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Table of Contents
REVIEW ARTICLE
Year : 2020  |  Volume : 3  |  Issue : 5  |  Page : 65-70

Repurposing valproate to prevent acute respiratory distress syndrome/acute lung injury in COVID-19: A review of immunomodulatory action


1 Department of Medical Oncology, Homi Bhabha National Institute, Tata Memorial Hospital, Mumbai, Maharashtra, India
2 Department of Clinical Research, Apollo Proton Cancer Centre, Chennai, Tamil Nadu, India

Date of Submission14-Apr-2020
Date of Decision15-Apr-2020
Date of Acceptance16-Apr-2020
Date of Web Publication25-Apr-2020

Correspondence Address:
Anant Ramaswamy
Homi Bhabha Building, 323, Tata Memorial Hospital, Mumbai - 400 012, Maharashtra
India
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Source of Support: None, Conflict of Interest: None


DOI: 10.4103/CRST.CRST_156_20

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  Abstract 


The novel coronavirus disease 2019 (COVID-19) is reported to cause acute respiratory distress syndrome (ARDS) in 20%–40% of the hospitalized patients. The pathophysiology of ARDS caused by a viral infection is still unknown; however, a histopathological hallmark of ARDS is diffuse alveolar damage due to excessive inflammation of the lung tissue from the inflammatory mediators released by the local epithelial and endothelial cells. ARDS is caused when there is an excessive inflammatory response compared to the anti-inflammatory response to the viral agent. It is often associated with multiorgan failure and increased chances of mortality. Epigenetic changes are known to cause rapid changes in the gene expression, thereby increasing hyperinflammatory/anti-inflammatory responses. Valproate (VPA), a histone deacetylase inhibitor, has been shown to inhibit the production of the nuclear factor-κB (NF-κB), tumor necrosis factor-alpha, and interleukin-6 in human cells stimulated with lipopolysaccharide. VPA has also been shown to block the migration of macrophages through the inhibition of pro-inflammatory cytokines. VPA can promote the differentiation of T cells toward Th2/M2 rather than Th1/M1, and it also stimulates the generation of the regulatory T cells (Treg), thereby reducing the percentage of CD8+ T lymphocytes. However, the anti-inflammatory action of VPA could decrease the cytokine expression and suppress the effector T cells, thereby delaying the viral clearance. This delayed clearance of the virus could be taken care of by the proposed direct antiviral activity of VPA.

Keywords: Acute respiratory distress syndrome, antiviral, COVID-19, immunomodulator, pneumonia, repurposing, SARS-CoV-2, valproate


How to cite this article:
Bhargava P, Panda P, Ostwal V, Ramaswamy A. Repurposing valproate to prevent acute respiratory distress syndrome/acute lung injury in COVID-19: A review of immunomodulatory action. Cancer Res Stat Treat 2020;3, Suppl S1:65-70

How to cite this URL:
Bhargava P, Panda P, Ostwal V, Ramaswamy A. Repurposing valproate to prevent acute respiratory distress syndrome/acute lung injury in COVID-19: A review of immunomodulatory action. Cancer Res Stat Treat [serial online] 2020 [cited 2020 Jun 1];3, Suppl S1:65-70. Available from: http://www.crstonline.com/text.asp?2020/3/5/65/283314




  Introduction Top


Severe acute respiratory syndrome-coronavirus-2 (SARS-CoV-2) is a recently discovered novel strain of the betacoronavirus, which is the causal agent of the coronavirus disease 2019 (COVID-19) pandemic. SARS-CoV-2 causes a spectrum of symptomatic infections ranging from mild (in majority of the cases) to critical disease (e.g., with respiratory failure, multiorgan dysfunction, or shock).[1],[2] Some patients with severe COVID-19 have shown laboratory evidence of an inflammatory response, similar to the cytokine release syndrome, with elevated pro-inflammatory cytokines and persistent fevers; such patient profiles have been associated with critical and fatal illnesses.[1],[3] Patients with known comorbidities, such as chronic lung disease, diabetes mellitus, hypertension, and cardiovascular disease, have an increased severity of illness and higher mortality rates.[4],[5] Approximately 20%–41% of the hospitalized patients developed acute respiratory distress syndrome (ARDS) in two of the early studies published from China.[6],[7]


