3-Hydroxymorphinan, a metabolite of dextromethorphan, protects nigrostriatal pathway against MPTP-elicited damage both in vivo and in vitro.
We investigated the neuroprotective property of analogs of dextromethorphan (DM) in lipopolysaccharide (LPS) and 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) models to identify neuroprotective drugs for Parkinson's disease (PD). In vivo studies showed that daily injections with DM analogs protected dopamine (DA) neurons in substantia nigra pars compacta and restored DA levels in striatum using two different models for PD. Of the five analogs studied, 3-hydroxymorphinan (3-HM), a metabolite of DM, was the most potent, and restored DA neuronal loss and DA depletion up to 90% of the controls. Behavioral studies showed an excellent correlation between potency for preventing toxin-induced decrease in motor activities and neuroprotective effects among the DM analogs studied, of which 3-HM was the most potent in attenuating behavioral damage. In vitro studies revealed two glia-dependent mechanisms for the neuroprotection by 3-HM. First, astroglia mediated the 3-HM-induced neurotrophic effect by increasing the gene expression of neurotrophic factors, which was associated with the increased acetylation of histone H3. Second, microglia participated in 3-HM-mediated neuroprotection by reducing MPTP-elicited reactive microgliosis as evidenced by the decreased production of reactive oxygen species. In summary, we show the potent neuroprotection by 3-HM in LPS and MPTP PD models investigated. With its high efficacy and low toxicity, 3-HM may be a novel therapy for PD.
Zhang
Wei
W
Neuropharmacology Section, Laboratory of Pharmacology and Chemistry, National Institute of Environmental Health Science/National Institutes of Health, Research Triangle Park, North Carolina, USA.
Shin
Eun-Joo
EJ
Wang
Tongguang
T
Lee
Phil Ho
PH
Pang
Hao
H
Wie
Myung-Bok
MB
Kim
Won-Ki
WK
Kim
Seong-Jin
SJ
Huang
Wen-Hsin
WH
Wang
Yongjun
Y
Zhang
Wanqin
W
Hong
Jau-Shyong
JS
Kim
Hyoung-Chun
HC
D015632:1-Methyl-4-phenyl-1,2,3,6-tetrahydropyridine / Q000009:adverse effects* / Q000037:antagonists & inhibitors; D000818:Animals; D000893:Anti-Inflammatory Agents / Q000737:chemistry / Q000627:therapeutic use; D001253:Astrocytes / Q000187:drug effects / Q000378:metabolism; D001522:Behavior, Animal / Q000187:drug effects; D003915:Dextromethorphan / Q000031:analogs & derivatives* / Q000737:chemistry / Q000378:metabolism* / Q000627:therapeutic use; D004298:Dopamine / Q000378:metabolism; D004305:Dose-Response Relationship, Drug; D008070:Lipopolysaccharides / Q000009:adverse effects; D051379:Mice; D008810:Mice, Inbred C57BL; D015394:Molecular Structure; D010300:Parkinson Disease / Q000188:drug therapy*; D020734:Parkinsonian Disorders / Q000139:chemically induced / Q000188:drug therapy*; D051381:Rats; D017382:Reactive Oxygen Species; D013378:Substantia Nigra / Q000187:drug effects / Q000378:metabolism / Q000473:pathology
D000893:Anti-Inflammatory Agents; D008070:Lipopolysaccharides; D017382:Reactive Oxygen Species; D003915:Dextromethorphan; D015632:1-Methyl-4-phenyl-1,2,3,6-tetrahydropyridine; C054116:norlevorphanol; D004298:Dopamine