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3-hydroxymorphinan is neurotrophic to dopaminergic neurons and is also neuroprotective against LPS-induced neurotoxicity.
FASEB J. 2005 Mar; 19(3):395-7.FJ

Abstract

The purpose of this study was to develop a novel therapy for Parkinson's disease (PD). We recently reported that dextromethorphan (DM), an active ingredient in a variety of widely used anticough remedies, protected dopaminergic neurons in rat primary mesencephalic neuron-glia cultures against lipopolysaccharide (LPS)-mediated degeneration and provided potent protection for dopaminergic neurons in a MPTP mouse model. The underlying mechanism for the protective effect of DM was attributed to its anti-inflammatory activity through inhibition of microglia activation. In an effort to develop more potent compounds for the treatment of PD, we have screened a series of analogs of DM, and 3-hydroxymorphinan (3-HM) emerged as a promising candidate for this purpose. Our study using primary mesencephalic neuron-glia cultures showed that 3-HM provided more potent neuroprotection against LPS-induced dopaminergic neurotoxicity than its parent compound. The higher potency of 3-HM was attributed to its neurotrophic effect in addition to the anti-inflammatory effect shared by both DM and 3-HM. First, we showed that 3-HM exerted potent neuroprotective and neurotrophic effects on dopaminergic neurons in rat primary mesencephalic neuron-glia cultures treated with LPS. The neurotrophic effect of 3-HM was glia-dependent since 3-HM failed to show any protective effect in the neuron-enriched cultures. We subsequently demonstrated that it was the astroglia, not the microglia, that contributed to the neurotrophic effect of 3-HM. This conclusion was based on the reconstitution studies, in which we added different percentages of microglia (10-20%) or astroglia (40-50%) back to the neuron-enriched cultures and found that 3-HM was neurotrophic after the addition of astroglia, but not microglia. Furthermore, 3-HM-treated astroglia-derived conditioned media exerted a significant neurotrophic effect on dopaminergic neurons. It appeared likely that 3-HM caused the release of neurotrophic factor(s) from astroglia, which in turn was responsible for the neurotrophic effect. Second, the anti-inflammatory mechanism was also important for the neuroprotective activity of 3-HM because the more microglia were added back to the neuron-enriched cultures, the more significant neuroprotective effect was observed. The anti-inflammatory mechanism of 3-HM was attributed to its inhibition of LPS-induced production of an array of pro-inflammatory and neurotoxic factors, including nitric oxide (NO), tumor necrosis factor alpha (TNF-alpha), prostaglandin E2 (PGE2) and reactive oxygen species (ROS). In conclusion, this study showed that 3-HM exerted potent neuroprotection by acting on two different targets: a neurotrophic effect mediated by astroglia and an anti-inflammatory effect mediated by the inhibition of microglial activation. 3-HM thus possesses these two important features necessary for an effective neuroprotective agent. In view of the well-documented very low toxicity of DM and its analogs, this report may provide an important new direction for the development of therapeutic interventions for inflammation-related diseases such as PD.

Authors+Show Affiliations

Neuropharmacology Section, Laboratory of Pharmacology and Chemistry, National Institute of Environmental Health Sciences/National Institutes of Health, Research Triangle Park, P.O. Box 12233, NC, USA. zhang11@niehs.nih.govNo affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info available

Pub Type(s)