  Pathogenesis of Acute Respiratory Distress Syndrome in Coronavirus Disease 2019 Pneumonia Top


The pathogenesis of ARDS in patients infected with SARS-CoV-2 is incompletely understood. However, the histopathological hallmark of ARDS is diffuse alveolar damage due to excessive inflammation of the lung tissue from the inflammatory mediators released by the local epithelial and endothelial cells. The preferential cellular injury to the Type II alveolar cells and the activation of endothelial cells lead to the obstruction/destruction of the pulmonary vasculature, thereby causing increased permeability of the lung tissue. This increase in permeability leads to the deposition of proteins and debris in the alveoli and the formation of an inflammatory pulmonary edema.[8]

Stimulation of the nuclear factor-κB (NF-κB) pathway by the SARS-CoV-2 envelope protein has been shown to play an important role in increasing the transcription of pro-inflammatory molecules, including cytokines such as interleukin-6 (IL-6), tumor necrosis factor-alpha (TNF-α), interleukin-1β, monocyte chemoattractant protein 1 (MCP1), adhesion molecules, and inducible nitric oxide synthase.[9],[10],[11] The released cytokines attract the neutrophils to the lungs; upon activation in the lung parenchyma, these neutrophils release toxic mediators that further damage the alveolar epithelium and pulmonary vasculature and also stimulate pulmonary fibrosis.[12] Many patients with severe COVID-19 show substantially increased serum levels of pro-inflammatory cytokines such as IL-6, IL-1β, IL-2, IL-8, IL-17, granulocyte-colony-stimulating factor (G-CSF), granulocyte-macrophage CSF, and TNF-α.[13]

Steroids have traditionally been used in advanced ARDS to reduce inflammation, thereby preventing fibrosis and further complications, but with little success. Moreover, steroids have been associated with a delayed clearance of the virus and an increased risk of mortality in patients with influenza and Middle East respiratory syndrome-related coronavirus infection. Hence, the World Health Organization (WHO) and the Centers for Disease Control and Prevention guidelines recommend against the use of steroids in patients with COVID-19 pneumonia.[14],[15] There are some data that tocilizumab, an IL-6 antibody, may be effective in patients with severe COVID-19 infection,[16],[17] and trials evaluating its use are ongoing;[18] we await the results for its use in clinical practice. One has to keep in mind that even if the use of tocilizumab is approved, its high cost will likely make it unaffordable for the majority of patients. Therefore, there is a need to look for other medications that can control ARDS.


  Epigenetics Top


The heterochromatin is a condensed form of chromatin that does not allow the binding of transcription factors and transcription initiation machinery.[19] The euchromatin, on the other hand, is a lightly packed form of chromatin that allows the transcription factors and transcription initiation machinery to bind to the chromosomal DNA, thereby initiating its transcription. The conversion of heterochromatin to euchromatin is caused by acetylation of the ε-amino group of the conserved lysine residue on the histone proteins by the enzymes called histone acetyltransferases. This reversible acetylation leads to a loss of positive charge on the lysine residue, thereby weakening the binding of the histones to the negatively charged DNA. Histone deacetylases (HDACs) are enzymes that reverse the acetylation of the lysine residues, thus restoring the heterochromatin structure.[20]

As illustrated in the pathophysiology of ARDS, the gene expression of inflammatory mediators increases, whereas that of the anti-inflammatory mediators decreases; such changes in gene expression can be achieved by epigenetic regulation. Therefore, decreasing the expression of pro-inflammatory genes by using epigenetic modulators could help in reducing ARDS.


