Hydroxychloroquine reduces microglial activity and attenuates experimental autoimmune encephalomyelitis.
BACKGROUND
Microglial activation is thought to be a key pathophysiological mechanism underlying disease activity in all forms of MS. Hydroxychloroquine (HCQ) is an antimalarial drug with immunomodulatory properties that is widely used in the treatment of rheumatological diseases. In this series of experiments, we explore the effect of HCQ on human microglial activation in vitro and on the development of experimental autoimmune encephalitis (EAE) in vivo.


METHODS
We activated human microglia with lipopolysaccharide (LPS), and measured concentrations of several pro- and anti-inflammatory cytokines in untreated and HCQ pretreated cultures. We investigated the effect of HCQ pretreatment at two doses on the development of EAE and spinal cord histology.


RESULTS
HCQ pretreatment reduced the production of pro-inflammatory (TNF-alpha, IL-6, and IL-12) and anti-inflammatory (IL-10 and IL-1 receptor antagonist) cytokines in LPS-stimulated human microglia. HCQ pretreatment delayed the onset of EAE, and reduced the number of Iba-1 positive microglia/macrophages and signs of demyelination in the spinal cords of HCQ treated animals.


CONCLUSIONS
HCQ treatment reduces the activation of human microglia in vitro, delays the onset of EAE, and decreases the representation of activated macrophages/microglia and demyelination in the spinal cord of treated mice. HCQ is a plausible candidate for further clinical studies in MS.
Department of Clinical Neurosciences and Hotchkiss Brain Institute, University of Calgary, Calgary, AB, Canada; Department of Community Health Sciences, University of Calgary, Calgary, AB, Canada. Electronic address: mwkoch@ucalgary.ca.
Marcus W
MW
Koch
Department of Clinical Neurosciences and Hotchkiss Brain Institute, University of Calgary, Calgary, AB, Canada; Department of Neurological Sciences, University of Nebraska, Omaha, NE, USA.
Rana
R
Zabad
Department of Clinical Neurosciences and Hotchkiss Brain Institute, University of Calgary, Calgary, AB, Canada; Department of Medicine, University of Alberta, Edmonton, AB, Canada.
Fabrizio
F
Giuliani
Department of Clinical Neurosciences and Hotchkiss Brain Institute, University of Calgary, Calgary, AB, Canada.
Walter
W
Hader
Department of Medical Genetics, University of Calgary, Calgary, AB, Canada.
Ray
R
Lewkonia
Department of Clinical Neurosciences and Hotchkiss Brain Institute, University of Calgary, Calgary, AB, Canada.
Luanne
L
Metz
Department of Clinical Neurosciences and Hotchkiss Brain Institute, University of Calgary, Calgary, AB, Canada.
V
V
Wee Yong
D000818:Animals; D016207:Cytokines / Q000378:metabolism*; D004681:Encephalomyelitis, Autoimmune, Experimental / Q000188:drug therapy* / Q000378:metabolism / Q000473:pathology; D006801:Humans; D006886:Hydroxychloroquine / Q000494:pharmacology / Q000627:therapeutic use*; D008264:Macrophages / Q000187:drug effects / Q000378:metabolism; D051379:Mice; D017628:Microglia / Q000187:drug effects* / Q000378:metabolism; D013116:Spinal Cord / Q000187:drug effects* / Q000378:metabolism / Q000473:pathology; D016896:Treatment Outcome
D016207:Cytokines; D006886:Hydroxychloroquine
EAE; Hydroxychloroquine; Macrophage; Microglia; Multiple sclerosis