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 (10mg/kg, i.p., "DM-10") and low (0.1mg/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.
| Original language | English (US) |
|---|---|
| Pages (from-to) | 63-72 |
| Number of pages | 10 |
| Journal | Neurobiology of Disease |
| Volume | 44 |
| Issue number | 1 |
| DOIs | |
| State | Published - Oct 2011 |
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Keywords
- Axonal loss
- CNS infiltration
- Demyelination
- EAE
- Low dose dextromethorphan
- Microglia
- NOX2 NADPH oxidase
ASJC Scopus subject areas
- Neurology
Cite this
Low dose dextromethorphan attenuates moderate experimental autoimmune encephalomyelitis by inhibiting NOX2 and reducing peripheral immune cells infiltration in the spinal cord. / Chechneva, Olga V.; Mayrhofer, Florian; Daugherty, Daniel J.; Pleasure, David E; Hong, Jau Shyong; Deng, Wenbin.
In: Neurobiology of Disease, Vol. 44, No. 1, 10.2011, p. 63-72.Research output: Contribution to journal › Article
}
TY - JOUR
T1 - Low dose dextromethorphan attenuates moderate experimental autoimmune encephalomyelitis by inhibiting NOX2 and reducing peripheral immune cells infiltration in the spinal cord
AU - Chechneva, Olga V.
AU - Mayrhofer, Florian
AU - Daugherty, Daniel J.
AU - Pleasure, David E
AU - Hong, Jau Shyong
AU - Deng, Wenbin
PY - 2011/10
Y1 - 2011/10
N2 - 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 (10mg/kg, i.p., "DM-10") and low (0.1mg/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.
AB - 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 (10mg/kg, i.p., "DM-10") and low (0.1mg/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.
KW - Axonal loss
KW - CNS infiltration
KW - Demyelination
KW - EAE
KW - Low dose dextromethorphan
KW - Microglia
KW - NOX2 NADPH oxidase
UR - http://www.scopus.com/inward/record.url?scp=79961128957&partnerID=8YFLogxK
UR - http://www.scopus.com/inward/citedby.url?scp=79961128957&partnerID=8YFLogxK
U2 - 10.1016/j.nbd.2011.06.004
DO - 10.1016/j.nbd.2011.06.004
M3 - Article
C2 - 21704706
AN - SCOPUS:79961128957
VL - 44
SP - 63
EP - 72
JO - Neurobiology of Disease
JF - Neurobiology of Disease
SN - 0969-9961
IS - 1
ER -