Skip to main content
Top
Published in: BMC Complementary Medicine and Therapies 1/2016

Open Access 01-12-2016 | Research article

Alkaloids from piper longum protect dopaminergic neurons against inflammation-mediated damage induced by intranigral injection of lipopolysaccharide

Authors: Huan He, Wei-Wei Guo, Rong-Rong Xu, Xiao-Qing Chen, Nan Zhang, Xia Wu, Xiao-Min Wang

Published in: BMC Complementary Medicine and Therapies | Issue 1/2016

Login to get access

Abstract

Background

Alkaloids from Piper longum (PLA), extracted from P. longum, have potent anti-inflammatory effects. The aim of this study was to investigate whether PLA could protect dopaminergic neurons against inflammation-mediated damage by inhibiting microglial activation using a lipopolysaccharide (LPS)-induced dopaminergic neuronal damage rat model.

Methods

The animal behaviors of rotational behavior, rotarod test and open-field test were investigated. The survival ratio of dopaminergic neurons and microglial activation were examined. The dopamine (DA) and its metabolite were detected by high performance liquid chromatography (HPLC). The effects of PLA on the expression of interleukin (IL)-6, interleukin (IL)-1β and tumor necrosis factor (TNF)-α were detected by enzyme-linked immunosorbent assay (ELISA). Reactive oxygen species (ROS) and nitric oxide (NO) were also estimated.

Results

We showed that the survival ratio of tyrosine hydroxylase-immunoreactive (TH-ir) neurons in the substantia nigra pars compacta (SNpc) and DA content in the striatum were reduced after a single intranigral dose of LPS (10 μg) treatment. The survival rate of TH-ir neurons in the SNpc and DA levels in the striatum were significantly improved after treatment with PLA for 6 weeks. The over-activated microglial cells were suppressed by PLA treatment. We also observed that the levels of inflammatory cytokines, including TNF-α, IL-6 and IL-1β were decreased and the excessive production of ROS and NO were abolished after PLA treatment. Therefore, the behavioral dysfunctions induced by LPS were improved after PLA treatment.

