SARS-CoV-2 Infection, Sex-Related Differences, and a Possible Personalized Treatment Approach with Valproic Acid: A Review

Overview

Journal Biomedicines

Specialty Biomedical Engineering

Date 2022 May 28

PMID 35625699

Authors

Donatas Stakisaitis

Linas Kapocius

Angelija Valanciute

Ingrida Balnyte

Tomas Tamosuitis

Arunas Vaitkevicius

Kestutis Suziedelis

Daiva Urboniene

Vacis Tatarunas

Evelina Kilimaite

Dovydas Gecys

Vaiva Lesauskaite

Affiliations

Soon will be listed here.

Abstract

Sex differences identified in the COVID-19 pandemic are necessary to study. It is essential to investigate the efficacy of the drugs in clinical trials for the treatment of COVID-19, and to analyse the sex-related beneficial and adverse effects. The histone deacetylase inhibitor valproic acid (VPA) is a potential drug that could be adapted to prevent the progression and complications of SARS-CoV-2 infection. VPA has a history of research in the treatment of various viral infections. This article reviews the preclinical data, showing that the pharmacological impact of VPA may apply to COVID-19 pathogenetic mechanisms. VPA inhibits SARS-CoV-2 virus entry, suppresses the pro-inflammatory immune cell and cytokine response to infection, and reduces inflammatory tissue and organ damage by mechanisms that may appear to be sex-related. The antithrombotic, antiplatelet, anti-inflammatory, immunomodulatory, glucose- and testosterone-lowering in blood serum effects of VPA suggest that the drug could be promising for therapy of COVID-19. Sex-related differences in the efficacy of VPA treatment may be significant in developing a personalised treatment strategy for COVID-19.

Citing Articles

Neurological complications caused by SARS-CoV-2.

Pang Z, Tang A, He Y, Fan J, Yang Q, Tong Y Clin Microbiol Rev. 2024; 37(4):e0013124.

PMID: 39291997 PMC: 11629622. DOI: 10.1128/cmr.00131-24.

Anxiolytic and sedative effects of sodium valproate with different experimental paradigms in male and female rats.

de Los Angeles Cintado M, De La Casa L, Gonzalez G Neuropsychopharmacol Rep. 2024; 44(4):737-748.

PMID: 39270067 PMC: 11609752. DOI: 10.1002/npr2.12483.

Differential Impact of Valproic Acid on , , , , and Expression in Adult Glioblastoma Cells.

Jukneviciene M, Balnyte I, Valanciute A, Alonso M, Preiksaitis A, Suziedelis K Biomedicines. 2024; 12(7).

PMID: 39061990 PMC: 11274075. DOI: 10.3390/biomedicines12071416.

Effects of Combined Treatment with Sodium Dichloroacetate and Sodium Valproate on the Genes in Inflammation- and Immune-Related Pathways in T Lymphocytes from Patients with SARS-CoV-2 Infection with Pneumonia: Sex-Related Differences.

Stakisaitis D, Kapocius L, Tatarunas V, Gecys D, Mickiene A, Tamosuitis T Pharmaceutics. 2024; 16(3).

PMID: 38543303 PMC: 10974540. DOI: 10.3390/pharmaceutics16030409.

Gender Medicine and Pharmacology.

Allegra S, Chiara F, De Francia S Biomedicines. 2024; 12(2).

PMID: 38397867 PMC: 10886881. DOI: 10.3390/biomedicines12020265.

References

Brewster U, Perazella M . The renin-angiotensin-aldosterone system and the kidney: effects on kidney disease. Am J Med. 2004; 116(4):263-72. DOI: 10.1016/j.amjmed.2003.09.034. View

Zhou P, Yang X, Wang X, Hu B, Zhang L, Zhang W . A pneumonia outbreak associated with a new coronavirus of probable bat origin. Nature. 2020; 579(7798):270-273. PMC: 7095418. DOI: 10.1038/s41586-020-2012-7. View

Wrapp D, Wang N, Corbett K, Goldsmith J, Hsieh C, Abiona O . Cryo-EM structure of the 2019-nCoV spike in the prefusion conformation. Science. 2020; 367(6483):1260-1263. PMC: 7164637. DOI: 10.1126/science.abb2507. View

Nasreddine W, Beydoun A . Valproate-induced thrombocytopenia: a prospective monotherapy study. Epilepsia. 2007; 49(3):438-45. DOI: 10.1111/j.1528-1167.2007.01429.x. View

Brookes R, Crichton S, Wolfe C, Yi Q, Li L, Hankey G . Sodium Valproate, a Histone Deacetylase Inhibitor, Is Associated With Reduced Stroke Risk After Previous Ischemic Stroke or Transient Ischemic Attack. Stroke. 2017; 49(1):54-61. PMC: 5753817. DOI: 10.1161/STROKEAHA.117.016674. View

