxidase activity and rescuing nitrites.

Project description:In order to determine differences in cardiovascular cell response during nutrient stress to different cardiovascular protective drugs, we investigated cell responses of serum starved mouse cardiomyocyte HL-1 cells and primary cultures of human coronary artery vascular smooth muscles (hCAVSMCs) to treatment with β-blockers (atenolol, metoprolol, carvedilol, nebivolol, 3 μM each), AT1R blocker losartan (1 μM) and AT2R agonists (CGP42112A and novel agonist NP-6A4, 300 nM each). Treatment with nebivolol, carvedilol, metoprolol and atenolol suppressed Cell Index (CI) of serum-starved HL-1 cells (≤17%, ≤8%, ≤15% and ≤15% respectively) as measured by the Xcelligence Real-Time Cell Analyzer (RTCA). Conversely, CI was increased by Ang II (≥9.6%), CGP42112A (≥14%), and NP-6A4 (≥25%) respectively and this effect was blocked by AT2R antagonist PD123319, but not by AT1R antagonist losartan. Thus, the CI signature for each drug could be unique. MTS cell proliferation assay showed that NP-6A4, but not other drugs, increased viability (≥20%) of HL-1 and hCAVSMCs. Wheat Germ Agglutinin (WGA) staining showed that nebivolol was most effective in reducing cell sizes of HL-1 and hCAVSMCs. Myeloid Cell Leukemia 1 (MCL-1) is a protein critical for cardiovascular cell survival and implicated in cell adhesion. β-blockers significantly suppressed and NP-6A4 increased MCL-1 expression in HL-1 and hCAVSMCs as determined by immunofluorescence. Thus, reduction in cell size and/or MCL-1 expression might underlie β-blocker-induced reduction in CI of HL-1. Conversely, increase in cell viability and MCL-1 expression by NP-6A4 through AT2R could have resulted in NP-6A4 mediated increase in CI of HL-1. These data show for the first time that activation of the AT2R-MCL-1 axis by NP-6A4 in nutrient-stressed mouse and human cardiovascular cells (mouse HL-1 cells and primary cultures of hCAVSMCs) might underlie improved survival of cells treated by NP-6A4 compared to other drugs tested in this study.

Dataset Information

Angiotensin receptor (AT2R) agonist C21 prevents cognitive decline after permanent stroke in aged animals-A randomized double- blind pre-clinical study.

Publications

Angiotensin receptor (AT2R) agonist C21 prevents cognitive decline after permanent stroke in aged animals-A randomized double- blind pre-clinical study.

Similar Datasets

OmicsDI is part of the ELIXIR infrastructure

Tweets