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: 5.2). 06/2011; 44(1):63-72. DOI: 10.1016/j.nbd.2011.06.004
Source: PubMed

ABSTRACT 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.

  • [Show abstract] [Hide abstract]
    ABSTRACT: Significance: Voltage-gated proton channels are increasingly implicated in cellular proton homeostasis. Proton currents were originally identified in snail neurons less than 40 years ago, and subsequently shown to play an important auxiliary role in the functioning of ROS-generating NADPH oxidases. Molecular identification of voltage-gated proton channels was achieved less than 10 years ago. Interestingly, so far only one gene coding for voltage-gated proton channels has been identified, namely HVCN1, which codes for the HV1 proton channel protein. Over the last years, a first picture of putative physiological functions of HV1 is emerging. Recent Advances: The best-studied role remains charge and pH compensation during the respiratory burst of the phagocyte NADPH oxidase. Strong evidence for a role of HV1 is also emerging in sperm biology, but the relationship with the sperm NADPH oxidase NOX5 remains unclear. Probably in many instances, HV1 functions independently of NADPH oxidases: for example in snail neurons, basophils, osteoclasts, and cancer cells. Critical Issues: Generally ion channels are good drug targets, however this feature has so far not been exploited for HV1, and hitherto no inhibitors compatible with clinical use exist. Yet, there are emerging indications for HV1 inhibitors, ranging from diseases with a strong activation of the phagocyte NADPH oxidase (e.g. stroke) to infertility, osteoporosis and cancer. Future Directions: Clinically useful HV1-active drugs should be developed and might become interesting drugs of the future.
    Antioxidants & Redox Signaling 02/2014; DOI:10.1089/ars.2013.5806 · 7.67 Impact Factor
  • [Show abstract] [Hide abstract]
    ABSTRACT: Ischemic stroke occurs as a result of blood supply interruption to the brain causing tissue degeneration, patient disabilities or death. Currently, treatment of ischemic stroke is limited to thrombolytic therapy with a narrow time window of administration. The sonic hedgehog (Shh) signaling pathway has a fundamental role in the central nervous system development, but its impact on neural cell survival and tissue regeneration/repair after ischemic stroke has not been well investigated. Here we report the neuroprotective properties of a small-molecule agonist of the Shh co-receptor Smoothened, purmorphamine (PUR), in the middle cerebral artery occlusion model of ischemic stroke. We found that intravenous administration of PUR at 6 h after injury was neuroprotective and restored neurological deficit after stroke. PUR promoted a transient upregulation of tissue-type plasminogen activator in injured neurons, which was associated with a reduction of apoptotic cell death in the ischemic cortex. We also observed a decrease in blood-brain barrier permeability after PUR treatment. At 14 d postinjury, attenuation of inflammation and reactive astrogliosis was found in PUR-treated animals. PUR increased the number of newly generated neurons in the peri-infarct and infarct area and promoted neovascularization in the ischemic zone. Notably, PUR treatment did not significantly alter the ischemia-induced level of Gli1, a Shh target gene of tumorigenic potential. Thus our study reports a novel pharmacological approach for postischemic treatment using a small-molecule Shh agonist, providing new insights into hedgehog signaling-mediated mechanisms of neuroprotection and regeneration after stroke.
    Cell Death & Disease 10/2014; 5:e1481. DOI:10.1038/cddis.2014.446 · 5.18 Impact Factor
  • [Show abstract] [Hide abstract]
    ABSTRACT: Dextromethorphan (DM), a sigma receptor agonist and NMDA receptor antagonist, protects neurons from glutamate excitotoxicity, hypoxia and ischemia, and inhibits microglial activation, but its effects on differentiation and protection of cells in the oligodendroglial lineage are unknown. It is important to protect oligodendroglia (OL) to prevent demyelination and preserve axons, and to protect oligodendroglial progenitors (OPC) to optimize myelination during development and remyelination following damage. Enriched glial cultures from newborn rat brain were used 1-2 days or 6-8 days after shakeoff for OPC or mature OL. DM had large effects on glial proliferation in less mature cultures in contrast to small variable effects in mature cultures; 1 μM DM stimulated proliferation of OPC by 4-fold, microglia (MG) by 2.5-fold and astroglia (AS) by 2-fold. In agreement with increased OPC proliferation, treatment of OPC with DM for 3 days increased the % of OPC relative to OL, with a smaller difference by 5 days, suggesting that maturation of OPC to OL was "catching up" by 5 days. DM at 2 and 20 μM protected both OL and OPC from killing by glutamate as well as NMDA, AMPA, quinolinic acid, staurosporine, and reactive oxygen species (ROS). DM did not protect against kynurenic acid, and only modestly against NO. These agents and DM were not toxic to AS or MG at the concentrations used. Thus, DM stimulates proliferation of OPC, and protects both OL and OPC against excitotoxic and inflammatory insults. GLIA 2014.
    Glia 05/2014; 62(5). DOI:10.1002/glia.22639 · 5.47 Impact Factor


Available from