Conclusion

This study suggests that PLA plays a significant role in protecting dopaminergic neurons against inflammatory reaction induced damage.
Literature
1.
go back to reference Hu Y, Yu SY, Zuo LJ, Cao CJ, Wang F, Chen ZJ, et al. Parkinson disease with REM sleep behavior disorder: features, α-synuclein, and inflammation. Neurology. 2015;84:888–94.CrossRefPubMed Hu Y, Yu SY, Zuo LJ, Cao CJ, Wang F, Chen ZJ, et al. Parkinson disease with REM sleep behavior disorder: features, α-synuclein, and inflammation. Neurology. 2015;84:888–94.CrossRefPubMed
2.
go back to reference Barcia C, Hunot S, Guillemin GJ, Pitossi F. Inflammation and Parkinson’s disease. Parkinsons Dis. 2011; 2011:729054. Barcia C, Hunot S, Guillemin GJ, Pitossi F. Inflammation and Parkinson’s disease. Parkinsons Dis. 2011; 2011:729054.
3.
go back to reference Hirsch EC, Hunot S, Hartmann A. Neuroinflammatory processes in Parkinson’s disease. Parkinsonism Relat Disord. 2005;11 Suppl 1:S9–S15.CrossRefPubMed Hirsch EC, Hunot S, Hartmann A. Neuroinflammatory processes in Parkinson’s disease. Parkinsonism Relat Disord. 2005;11 Suppl 1:S9–S15.CrossRefPubMed
4.
go back to reference Pal GD, Shaikh M, Forsyth CB, Ouyang B, Keshavarzian A, Shannon KM. Abnormal lipopolysaccharide binding protein as marker of gastrointestinal inflammation in Parkinson disease. Front Neurosci. 2015;9:306.CrossRefPubMedPubMedCentral Pal GD, Shaikh M, Forsyth CB, Ouyang B, Keshavarzian A, Shannon KM. Abnormal lipopolysaccharide binding protein as marker of gastrointestinal inflammation in Parkinson disease. Front Neurosci. 2015;9:306.CrossRefPubMedPubMedCentral
5.
go back to reference Long-Smith CM, Sullivan AM, Nolan YM. The influence of microglia on the pathogenesis of Parkinson’s disease. Prog Neurobiol. 2009;89:277–87.CrossRefPubMed Long-Smith CM, Sullivan AM, Nolan YM. The influence of microglia on the pathogenesis of Parkinson’s disease. Prog Neurobiol. 2009;89:277–87.CrossRefPubMed
6.
go back to reference Hirsch EC, Hunot S, Damier P, Faucheux B. Glial cells and inflammation in Parkinson’s disease: a role in neurodegeneration? Ann Neurol. 1998;44:S115–20.CrossRefPubMed Hirsch EC, Hunot S, Damier P, Faucheux B. Glial cells and inflammation in Parkinson’s disease: a role in neurodegeneration? Ann Neurol. 1998;44:S115–20.CrossRefPubMed
7.
go back to reference Casano A, Peri F. Developmental brain apoptosis: Is this a call for microglia? Int J Dev Neurosci. 2015;47:7–8.CrossRef Casano A, Peri F. Developmental brain apoptosis: Is this a call for microglia? Int J Dev Neurosci. 2015;47:7–8.CrossRef
8.
go back to reference Block ML, Zecca L, Hong J. Microglia-mediated neurotoxicity: uncovering the molecular mechanisms. Nat Rev Neurosci. 2007;8:57–69.CrossRefPubMed Block ML, Zecca L, Hong J. Microglia-mediated neurotoxicity: uncovering the molecular mechanisms. Nat Rev Neurosci. 2007;8:57–69.CrossRefPubMed
9.
go back to reference Block ML, Hong JS. Microglia and inflammation-mediated neurodegeneration: multiple triggers with a common mechanism. Prog Neurobiol. 2005;76:77–98.CrossRefPubMed Block ML, Hong JS. Microglia and inflammation-mediated neurodegeneration: multiple triggers with a common mechanism. Prog Neurobiol. 2005;76:77–98.CrossRefPubMed
10.
go back to reference Miguelez C, Navailles S, De Deurwaerdère P, Ugedo L. The acute and long-term L-DOPA effects are independent from changes in the activity of dorsal raphe serotonergic neurons in 6-OHDA lesioned rats. Br J Pharmacol. 2016;doi: 10.1111/bph.13447. Miguelez C, Navailles S, De Deurwaerdère P, Ugedo L. The acute and long-term L-DOPA effects are independent from changes in the activity of dorsal raphe serotonergic neurons in 6-OHDA lesioned rats. Br J Pharmacol. 2016;doi: 10.​1111/​bph.​13447.
11.
