3-Hydroxymorphinan, a metabolite of dextromethorphan, protects nigrostriatal pathway against MPTP-elicited damage both in vivo and in vitro

Wei Zhang, Eun Joo Shin, Tongguang Wang, Ho Lee Phil, Hao Pang, Myung Bok Wie, Won-Ki Kim, Seong Jin Kim, Wen Hsin Huang, Yongjun Wang, Wanqin Zhang, Jau Shyong Hong, Hyoung Chun Kim

Research output: Contribution to journalArticle

65 Citations (Scopus)

Abstract

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.

Original languageEnglish
Pages (from-to)2496-2511
Number of pages16
JournalFASEB Journal
Volume20
Issue number14
DOIs
Publication statusPublished - 2006 Dec 1
Externally publishedYes

Fingerprint

Dextromethorphan
1-Methyl-4-phenyl-1,2,3,6-tetrahydropyridine
Parkinson disease
Metabolites
dopamine
metabolites
neuroprotective effect
Parkinson Disease
Dopamine
lipopolysaccharides
Neuroprotective Agents
neurotrophins
disease models
astrocytes
neuroglia
acetylation
in vivo studies
Lipopolysaccharides
histones
in vitro studies

Keywords

  • Astroglia
  • Microglia
  • Neurotrophic factors
  • PD
  • ROS
  • Striatum
  • Substantia nigra pars compacta (SNpc)

ASJC Scopus subject areas

  • Agricultural and Biological Sciences (miscellaneous)
  • Biochemistry, Genetics and Molecular Biology(all)
  • Biochemistry
  • Cell Biology

Cite this

3-Hydroxymorphinan, a metabolite of dextromethorphan, protects nigrostriatal pathway against MPTP-elicited damage both in vivo and in vitro. / Zhang, Wei; Shin, Eun Joo; Wang, Tongguang; Phil, Ho Lee; Pang, Hao; Wie, Myung Bok; Kim, Won-Ki; Kim, Seong Jin; Huang, Wen Hsin; Wang, Yongjun; Zhang, Wanqin; Hong, Jau Shyong; Kim, Hyoung Chun.

In: FASEB Journal, Vol. 20, No. 14, 01.12.2006, p. 2496-2511.

Research output: Contribution to journalArticle

Zhang, W, Shin, EJ, Wang, T, Phil, HL, Pang, H, Wie, MB, Kim, W-K, Kim, SJ, Huang, WH, Wang, Y, Zhang, W, Hong, JS & Kim, HC 2006, '3-Hydroxymorphinan, a metabolite of dextromethorphan, protects nigrostriatal pathway against MPTP-elicited damage both in vivo and in vitro', FASEB Journal, vol. 20, no. 14, pp. 2496-2511. https://doi.org/10.1096/fj.06-6006com
Zhang, Wei ; Shin, Eun Joo ; Wang, Tongguang ; Phil, Ho Lee ; Pang, Hao ; Wie, Myung Bok ; Kim, Won-Ki ; Kim, Seong Jin ; Huang, Wen Hsin ; Wang, Yongjun ; Zhang, Wanqin ; Hong, Jau Shyong ; Kim, Hyoung Chun. / 3-Hydroxymorphinan, a metabolite of dextromethorphan, protects nigrostriatal pathway against MPTP-elicited damage both in vivo and in vitro. In: FASEB Journal. 2006 ; Vol. 20, No. 14. pp. 2496-2511.
@article{d59bbe3a59bd40b19e841b21758b5f2f,
title = "3-Hydroxymorphinan, a metabolite of dextromethorphan, protects nigrostriatal pathway against MPTP-elicited damage both in vivo and in vitro",
abstract = "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.",
keywords = "Astroglia, Microglia, Neurotrophic factors, PD, ROS, Striatum, Substantia nigra pars compacta (SNpc)",
author = "Wei Zhang and Shin, {Eun Joo} and Tongguang Wang and Phil, {Ho Lee} and Hao Pang and Wie, {Myung Bok} and Won-Ki Kim and Kim, {Seong Jin} and Huang, {Wen Hsin} and Yongjun Wang and Wanqin Zhang and Hong, {Jau Shyong} and Kim, {Hyoung Chun}",
year = "2006",
month = "12",
day = "1",
doi = "10.1096/fj.06-6006com",
language = "English",
volume = "20",
pages = "2496--2511",
journal = "The FASEB journal : official publication of the Federation of American Societies for Experimental Biology",
issn = "1530-6860",
publisher = "FASEB",
number = "14",

}

TY - JOUR

T1 - 3-Hydroxymorphinan, a metabolite of dextromethorphan, protects nigrostriatal pathway against MPTP-elicited damage both in vivo and in vitro

AU - Zhang, Wei

AU - Shin, Eun Joo

AU - Wang, Tongguang

AU - Phil, Ho Lee

AU - Pang, Hao

AU - Wie, Myung Bok

AU - Kim, Won-Ki

AU - Kim, Seong Jin

AU - Huang, Wen Hsin

AU - Wang, Yongjun

AU - Zhang, Wanqin

AU - Hong, Jau Shyong

AU - Kim, Hyoung Chun

PY - 2006/12/1

Y1 - 2006/12/1

N2 - 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.

AB - 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.

KW - Astroglia

KW - Microglia

KW - Neurotrophic factors

KW - PD

KW - ROS

KW - Striatum

KW - Substantia nigra pars compacta (SNpc)

UR - http://www.scopus.com/inward/record.url?scp=33845603005&partnerID=8YFLogxK

UR - http://www.scopus.com/inward/citedby.url?scp=33845603005&partnerID=8YFLogxK

U2 - 10.1096/fj.06-6006com

DO - 10.1096/fj.06-6006com

M3 - Article

VL - 20

SP - 2496

EP - 2511

JO - The FASEB journal : official publication of the Federation of American Societies for Experimental Biology

JF - The FASEB journal : official publication of the Federation of American Societies for Experimental Biology

SN - 1530-6860

IS - 14

ER -