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

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.

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

“…SLC5A8 transports DCA into the cell [ 22 , 70 , 71 ], correcting mitochondrial metabolism in tissue cells, and the DCA–VPA treatment should attenuate the inflammation and tissue damage and protect against disease progression. DCAs and VPAs have sex-specific metabolism and biological effects [ 16 , 140 ]. Therefore, further research on the sex-specific efficacy of the preparation is relevant.…”

“…DCA and VPA are investigational drugs exhibiting anti-inflammatory effects in viral and bacterial infections, and these effects are associated with the reversal of mitochondrial dysregulation and impaired immune responses [ 16 , 17 ]. Regulatory guidelines for investigational medicines research call for the importance of the impact of sex on the assessment of drug efficacy, and it is essential to provide relevant information on the sex-specific efficacy of drugs under development [ 18 , 19 ].…”

COVID‐19 metabolism: Mechanisms and therapeutic targets

“…Both actions may contribute to its inhibitory effect on SARS‐CoV‐2 entry. 238 Masitinib, a tyrosine kinase inhibitor, inactivates viral protease to restrict viral replication. Although Masitinib has a significant effect on body glucose metabolism, its exact metabolic target is still unknown.…”

“…Valproic acid (VPA), a histone deacetylase (HDAC) inhibitor, was reported to lower glucose levels and inhibit cytokine response. Both actions may contribute to its inhibitory effect on SARS‐CoV‐2 entry 238 . Masitinib, a tyrosine kinase inhibitor, inactivates viral protease to restrict viral replication.…”

Gut Microbiota Modulates the Protective Role of Ginsenoside Compound K Against Sodium Valproate-Induced Hepatotoxicity in Rat

“…Valproic acid and its derivatives function as effective anticonvulsants. They are also used for the treatment of several other conditions, including bipolar disorder, migraines, neuropathic pain, various forms of headache, Alzheimer's disease, multiple sclerosis, viral infections, and a wide variety of cancers (De Souza and Chatterji, 2015 ; Mishra et al, 2021 ; Stakisaitis et al, 2022 ). However, the potential adverse effects associated with valproic acid and its derivatives have been reported, either as monotherapy or polytherapy with other antiepileptic drugs or antipsychotic drugs (Nanau and Neuman, 2013 ; Hakami, 2021 ).…”