go back to reference Liu L, Song J, Lu J, Huang Y, Zeng Y, et al. TianmaGouteng Yin, a Traditional Chinese Medicine decoction, exerts neuroprotective effects in animal and cellular models of Parkinson’s disease. Sci Rep. 2015;5:16862.CrossRefPubMedPubMedCentral Liu L, Song J, Lu J, Huang Y, Zeng Y, et al. TianmaGouteng Yin, a Traditional Chinese Medicine decoction, exerts neuroprotective effects in animal and cellular models of Parkinson’s disease. Sci Rep. 2015;5:16862.CrossRefPubMedPubMedCentral
12.
go back to reference Zhou T, Zu G, Wang X, Zhang X, Li S, Liang Z, et al. Immunomodulatory and neuroprotective effects of ginsenoside Rg1 in the MPTP-induced mouse model of Parkinson’s disease. Int Immunopharmacol. 2015;29:334–43.CrossRefPubMed Zhou T, Zu G, Wang X, Zhang X, Li S, Liang Z, et al. Immunomodulatory and neuroprotective effects of ginsenoside Rg1 in the MPTP-induced mouse model of Parkinson’s disease. Int Immunopharmacol. 2015;29:334–43.CrossRefPubMed
13.
go back to reference Liang Z, Shi F, Wang Y, Lu L, Zhang Z, Wang X, et al. Neuroprotective effects of tenuigenin in a SH-SY5Y cell model with 6-OHDA-induced injury. Neurosci Lett. 2011;497:104–9.CrossRefPubMed Liang Z, Shi F, Wang Y, Lu L, Zhang Z, Wang X, et al. Neuroprotective effects of tenuigenin in a SH-SY5Y cell model with 6-OHDA-induced injury. Neurosci Lett. 2011;497:104–9.CrossRefPubMed
14.
go back to reference Zheng L, Wang H, Ba YY, Liu HL, Wang M, Guo WW, et al. Protective effect of alkaloids from Piper longum in rat dopaminergic neuron injury of 6-OHDA-induced Parkinson’s disease. Chin J Chin Mat Md. 2014;9:1660–4. Zheng L, Wang H, Ba YY, Liu HL, Wang M, Guo WW, et al. Protective effect of alkaloids from Piper longum in rat dopaminergic neuron injury of 6-OHDA-induced Parkinson’s disease. Chin J Chin Mat Md. 2014;9:1660–4.
15.
go back to reference Bi Y, Qu P, Wang Q, Zheng L, Liu H, Luo R, et al. Neuroprotective effects of alkaloids fromPiper longumin a MPTP-induced mouse model of Parkinson’s disease. Pharm Biol. 2015;53:1516–24.CrossRefPubMed Bi Y, Qu P, Wang Q, Zheng L, Liu H, Luo R, et al. Neuroprotective effects of alkaloids fromPiper longumin a MPTP-induced mouse model of Parkinson’s disease. Pharm Biol. 2015;53:1516–24.CrossRefPubMed
16.
17.
go back to reference Yang H, Wu X, Qu P, Duan Ch, Lu L, Zhang J. The application of Piper longum L. in manufacturing drugs of inhibiting neuroinflammation [P]. Chinese patent: CN102908401A, 2013-02-06. Yang H, Wu X, Qu P, Duan Ch, Lu L, Zhang J. The application of Piper longum L. in manufacturing drugs of inhibiting neuroinflammation [P]. Chinese patent: CN102908401A, 2013-02-06.
18.
go back to reference Zhou HF, Liu XY, Niu DB, Li FQ, He QH, Wang XM. Triptolide protects dopaminergic neurons from inflammation-mediated damage induced by lipopolysaccharide intranigral injection. Neurobiol Dis. 2005;18:441–9.CrossRefPubMed Zhou HF, Liu XY, Niu DB, Li FQ, He QH, Wang XM. Triptolide protects dopaminergic neurons from inflammation-mediated damage induced by lipopolysaccharide intranigral injection. Neurobiol Dis. 2005;18:441–9.CrossRefPubMed
19.
go back to reference Yuan HL, Li B, Xu J, Wang Y, He Y, Zheng Y, et al. Tenuigenin protects dopaminergic neurons from inflammation-mediated damage induced by the lipopolysaccharide. CNS Neurosci Ther. 2012;18:584–90.CrossRefPubMed Yuan HL, Li B, Xu J, Wang Y, He Y, Zheng Y, et al. Tenuigenin protects dopaminergic neurons from inflammation-mediated damage induced by the lipopolysaccharide. CNS Neurosci Ther. 2012;18:584–90.CrossRefPubMed
20.
go back to reference More SV, Kumar H, Kim IS, Song S, Choi D. Cellular and Molecular Mediators of Neuroinflammation in the Pathogenesis of Parkinson’s Disease. Mediators Inflamm. 2013; 2013:1–12. More SV, Kumar H, Kim IS, Song S, Choi D. Cellular and Molecular Mediators of Neuroinflammation in the Pathogenesis of Parkinson’s Disease. Mediators Inflamm. 2013; 2013:1–12.
21.
go back to reference Herrera AJ, Castaño A, Venero JL, Cano J, Machado A. The Single Intranigral Injection of LPS as a New Model for Studying the Selective Effects of Inflammatory Reactions on Dopaminergic System. Neurobiol Dis. 2000;7:429–47.CrossRefPubMed Herrera AJ, Castaño A, Venero JL, Cano J, Machado A. The Single Intranigral Injection of LPS as a New Model for Studying the Selective Effects of Inflammatory Reactions on Dopaminergic System. Neurobiol Dis. 2000;7:429–47.CrossRefPubMed
