Effects of Antimalarial Drugs on Neuroinflammation-Potential Use for Treatment of COVID-19-Related Neurologic Complications

Abstract

The SARS-CoV-2 virus that is the cause of coronavirus disease 2019 (COVID-19) affects not only peripheral organs such as the lungs and blood vessels, but also the central nervous system (CNS)—as seen by effects on smell, taste, seizures, stroke, neoropathological findings and possibly, loss of control of respiration resulting in silent hypoxemia. COVID-19 induces an inflammatory response and, in severe cases, a cytokine storm that can damage the CNS. Antimalarials have unique properties that distinguish them from other anti-inflammatory drugs. (A) They are very lipophilic, which enhances their ability to cross the blood-brain barrier (BBB). Hence, they have the potential to act not only in the periphery but also in the CNS, and could be a useful addition to our limited armamentarium against the SARS-CoV-2 virus. (B) They are non-selective inhibitors of phospholipase A2 isoforms, including cytosolic phospholipase A2 (cPLA2). The latter is not only activated by cytokines but itself generates arachidonic acid, which is metabolized by cyclooxygenase (COX) to pro-inflammatory eicosanoids. Free radicals are produced in this process, which can lead to oxidative damage to the CNS. There are at least 4 ways that antimalarials could be useful in combating COVID-19. (1) They inhibit PLA2. (2) They are basic molecules capable of affecting the pH of lysosomes and inhibiting the activity of lysosomal enzymes. (3) They may affect the expression and Fe2+/H+ symporter activity of iron transporters such as divalent metal transporter 1 (DMT1), hence reducing iron accumulation in tissues and iron-catalysed free radical formation. (4) They would affect viral replication. The latter may be related to their effect on inhibition of PLA2 isoforms. Inhibition of cPLA2 impairs an early step of coronavirus replication in cell culture. In addition, a secretory PLA2 (sPLA2) isoform, PLA2G2D, has been shown to be essential for the lethality of SARS-CoV in mice. It is important to take note of what ongoing clinical trials on chloroquine and hydroxychloroquine can eventually tell us about the use of antimalarials and other anti-inflammatory agents, not only for the treatment of COVID-19, but also for neurovascular disorders such as stroke and vascular dementia.

Severe Acute Respiratory Syndrome Coronavirus 2-Induced Neurological Complications

“…Anticoagulant therapy is applied for patients with coagulopathy. Antimalarials are assumed to inhibit the release of pro-inflammatory factors in the CNS by crossing the blood–brain barrier with their high lipophilic properties (Ong et al, 2020 ). Serotonin, a classic neurotransmitter, could suppress the inflammatory response in CNS and PNS.…”

Molecular docking, binding mode analysis, molecular dynamics, and prediction of ADMET/toxicity properties of selective potential antiviral agents against SARS-CoV-2 main protease: an effort toward drug repurposing to combat COVID-19

“…The compounds CQ, HCQ, ARB, and RDV were predicted to show substantial aromatase binding and blood–brain barrier (BBB) permeability properties. The ability of CQ and HCQ for transverse BBB is less known [ 53 ], which is not in favor of predicted BBB permeability property. Both ARB and RDV were predicted to show androgen receptor binding, while CQ and HCQ do not show such type of binding.…”

“…CQ, HCQ, and GA were predicted to induce phospholipidosis. CQ and HCQ are known to be non-selective inhibitors of various phospholipase A2 (PLA 2 ) isoforms and are thought to act by altering the pH of lysosomes [ 53 ], which is shown to be closely similar to the predicted property. In terms of reproductive toxicity, ARB and RDV were predicted as toxic and these molecules were found to be mild to moderate hepatotoxic as indicated by elevated levels of marker enzymes of hepatotoxicity.…”

Neurological involvement in the respiratory manifestations of COVID-19 patients

“…Chloroquine and hydroxychloroquine, which have been clinically used in COVID-19 patients, were reported to exhibit limited CNS penetration [ 140 ]. These drugs interfere with the glycosylation of ACE2 and therefore disturb the interaction of ACE2 with the spike protein of SARS-CoV-2.…”

“…To date, there are some candidate drugs that can be tested to stop the CNS infection of SARS-CoV-2 [ 140 , 147 ]. According to action sites, the drugs against neurotropic viruses can be divided into at least four kinds: blocking the invasion, transportation, replication, and release of viruses, respectively.…”