Please use this identifier to cite or link to this item: https://doi.org/10.1007/s12035-020-02093-z
Title: Effects of Antimalarial Drugs on Neuroinflammation-Potential Use for Treatment of COVID-19-Related Neurologic Complications
Authors: Ong, Wei-Yi 
Go, Mei-Lin 
Wang, De-Yun 
Cheah, Irwin Kee-Mun 
Halliwell, Barry 
Keywords: Science & Technology
Life Sciences & Biomedicine
Neurosciences
Neurosciences & Neurology
SARS-CoV-2
COVID-19
COVID
SARS
Coronavirus
Antimalarials
Statins
Chloroquine
Hydroxychloroquine
Quinacrine
Aminoacridine
Cytosolic phospholipase A(2)
cPLA(2)
Secretory phospholipase A(2)
sPLA(2)IID
TNF-alpha
DMT1
Iron transport
Arachidonic acid
Eicosanoids
Inflammation
Neuroinflammation
Microglia
Lysosomes
Oxidative stress
Free radical damage
Carotid body
Aortic body
Nucleus of the tractus solitarius
Glossopharyngeal nerve
Vagus nerve
Respiratory centre
Hippocampus
Stroke
Microvessels
Microcirculation
Brain endothelial cells
Vascular dementia
CYTOPLASMIC PHOSPHOLIPASE A(2)
DIVALENT METAL TRANSPORTER-1
NF-KAPPA-B
RAT HIPPOCAMPUS
PLASMA 7-KETOCHOLESTEROL
ARACHIDONIC-ACID
APOLIPOPROTEIN D
NEURONAL DEATH
QUINACRINE
CORONAVIRUS
Issue Date: 8-Sep-2020
Publisher: SPRINGER
Citation: Ong, Wei-Yi, Go, Mei-Lin, Wang, De-Yun, Cheah, Irwin Kee-Mun, Halliwell, Barry (2020-09-08). Effects of Antimalarial Drugs on Neuroinflammation-Potential Use for Treatment of COVID-19-Related Neurologic Complications. MOLECULAR NEUROBIOLOGY 58 (1) : 106-117. ScholarBank@NUS Repository. https://doi.org/10.1007/s12035-020-02093-z
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, 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.
Source Title: MOLECULAR NEUROBIOLOGY
URI: https://scholarbank.nus.edu.sg/handle/10635/218884
ISSN: 08937648
15591182
DOI: 10.1007/s12035-020-02093-z
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