Babu E, Ramachandran S, Coothankandaswamy V, Elangovan S, Prasad P, Ganapathy V . Role of SLC5A8, a plasma membrane transporter and a tumor suppressor, in the antitumor activity of dichloroacetate. Oncogene. 2011; 30(38):4026-37. PMC: 3140604. DOI: 10.1038/onc.2011.113. View

Chen L, Alam A, Pac-Soo A, Chen Q, Shang Y, Zhao H . Pretreatment with valproic acid alleviates pulmonary fibrosis through epithelial-mesenchymal transition inhibition in vitro and in vivo. Lab Invest. 2021; 101(9):1166-1175. PMC: 8367813. DOI: 10.1038/s41374-021-00617-2. View

Capodanno D, Huber K, Mehran R, Lip G, Faxon D, Granger C . Management of Antithrombotic Therapy in Atrial Fibrillation Patients Undergoing PCI: JACC State-of-the-Art Review. J Am Coll Cardiol. 2019; 74(1):83-99. DOI: 10.1016/j.jacc.2019.05.016. View

Puelles V, Lutgehetmann M, Lindenmeyer M, Sperhake J, Wong M, Allweiss L . Multiorgan and Renal Tropism of SARS-CoV-2. N Engl J Med. 2020; 383(6):590-592. PMC: 7240771. DOI: 10.1056/NEJMc2011400. View

10.

Mengist H, Fan X, Jin T . Designing of improved drugs for COVID-19: Crystal structure of SARS-CoV-2 main protease M. Signal Transduct Target Ther. 2020; 5(1):67. PMC: 7210460. DOI: 10.1038/s41392-020-0178-y. View

11.

Amirzargar M, Yaghubi F, Hosseinipanah M, Jafari M, Pourjafar M, Rezaeepoor M . Anti-inflammatory Effects of Valproic Acid in a Rat Model of Renal Ischemia/Reperfusion Injury: Alteration in Cytokine Profile. Inflammation. 2017; 40(4):1310-1318. DOI: 10.1007/s10753-017-0574-9. View

12.

Heurich A, Hofmann-Winkler H, Gierer S, Liepold T, Jahn O, Pohlmann S . TMPRSS2 and ADAM17 cleave ACE2 differentially and only proteolysis by TMPRSS2 augments entry driven by the severe acute respiratory syndrome coronavirus spike protein. J Virol. 2013; 88(2):1293-307. PMC: 3911672. DOI: 10.1128/JVI.02202-13. View

13.

Steadman Tyler C, Smoake J, Solomon E, Villicana E, Caldwell K, Allan A . Sex-Dependent Effects of the Histone Deacetylase Inhibitor, Sodium Valproate, on Reversal Learning After Developmental Arsenic Exposure. Front Genet. 2018; 9:200. PMC: 6013562. DOI: 10.3389/fgene.2018.00200. View

14.

Adcock I . HDAC inhibitors as anti-inflammatory agents. Br J Pharmacol. 2007; 150(7):829-31. PMC: 2013887. DOI: 10.1038/sj.bjp.0707166. View

15.

Dudley J, Lee N . Disparities in Age-specific Morbidity and Mortality From SARS-CoV-2 in China and the Republic of Korea. Clin Infect Dis. 2020; 71(15):863-865. PMC: 7184419. DOI: 10.1093/cid/ciaa354. View

16.

Wu C, Li A, Leng Y, Li Y, Kang J . Histone deacetylase inhibition by sodium valproate regulates polarization of macrophage subsets. DNA Cell Biol. 2011; 31(4):592-9. DOI: 10.1089/dna.2011.1401. View

17.

Gheblawi M, Wang K, Viveiros A, Nguyen Q, Zhong J, Turner A . Angiotensin-Converting Enzyme 2: SARS-CoV-2 Receptor and Regulator of the Renin-Angiotensin System: Celebrating the 20th Anniversary of the Discovery of ACE2. Circ Res. 2020; 126(10):1456-1474. PMC: 7188049. DOI: 10.1161/CIRCRESAHA.120.317015. View

18.

Liu J, Straby K . The human tRNA(m(2)(2)G(26))dimethyltransferase: functional expression and characterization of a cloned hTRM1 gene. Nucleic Acids Res. 2000; 28(18):3445-51. PMC: 110725. DOI: 10.1093/nar/28.18.3445. View

19.

Dalpiaz P, Lamas A, Caliman I, Ribeiro Jr R, Abreu G, Moyses M . Sex Hormones Promote Opposite Effects on ACE and ACE2 Activity, Hypertrophy and Cardiac Contractility in Spontaneously Hypertensive Rats. PLoS One. 2015; 10(5):e0127515. PMC: 4444272. DOI: 10.1371/journal.pone.0127515. View

20.

Bukowska A, Spiller L, Wolke C, Lendeckel U, Weinert S, Hoffmann J . Protective regulation of the ACE2/ACE gene expression by estrogen in human atrial tissue from elderly men. Exp Biol Med (Maywood). 2017; 242(14):1412-1423. PMC: 5544171. DOI: 10.1177/1535370217718808. View