Anti- epileptic drug Valproic acid may be potential therapeutic option for Covid 19: Study
The novel severe acute respiratory syndrome coronavirus-2 (SARS-CoV-2) has posed a serious threat to the global public health. Respiratory failure, followed by cardiovascular complications with wide-spread endothelial dysfunction and inflammation, is rapidly emerging as a key threat in COVID-19. A study was done by Dr Shweta Singh and Krishna K Singh published in International Journal...
The novel severe acute respiratory syndrome coronavirus-2 (SARS-CoV-2) has posed a serious threat to the global public health. Respiratory failure, followed by cardiovascular complications with wide-spread endothelial dysfunction and inflammation, is rapidly emerging as a key threat in COVID-19.
A study was done by Dr Shweta Singh and Krishna K Singh published in International Journal of Respiratory and Pulmonary medicine to entice the scientific and clinical society to investigate VPA as a potential therapeutic option against COVID-19.
Limited knowledge about the mechanism of infection/action of SARS-CoV-2 appears to be the major problem in the identification of therapeutic targets and respective drugs to treat COVID-19.
"Gordon, et al. followed a comprehensive approach and cloned, tagged and expressed 26 of the 29 SARS-CoV-2 proteins and identified 332 high-confidence SARS-CoV-2-human protein-protein interactions. In their human lung mRNA expression profile, they identified enrichment of SARS-CoV-2-interacting protein and an epigenetic regulator, histone deacetylase 2 (HDAC2), which regulates epigenetics by removing acetyl groups from histones."
VPA is a FDA-approved HDAC2 inhibitor drug used to treat central nervous system diseases such as bipolar disorder, epilepsy, and cancer. VPA inhibits HDAC2 by inducing its proteasomal degradation.
ACE-2 receptors are the cell-entry gate for SARS-CoV-2,which are present in both endothelial and epithelial cells. Endothelial cells(ECs) contribute to more than 30% of all cells in the lungs, constitute the innermost layer of every blood vessel and respond to constantly varying hemodynamics to maintain homeostasis.
Cardiovascular complications with wide-spread endothelial dysfunction, thrombosis and endotheliitis are rapidly emerging as a key threat in COVID-19 in addition to respiratory disease.
The effect of VPA on ACE-2 expression indicates that VPA can inhibit the SARS-CoV-2 rate of infection by reducing its receptor ACE-2 expression level and can be used as a prevention strategy against COVID-19.
The study on the reduced expression of IL-6 in VPA-treated ECs is also clinically relevant, as the level of IL-6 predicts respiratory failure, and IL-6 inhibitors are proposed to ameliorate severe lung damage in COVID-19 patients.
ICAM-1 is marker for endothelial "activation". Interestingly, VPA also significantly reduced ICAM1 expression, indicating reduced endothelial activation.
"The presented data provides a "treatment" strategy for COVID-19 as VPA-induced downregulation of IL-6 and ICAM-1 are the regulatory molecules implicated in SARS-CoV-2-induced inflammation and coagulation."
PCR array analysis for human endothelial-related genes in VPA-treated ECs is reported with a total of 14 significantly up- and 14 down-regulated genes .
The most upregulated endothelial genes which are relevant to COVID-19 prevention and/or treatment include BNP (Natriuretic peptide B; 145-fold), MMP-9 (Matrix metallopeptidase 9, 121-fold), PF-4 (Platelet factor 4, 25-fold), T-PA (Plasminogen activator, tissue, 18-fold), COX-2 (Prostaglandin-endoperoxide synthase 2, 3-fold) and TGFβ1 (Transforming growth factor, beta 1, 1.3-fold).
BNP was the most upregulated gene in VPA-treated ECs, which is also anti-inflammatory and inhibits interleukins.
T-PA treatment is suggested for COVID-19 associated acute respiratory distress syndrome (ARDS). VPA is known to have protective effects in severe hemorrhage and ischemia-reperfusion injury. Overall, VPA-induced T-PA appears to be beneficial to COVID-19 patients due to its anti-thrombotic activity and attenuation of ventilator-induced lung injury function.
The most downregulated and relevant to COVID-19 prevention and/or treatment genes include TFPI (Tissue factor pathway inhibitor, 6-fold) and SPHK (Sphingosine kinase 1, 5-fold). Tissue factor is an initiator of coagulation and inflammation in the lung.
The VPA-induced downregulation of SPHK1 appears to help COVID-19 treatment. SPHK1 is known to contribute to ventilator-associated lung injury; elevated SPHK1 enhances influenza virus infection.
"This new knowledge about the mechanism of action of VPA provides a novel potential therapeutic drug target for the prevention and treatment of COVID-19, and warrants immediate further investigation in animal models and in humans.
VPA is a FDA approved drug and any proof of these drugs showing protective effect against COVID-19 will reduce the required drug approval time. In addition, VPA can be fasttracked for testing against COVID-19."
Dr Ishan Kataria has done his MBBS from Medical College Bijapur and MS in Ophthalmology from Dr Vasant Rao Pawar Medical College, Nasik. Post completing MD, he pursuid Anterior Segment Fellowship from Sankara Eye Hospital and worked as a competent phaco and anterior segment consultant surgeon in a trust hospital in Bathinda for 2 years.He is currently pursuing Fellowship in Vitreo-Retina at Dr Sohan Singh Eye hospital Amritsar and is actively involved in various research activities under the guidance of the faculty.