Low dose dextromethorphan attenuates moderate experimental autoimmune encephalomyelitis by inhibiting NOX2 and reducing peripheral immune cells infiltration in the spinal cord

Department of Cell Biology and Human Anatomy, School of Medicine, University of California-Davis, 2425 Stockton Blvd, Sacramento, 95817 CA, USA.
Neurobiology of Disease (Impact Factor: 5.08). 06/2011; 44(1):63-72. DOI: 10.1016/j.nbd.2011.06.004
Source: PubMed


Dextromethorphan (DM) is a dextrorotary morphinan and a widely used component of cough medicine. Relatively high doses of DM in combination with quinidine are used for the treatment of mood disorders for patients with multiple sclerosis (MS). However, at lower doses, morphinans exert anti-inflammatory activities through the inhibition of NOX2-dependent superoxide production in activated microglia. Here we investigated the effects of high (10 mg/kg, i.p., "DM-10") and low (0.1 mg/kg, i.p., "DM-0.1") doses of DM on the development and progression of mouse experimental autoimmune encephalomyelitis (EAE), an animal model of MS. We found no protection by high dose DM treatment. Interestingly, a minor late attenuation by low dose DM treatment was seen in severe EAE that was characterized by a chronic disease course and a massive spinal cord infiltration of CD45(+) cells including T-lymphocytes, macrophages and neutrophils. Furthermore, in a less severe form of EAE, where lower levels of CD4(+) and CD8(+) T-cells, Iba1(+) microglia/macrophages and no significant infiltration of neutrophils were seen in the spinal cord, the treatment with DM-0.1 was remarkably more beneficial. The effect was the most significant at the peak of disease and was associated with an inhibition of NOX2 expression and a decrease in infiltration of monocytes and lymphocytes into the spinal cord. In addition, chronic treatment with low dose DM resulted in decreased demyelination and reduced axonal loss in the lumbar spinal cord. Our study is the first report to show that low dose DM is effective in treating EAE of moderate severity. Our findings reveal that low dose morphinan DM treatment may represent a new promising protective strategy for treating MS.

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    • "DXM protects mice against lipopolysaccharide/GalN-induced endotoxemia and liver damage; the mechanism of protection may involve faster TNF-í µí»¼ clearance, decreased superoxide production, and decreased expression of genes associated with inflammation and hepatocellular death [16]. In addition, DXM prevents moderate experimental autoimmune encephalomyelitis by inhibiting the NOX2-mediated production of ROS and decreasing the infiltration of monocytes and lymphocytes into the spinal cord [17]. DXM reduces Group A Streptococcal (GAS)-induced systemic inflammatory responses and organ injury in mice [18]. "
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    • "In solid tumors, the tumor microenvironments are also usually more acidic than normal, with values of extracellular pH ranging from 5.8 to 7.4, both in human and rodent malignant tissues345. Although immune cell infiltration is often observed in acidic inflammatory sites and tumor areas6789, relatively few studies have focused on the effect of extracellular acidic pH on the function of immune cells [10]. Observations made in stimulated macrophages indicated that extracellular acidification results in the inhibition of superoxide anion production, Fc-mediated phagocytosis, and TNF-α release [11], whereas Grabowski et al. [12] showed that environmental acidification increases the phagocytosis of opsonized particles by macrophages. "

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