22.
go back to reference Zhou Y, Zhang Y, Li J, Lv F, Zhao Y, Duan D, et al. A comprehensive study on long-term injury to nigral dopaminergic neurons following intracerebroventricular injection of lipopolysaccharide in rats. J Neurochem. 2012;123:771–80.CrossRefPubMed Zhou Y, Zhang Y, Li J, Lv F, Zhao Y, Duan D, et al. A comprehensive study on long-term injury to nigral dopaminergic neurons following intracerebroventricular injection of lipopolysaccharide in rats. J Neurochem. 2012;123:771–80.CrossRefPubMed
23.
go back to reference Hunter RL, Dragicevic N, Seifert K, Choi DY, Liu M, Kim HC, et al. Inflammation induces mitochondrial dysfunction and dopaminergic neurodegeneration in the nigrostriatal system. J Neurochem. 2007;100:1375–86.CrossRefPubMed Hunter RL, Dragicevic N, Seifert K, Choi DY, Liu M, Kim HC, et al. Inflammation induces mitochondrial dysfunction and dopaminergic neurodegeneration in the nigrostriatal system. J Neurochem. 2007;100:1375–86.CrossRefPubMed
24.
go back to reference Liu B, Jiang JW, Wilson BC, Du L, Yang SN, Wang JY, et al. Systemic infusion of naloxone reduces degeneration of rat substantia nigral dopaminergic neurons induced by intranigral injection of lipopolysaccharide. J Pharmacol ExpTher. 2000;295:125–32. Liu B, Jiang JW, Wilson BC, Du L, Yang SN, Wang JY, et al. Systemic infusion of naloxone reduces degeneration of rat substantia nigral dopaminergic neurons induced by intranigral injection of lipopolysaccharide. J Pharmacol ExpTher. 2000;295:125–32.
25.
go back to reference Xing B, Xin T, Hunter RL, Bing G. Pioglitazone inhibition of lipopolysaccharide-induced nitric oxide synthase is associated with altered activity of p38 MAP kinase and PI3K/Akt. J Neuroinflammation. 2008;5:4.CrossRefPubMedPubMedCentral Xing B, Xin T, Hunter RL, Bing G. Pioglitazone inhibition of lipopolysaccharide-induced nitric oxide synthase is associated with altered activity of p38 MAP kinase and PI3K/Akt. J Neuroinflammation. 2008;5:4.CrossRefPubMedPubMedCentral
26.
go back to reference Castano A, Herrera AJ, Cano J, Machado A. Lipopolysaccharide intranigral injection induces inflammatory reaction and damage in nigrostriatal dopaminergic system. J Neurochem. 1998;70:584–92. Castano A, Herrera AJ, Cano J, Machado A. Lipopolysaccharide intranigral injection induces inflammatory reaction and damage in nigrostriatal dopaminergic system. J Neurochem. 1998;70:584–92.
27.
go back to reference Iravani MM, Leung CCM, Sadeghian M, Haddon CO, Rose S, Jenner P. The acute and the long-term effects of nigral lipopolysaccharide administration on dopaminergic dysfunction and glial cell activation. Eur J Neurosci. 2005;22:317–30.CrossRefPubMed Iravani MM, Leung CCM, Sadeghian M, Haddon CO, Rose S, Jenner P. The acute and the long-term effects of nigral lipopolysaccharide administration on dopaminergic dysfunction and glial cell activation. Eur J Neurosci. 2005;22:317–30.CrossRefPubMed
28.
go back to reference Castano A, Herrera AJ, Cano J, Machado A. The degenerative effect of a single intranigral injection of LPS on the dopaminergic system is prevented by dexamethasone, and not mimicked by rh-TNF-α, IL-1β and IFN-γ. J Neurochem. 2002;81:150–7.CrossRefPubMed Castano A, Herrera AJ, Cano J, Machado A. The degenerative effect of a single intranigral injection of LPS on the dopaminergic system is prevented by dexamethasone, and not mimicked by rh-TNF-α, IL-1β and IFN-γ. J Neurochem. 2002;81:150–7.CrossRefPubMed
29.
go back to reference Tai W, Ye X, Bao X, Zhao B, Wang X, Zhang D. Inhibition of Src tyrosine kinase activity by squamosamide derivative FLZ attenuates neuroinflammation in both in vivo and in vitro Parkinson’s disease models. Neuropharmacology. 2013;75:201–12.CrossRefPubMed Tai W, Ye X, Bao X, Zhao B, Wang X, Zhang D. Inhibition of Src tyrosine kinase activity by squamosamide derivative FLZ attenuates neuroinflammation in both in vivo and in vitro Parkinson’s disease models. Neuropharmacology. 2013;75:201–12.CrossRefPubMed
