GABAA-Receptor Agonists Limit Pneumonitis and Death in Murine Coronavirus-Infected Mice
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Abstract
There is an urgent need for new approaches to limit the severity of coronavirus infections. Many cells of the immune system express receptors for the neurotransmitter γ-aminobutyric acid (GABA), and GABA-receptor (GABA-R) agonists have anti-inflammatory effects. Lung epithelial cells also express GABA-Rs, and GABA-R modulators have been shown to limit acute lung injuries. There is currently, however, no information on whether GABA-R agonists might impact the course of a viral infection. Here, we assessed whether clinically applicable GABA-R agonists could be repurposed for the treatment of a lethal coronavirus (murine hepatitis virus 1, MHV-1) infection in mice. We found that oral GABA administration before, or after the appearance of symptoms, very effectively limited MHV-1-induced pneumonitis, severe illness, and death. GABA treatment also reduced viral load in the lungs, suggesting that GABA-Rs may provide a new druggable target to limit coronavirus replication. Treatment with the GABAA-R-specific agonist homotaurine, but not the GABAB-R-specific agonist baclofen, significantly reduced the severity of pneumonitis and death rates in MHV-1-infected mice, indicating that the therapeutic effects were mediated primarily through GABAA-Rs. Since GABA and homotaurine are safe for human consumption, they are promising candidates to help treat coronavirus infections.
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SciScore for 10.1101/2020.10.04.325423: (What is this?)
Please note, not all rigor criteria are appropriate for all manuscripts.
Table 1: Rigor
Institutional Review Board Statement IACUC: The protocols for all experiments using vertebrate animals were approved by the Animal Research Committee at UCLA. Reagents: GABA was purchased from Millipore-Sigma (stock # A2129, St. Louis, MO, USA). Randomization The mice were immediately randomized and treated (or not treated) with GABA, as described below. Blinding not detected. Power Analysis not detected. Sex as a biological variable Mice: Female A/J mice (7 weeks in age) were purchased from the Jackson Laboratory and maintained in microisolator cages and fed with a standard diet and water ad libitum. Cell Line Authentication not detected. Table 2: Resources
Experimental Models: Cell Lines Sentences Resources Viru… SciScore for 10.1101/2020.10.04.325423: (What is this?)
Please note, not all rigor criteria are appropriate for all manuscripts.
Table 1: Rigor
Institutional Review Board Statement IACUC: The protocols for all experiments using vertebrate animals were approved by the Animal Research Committee at UCLA. Reagents: GABA was purchased from Millipore-Sigma (stock # A2129, St. Louis, MO, USA). Randomization The mice were immediately randomized and treated (or not treated) with GABA, as described below. Blinding not detected. Power Analysis not detected. Sex as a biological variable Mice: Female A/J mice (7 weeks in age) were purchased from the Jackson Laboratory and maintained in microisolator cages and fed with a standard diet and water ad libitum. Cell Line Authentication not detected. Table 2: Resources
Experimental Models: Cell Lines Sentences Resources Virus: MHV-1, DBT cells, and HeLa-CECAM1 were generously provided by Dr. Stanley Perlman (University of Iowa). HeLa-CECAM1suggested: NoneExperimental Models: Organisms/Strains Sentences Resources Viral infection and GABA treatment: At 8 weeks in age, female A/J mice were anesthetized and inoculated intranasally with 5000 PFU MHV-1 in 50 μl cold Dulbecco’s modified Eagle’s medium (DMEM). A/Jsuggested: NoneResults from OddPub: We did not detect open data. We also did not detect open code. Researchers are encouraged to share open data when possible (see Nature blog).
Results from LimitationRecognizer: An explicit section about the limitations of the techniques employed in this study was not found. We encourage authors to address study limitations.Results from TrialIdentifier: We found the following clinical trial numbers in your paper:
Identifier Status Title NCT02002130 Active, not recruiting The Use of Glutamic Acid Decarboxylase (GAD) and Gamma-Amino… NCT03635437 Recruiting Evaluation of Safety and Diabetes Status Upon Oral Treatment… NCT03721991 Unknown status GABA Treatment in Subjects With Type 1 Diabetes NCT04375020 Completed GABA and Beta-cell Regeneration Results from Barzooka: We did not find any issues relating to the usage of bar graphs.
Results from JetFighter: We did not find any issues relating to colormaps.
Results from rtransparent:- Thank you for including a conflict of interest statement. Authors are encouraged to include this statement when submitting to a journal.
- Thank you for including a funding statement. Authors are encouraged to include this statement when submitting to a journal.
- No protocol registration statement was detected.
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