  Proposed Mechanism of Action of Valproate in Acute Respiratory Distress Syndrome Prevention Top


Valproate (VPA) is commonly used as an anti-epileptic and mood-stabilizing agent. Being an HDAC inhibitor, VPA also modulates epigenetic changes. As depicted in [Figure 1], HDAC inhibition leads to an increase in the acetylation of histones, thus modifying the expression of genes that regulate the cell cycle, cell differentiation, and apoptosis.[21]
Figure 1: HDAC inhibitor activity of VPA described in the literature. Schematic representation of direct and indirect targets of VPA. VPA directly inhibits HDAC Class I and less strongly Class II/a, but induces HDAC 9 and 11. Probably due to its epigenetic properties, or interactions not yet established, VPA alters, directly or indirectly, the expression of many molecules involved in molecular pathways such as apoptosis, inflammation, differentiation, and proliferation. VPA: Valproic acid, HDAC: Histone deacetylase, TNF: Tumor necrosis factor, IL-6: Interleukin-6, NF-κB: Nuclear factor-κB, Ac-CoA: Acetyl CoA

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In vitro studies have shown that VPA can inhibit the production of NF-κB, TNF-α, and IL-6 in human cells stimulated with lipopolysaccharides.[22] VPA has also been shown to decrease the expression of nitric oxide, downregulate the macrophage response, and block macrophage migration by inhibiting pro-inflammatory cytokines; pathogen-associated molecular pattern receptors of toll-like receptors, NOD-like receptors, retinoic acid-inducible gene-I, and C-type lectin families; the adapter molecules MyD88; kinases such as MAP3K, TNF receptor-associated factor 1, IL-1 receptor-associated kinases; phosphatases; and transcriptional modulators.[23],[24] VPA can promote the differentiation of T cells toward Th2/M2 rather than Th1/M1, and it also stimulates the generation of the regulatory T cells (Treg), thereby reducing the percentage of CD8+ T lymphocytes.[25]

Decreased neutrophil migrations will lead to decreased extracellular secretion of myeloperoxidase (MPO). MPO is known to exacerbate ARDS by differentially affecting the expression of claudins and molecules responsible for the maintenance of tight junctions between pneumocytes and indirectly upregulating the synthesis of the macrophage inflammatory protein 1, further perpetuating neutrophil infiltration in the lungs and propagating lung injury.[26],[27],[28]

VPA also inhibits lipopolysaccharide-activated dendritic cells, thereby reducing the expression of CD83 and CD80 and limiting the production of IL-6, IL-10, IL-23, and TNF-α. Reduction in IL-23 levels indirectly leads to the reduced ability of dendritic cells to promote the induction of Th17 cells.[29] VPA modifies the expression of the activation markers such as CD69 and CD38 and reduces the expression of heat shock protein-90 and Fas ligand (FasL), thereby reducing the proliferation and cytolytic function of CD8+ T lymphocytes.[30] VPA acting via caspase 3-mediated apoptosis reduces the percentage of CD8+ T lymphocytes. However, it should be noted that VPA does not affect the activation or viability of CD8+ T lymphocytes in response to viral peptide exposure.[31]

VPA-induced acetylation of the histone H4 in the FOXP3 promoter region leads to increased transcription and therefore, an increased expression of FOXP3. This induces the polarization of CD4+/CD25 T lymphocytes toward Treg cells. VPA also increases the half-life of FOXP3 by selectively inducing a microRNA (miRNA) expression profile characteristic of the natural Treg cells.[32],[33] In the infectious setting, Tregs can dampen the immune response by suppression of activated CD4+/CD8+ T cells, B cells, natural killer cells, and dendritic cells. This reduction of inflammation may theoretically come at the cost of reduced viral clearance.[34] However, in an experiment on immunodeficient mice by Arts et al., an adoptive transfer of Tregs controlled the lethal inflammation mediated by innate immune cells caused in response to the influenza A viral infection.[35]