30.
go back to reference Liu J, Huang D, Xu J, Tong J, Wang Z, Huang L, et al. Tiagabine Protects Dopaminergic Neurons against Neurotoxins by Inhibiting Microglial Activation. Sci Rep. 2015;5:15720.CrossRefPubMedPubMedCentral Liu J, Huang D, Xu J, Tong J, Wang Z, Huang L, et al. Tiagabine Protects Dopaminergic Neurons against Neurotoxins by Inhibiting Microglial Activation. Sci Rep. 2015;5:15720.CrossRefPubMedPubMedCentral
31.
go back to reference Wang J, He C, Wu WY, Chen F, Wu YY, Li WZ, et al. Biochanin A protects dopaminergic neurons against lipopolysaccharide-induced damage and oxidative stress in a rat model of Parkinson’s disease. Pharmacol Biochem Behav. 2015;138:96–103.CrossRefPubMed Wang J, He C, Wu WY, Chen F, Wu YY, Li WZ, et al. Biochanin A protects dopaminergic neurons against lipopolysaccharide-induced damage and oxidative stress in a rat model of Parkinson’s disease. Pharmacol Biochem Behav. 2015;138:96–103.CrossRefPubMed
32.
go back to reference Bai L, Zhang X, Li X, Liu N, Lou F, Ma H, et al. Somatostatin prevents lipopolysaccharide-induced neurodegeneration in the rat substantia nigra by inhibiting the activation of microglia. Mol Med Rep. 2015;12:1002–8.PubMedPubMedCentral Bai L, Zhang X, Li X, Liu N, Lou F, Ma H, et al. Somatostatin prevents lipopolysaccharide-induced neurodegeneration in the rat substantia nigra by inhibiting the activation of microglia. Mol Med Rep. 2015;12:1002–8.PubMedPubMedCentral
33.
go back to reference Dutta G, Zhang P, Liu B. The lipopolysaccharide Parkinson’s disease animal model: mechanistic studies and drug discovery. Fundam Clin Pharmacol. 2008;22:453–64.CrossRefPubMedPubMedCentral Dutta G, Zhang P, Liu B. The lipopolysaccharide Parkinson’s disease animal model: mechanistic studies and drug discovery. Fundam Clin Pharmacol. 2008;22:453–64.CrossRefPubMedPubMedCentral
34.
go back to reference Liu M, Bing G. Lipopolysaccharide animal models for Parkinson’s disease. Parkinsons Dis. 2011; 2011:327089. Liu M, Bing G. Lipopolysaccharide animal models for Parkinson’s disease. Parkinsons Dis. 2011; 2011:327089.
35.
go back to reference Liu H, Luo R, Chen X, Liu J, Bi Y, Zheng L, et al. Tissue distribution profiles of three antiparkinsonian alkaloids from Piper longum L. in rats determined by liquid chromatography-tandem mass spectrometry. J Chromatogr B AnalytTechnol Biomed Life Sci. 2013;928:78–82.CrossRef Liu H, Luo R, Chen X, Liu J, Bi Y, Zheng L, et al. Tissue distribution profiles of three antiparkinsonian alkaloids from Piper longum L. in rats determined by liquid chromatography-tandem mass spectrometry. J Chromatogr B AnalytTechnol Biomed Life Sci. 2013;928:78–82.CrossRef
36.
go back to reference Cui YQ, Jia YJ, Zhang T, Zhang QB, Wang XM. Fucoidan protects against lipopolysaccharide-induced rat neuronal damage and inhibits the production of proinflammatory mediators in primary microglia. CNS Neurosci Ther. 2012;18:827–33.CrossRefPubMed Cui YQ, Jia YJ, Zhang T, Zhang QB, Wang XM. Fucoidan protects against lipopolysaccharide-induced rat neuronal damage and inhibits the production of proinflammatory mediators in primary microglia. CNS Neurosci Ther. 2012;18:827–33.CrossRefPubMed
Metadata
Title
Alkaloids from piper longum protect dopaminergic neurons against inflammation-mediated damage induced by intranigral injection of lipopolysaccharide
Authors
Huan He
Wei-Wei Guo
Rong-Rong Xu
Xiao-Qing Chen
Nan Zhang
Xia Wu
Xiao-Min Wang
Publication date
01-12-2016
Publisher
BioMed Central
Published in
BMC Complementary Medicine and Therapies / Issue 1/2016
Electronic ISSN: 2662-7671
DOI
https://doi.org/10.1186/s12906-016-1392-6

Other articles of this Issue 1/2016

BMC Complementary Medicine and Therapies 1/2016 Go to the issue