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

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 PLA_2. (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.

Keywords: Aminoacridine; Antimalarials; Aortic body; Arachidonic acid; Brain endothelial cells; COVID; COVID-19; Carotid body; Chloroquine; Coronavirus; Cytosolic phospholipase A2; DMT1; Eicosanoids; Free radical damage; Glossopharyngeal nerve; Hippocampus; Hydroxychloroquine; Inflammation; Iron transport; Lysosomes; Microcirculation; Microglia; Microvessels; Neuroinflammation; Nucleus of the tractus solitarius; Oxidative stress; Quinacrine; Respiratory centre; SARS; SARS-CoV-2; Secretory phospholipase A2; Statins; Stroke; TNF-α; Vagus nerve; Vascular dementia; cPLA2; sPLA2 IID.