Journal Article

Language

eng

PubMed ID

15596482

Citation

Zhang, Wei, et al. "3-hydroxymorphinan Is Neurotrophic to Dopaminergic Neurons and Is Also Neuroprotective Against LPS-induced Neurotoxicity." FASEB Journal : Official Publication of the Federation of American Societies for Experimental Biology, vol. 19, no. 3, 2005, pp. 395-7.
Zhang W, Qin L, Wang T, et al. 3-hydroxymorphinan is neurotrophic to dopaminergic neurons and is also neuroprotective against LPS-induced neurotoxicity. FASEB J. 2005;19(3):395-7.
Zhang, W., Qin, L., Wang, T., Wei, S. J., Gao, H. M., Liu, J., Wilson, B., Liu, B., Zhang, W., Kim, H. C., & Hong, J. S. (2005). 3-hydroxymorphinan is neurotrophic to dopaminergic neurons and is also neuroprotective against LPS-induced neurotoxicity. FASEB Journal : Official Publication of the Federation of American Societies for Experimental Biology, 19(3), 395-7.
Zhang W, et al. 3-hydroxymorphinan Is Neurotrophic to Dopaminergic Neurons and Is Also Neuroprotective Against LPS-induced Neurotoxicity. FASEB J. 2005;19(3):395-7. PubMed PMID: 15596482.
* Article titles in AMA citation format should be in sentence-case
TY - JOUR T1 - 3-hydroxymorphinan is neurotrophic to dopaminergic neurons and is also neuroprotective against LPS-induced neurotoxicity. AU - Zhang,Wei, AU - Qin,Liya, AU - Wang,Tongguang, AU - Wei,Sung-Jen, AU - Gao,Hui-ming, AU - Liu,Jie, AU - Wilson,Belinda, AU - Liu,Bin, AU - Zhang,Wanqin, AU - Kim,Hyoung-Chun, AU - Hong,Jau-Shyong, Y1 - 2004/12/13/ PY - 2004/12/15/pubmed PY - 2005/10/26/medline PY - 2004/12/15/entrez SP - 395 EP - 7 JF - FASEB journal : official publication of the Federation of American Societies for Experimental Biology JO - FASEB J VL - 19 IS - 3 N2 - The purpose of this study was to develop a novel therapy for Parkinson's disease (PD). We recently reported that dextromethorphan (DM), an active ingredient in a variety of widely used anticough remedies, protected dopaminergic neurons in rat primary mesencephalic neuron-glia cultures against lipopolysaccharide (LPS)-mediated degeneration and provided potent protection for dopaminergic neurons in a MPTP mouse model. The underlying mechanism for the protective effect of DM was attributed to its anti-inflammatory activity through inhibition of microglia activation. In an effort to develop more potent compounds for the treatment of PD, we have screened a series of analogs of DM, and 3-hydroxymorphinan (3-HM) emerged as a promising candidate for this purpose. Our study using primary mesencephalic neuron-glia cultures showed that 3-HM provided more potent neuroprotection against LPS-induced dopaminergic neurotoxicity than its parent compound. The higher potency of 3-HM was attributed to its neurotrophic effect in addition to the anti-inflammatory effect shared by both DM and 3-HM. First, we showed that 3-HM exerted potent neuroprotective and neurotrophic effects on dopaminergic neurons in rat primary mesencephalic neuron-glia cultures treated with LPS. The neurotrophic effect of 3-HM was glia-dependent since 3-HM failed to show any protective effect in the neuron-enriched cultures. We subsequently demonstrated that it was the astroglia, not the microglia, that contributed to the neurotrophic effect of 3-HM. This conclusion was based on the reconstitution studies, in which we added different percentages of microglia (10-20%) or astroglia (40-50%) back to the neuron-enriched cultures and found that 3-HM was neurotrophic after the addition of astroglia, but not microglia. Furthermore, 3-HM-treated astroglia-derived conditioned media exerted a significant neurotrophic effect on dopaminergic neurons. It appeared likely that 3-HM caused the release of neurotrophic factor(s) from astroglia, which in turn was responsible for the neurotrophic effect. Second, the anti-inflammatory mechanism was also important for the neuroprotective activity of 3-HM because the more microglia were added back to the neuron-enriched cultures, the more significant neuroprotective effect was observed. The anti-inflammatory mechanism of 3-HM was attributed to its inhibition of LPS-induced production of an array of pro-inflammatory and neurotoxic factors, including nitric oxide (NO), tumor necrosis factor alpha (TNF-alpha), prostaglandin E2 (PGE2) and reactive oxygen species (ROS). In conclusion, this study showed that 3-HM exerted potent neuroprotection by acting on two different targets: a neurotrophic effect mediated by astroglia and an anti-inflammatory effect mediated by the inhibition of microglial activation. 3-HM thus possesses these two important features necessary for an effective neuroprotective agent. In view of the well-documented very low toxicity of DM and its analogs, this report may provide an important new direction for the development of therapeutic interventions for inflammation-related diseases such as PD. SN - 1530-6860 UR - https://www.unboundmedicine.com/medline/citation/15596482/3_hydroxymorphinan_is_neurotrophic_to_dopaminergic_neurons_and_is_also_neuroprotective_against_LPS_induced_neurotoxicity_ L2 - https://doi.org/10.1096/fj.04-1586fje DB - PRIME DP - Unbound Medicine ER -