Adenosine A2A Receptor (A2AR) Agonist Apadenoson Promotes Survival in K28-hACE2 Mice and Syrian Hamsters Infected with Sars-CoV-2
American Journal of Transplantation
; 22(Supplement 3):908-909, 2022.
Article
in English
| EMBASE | ID: covidwho-2063435
ABSTRACT
Purpose:
To determine if Apadenoson or Regadenoson has a therapeutic effect in attenuating hyper-inflammation and improving survival rate in K18-hACE2mice or Syrian hamsters infected with SARS-CoV-2. Method(s) 6-8 weeks old male K18-hACE2mice were divided into Control group that received vehicle;Test group 1 that received the drug (Apadenoson or Regadenoson) 24hrs prior to challenge with SARS-CoV-2;and Test Group 2 (Drug-delay), that received the drug with a 5 hr delay post-viral infection (n=6/grp). Viral dose was 1250 PfuHong Kong/VM20001061/2020 delivered via intranasal route. Drug was delivered subcutaneously using 1007D ALZET pumps. 6 weeks old Syrian hamsters were divided into Control group that received Vehicle and Virus (n=4) and 2 test groups (n=5/group) that received Apadenoson+Virus and Regadenoson+Virus. Drugs were delivered by 2ML2 ALZET pumps (4ug/kg/hr). Hamsters were inoculated intratracheally with 750PFU SARS-CoV-2 WA1 strain prior to treatment. Mice were weighed and clinical scores recorded daily. Bronchoalveolar lavage fluid (BALF) and serum were collected along with lungs. Plethysmography was done on days 0, 2, 4 and 7. Result(s) Apadenoson administered post-infection was efficacious in decreasing weight loss, improving clinical score, and increasing the survival rate in K18-hACE2 mice, i.e. 50% survival was observed at Day 5 and at Day 7 post-infection for drug given before or after infection respectively. Apadenoson given post-infection improved the histopathology that was observed in the vehicle control group, decreased pro-inflammatory IL-6, IFN-gamma, MCCP-1, MIP-1beta, IP-10, and Rantes in serum, increased anti-inflammatory Ang1-7 levels, and decreased monocytes in BALF. 42% of mice that received Regadenoson pre-challenge survived infection compared to 6.25% in the vehicle or Drug delay (drug given post-infection) groups. Viral titers in the lungs of Regadenoson-treated mice were found decreased. Treatment also significantly decreased CD4+, CD8+T cells, eosinophils, and neutrophils in BALF. Plethysmography, in hamsters, showed significant improvement of pulmonary function parameters, Rpef and PenH, following treatment with Apadenoson given post-infection. Apadenoson cleared the virus from BALF and maintained Ang1-7 levels. Both drugs decreased plasma IFN-gamma levels. Conclusion(s) Treatment with Apadenoson attenuated inflammation, improved pulmonary function, decreased weight loss, and enhanced survival rate following infection with SARS-CoV-2 virus. The results demonstrate the translational significance of Apadenoson in the treatment of COVID-19.
adult; animal experiment; animal model; animal tissue; body weight loss; bronchoalveolar lavage fluid; CD8+ T lymphocyte; conference abstract; controlled study; coronavirus disease 2019; drug therapy; eosinophil; gene expression; histopathology; hyperinflammation; inflammation; lung function; male; monocyte; mouse; neutrophil; nonhuman; osmotic pump; plethysmography; protein blood level; Severe acute respiratory syndrome coronavirus 2; survival rate; Syrian hamster; T lymphocyte; therapy effect; virus load; adenosine A2a receptor; angiotensin[1-7]; apadenoson; CD4 antigen; endogenous compound; gamma interferon; interleukin 6; macrophage inflammatory protein 1beta; rantes; regadenoson
Full text:
Available
Collection:
Databases of international organizations
Database:
EMBASE
Type of study:
Prognostic study
Language:
English
Journal:
American Journal of Transplantation
Year:
2022
Document Type:
Article
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