  In Vivo Examples of Reduction in Inflammation Top


In an experimental study on rats by Wu et al., VPA blocked the NF-κB signaling, thereby reducing the production of inflammatory cytokines and reactive oxygen species. This led to reduced acute lung edema and attenuated lung injury in response to ischemia/reperfusion.[36] In another study on rats by Fukudome et al., VPA prevented hemorrhage-induced acute lung injury (ALI) in rats by decreasing the expression of cytokine-induced monocyte chemoattractant protein-1.[37] In another study using a mouse model of lipopolysaccharide-induced ALI, Ji et al. observed that VPA administration 6 hours before the inflammatory stimulus inhibited NF-κB activation and neutrophil infiltration in the lungs in response to sepsis-induced lung injury.[38] On autopsy of these mice, lung lesions were attenuated in VPA-pretreated mice with decreased leukocyte infiltration and lower MPO activities, suggesting a protective effect of VPA in ALI. Kasotakis et al. demonstrated an ameliorated inflammatory phenotype of Gram-negative pneumonia-induced ALI using early administration of VPA in the murine model.[39]

In the DBA/1 murine collagen-induced arthritis model by Saouaf et al. and C57BL/6 DSS-induced colitis model by Tao et al., VPA treatment increased the Treg population that inhibited the proliferation of the T effector cells, thereby reducing the intensity of inflammation in the respective models.[40],[41] In another experimental rate experiment autoimmune encephalitis (EAE) model by Zhang et al., the miRNA expression of FOXP3 and IL-10 was increased by VPA treatment.[42]

In a retrospective study on patients with subarachnoid hemorrhage, 521 patients who received VPA for seizures had reduced incidences of pneumonia- and sepsis-related ALI compared to the 1042 patients who received other anticonvulsants. The authors postulated that the difference in respiratory failure could be due to the epigenetic mediated anti-inflammatory effects of VPA.[43]

VPA when administered at a dose similar to that used in seizures (20–40 mg/kg/day) has been shown to be an effective HDAC inhibitor too.[44]


  Valproate as an Antiviral Agent Top


The best way to treat ARDS is to treat the underlying cause of ARDS. Early antiviral treatment in COVID-19 may lead to a decrease in the viral load and virus originated particles. SARS-CoV-2 requires nsp12, an RNA-dependent RNA polymerase, for viral replication in human hosts. Valproic acid Co-A, a metabolite from the prodrug VPA, forms a stable interaction with nsp12 of coronavirus, thereby inhibiting the viral replication, as predicted by computer simulation from a preliminary work by Bhaveshand Patra.[45]


  Drug Interactions of Valproate Top


Valproate may lead to hepatotoxicity. As there are a significant proportion of geriatric patients who get admitted in ARDS, drug interactions with their concomitant medications for comorbidities such as coronary artery disease, hypertension, and diabetes mellitus need careful assessment.[46] A search of the 'Drug Interactions Checker-Medscape Drug Reference' and 'Drug Interaction Checker – Find Interactions Between Medications' revealed no reported drug interaction of VPA with hydroxychloroquine, lopinavir/ritonavir, azithromycin, or ivermectin. There were no data on remdesivir on these websites.

Drug Interactions Checker – For Drugs, Food and Alcohol and Epocrates Online MultiCheck: showed that lopinavir/ritonavir may decrease the blood levels of VPA, while no drug interaction with other drugs was reported. Again, there were no data on remdesivir on these websites.

However, it is essential to consider the interaction of VPA with other drugs when using it for patients with COVID-19. Carbapenems may decrease the serum concentration of VPA. Salicylates may increase the serum concentration of VPA products.


  Future Direction Top


Several in vitro and animal studies have demonstrated that preemptive systemic administration of VPA can mitigate both the pulmonary and systemic immune responses to inflammation, and thus, may be an option to explore in order to improve the clinical setting. However, there is a theoretical risk of delayed viral clearance by the innate immunity, which may be overcome by the direct antiviral activity of VPA.

Given the antiviral and anti-inflammatory activities of VPA, we hypothesize that VPA might prevent the ALI and inflammation that is induced in COVID-19 pneumonia, if initiated early in the infection. Although the use of valproate in patients with COVID-19 pneumonia could be an attractive proof-of-mechanism or proof-of-concept study, its use must be scientifically proven. A proof-of-concept study in mildly symptomatic patients could be initiated at centers with a high volume of COVID-19 patients.

Financial support and sponsorship

Nil.

Conflicts of interest

There are no conflicts of interest.



 
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