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, neuropathological 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 could 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.