Paroxetine Prevents Loss of Nigrostriatal Dopaminergic Neurons by Inhibiting Brain Inflammation and Oxidative Stress in an Experimental Model of Parkinson's Disease

被引：132

作者：

Chung, Young C. ^{[1
,2
,3
,4
]}

Kim, Sang R. ^{[2
]}

Jin, Byung K. ^{[1
,4
]}

机构：

[1] Kyung Hee Univ, Dept Biochem & Mol Biol, Neurodegenerat Control Res Ctr, Seoul 130701, South Korea

[2] Ajou Univ, Neurosci Grad Program, Suwon 441749, South Korea

[3] Ajou Univ, Sch Med, Div Cell Transformat & Restorat, Suwon 441749, South Korea

[4] Kyung Hee Univ, Sch Med, Aged Related & Brain Dis Res Ctr, Seoul 130701, South Korea

来源：

JOURNAL OF IMMUNOLOGY | 2010年 / 185卷 / 02期

关键词：

1-METHYL-4-PHENYL-1,2,3,6-TETRAHYDROPYRIDINE MOUSE MODEL; NITRIC-OXIDE SYNTHASE; NADPH OXIDASE; MICROGLIAL ACTIVATION; MPTP MODEL; TNF-ALPHA; IN-VITRO; NEUROTOXICITY; MYELOPEROXIDASE; CELLS;

D O I：

10.4049/jimmunol.1000208

中图分类号：

R392 [医学免疫学]; Q939.91 [免疫学];

学科分类号：

100102 ;

摘要：

The present study examined whether the antidepressant paroxetine promotes the survival of nigrostriatal dopaminergic (DA) neurons in the 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) mouse model of Parkinson's disease. MPTP induced degeneration of nigrostriatal DA neurons and glial activation as visualized by tyrosine hydroxylase, macrophage Ag complex-1, and/or glial fibrillary acidic protein immunoreactivity. Real-time PCR, Western blotting, and immunohistochemistry showed upregulation of proinflammatory cytokines, activation of microglial NADPH oxidase and astroglial myeloperoxidase, and subsequent reactive oxygen species production and oxidative DNA damage in the MPTP-treated substantia nigra. Treatment with paroxetine prevented degeneration of nigrostriatal DA neurons, increased striatal dopamine levels, and improved motor function. This neuroprotection afforded by paroxetine was associated with the suppression of astroglial myeloperoxidase expression and/or NADPH oxidase-derived reactive oxygen species production and reduced expression of proinflammatory cytokines, including IL-1 beta, TNF-alpha, and inducible NO synthase, by activated microglia. The present findings show that paroxetine may possess anti-inflammatory properties and inhibit glial activation-mediated oxidative stress, suggesting that paroxetine and its analogues may have therapeutic value in the treatment of aspects of Parkinson's disease related to neuroinflammation. The Journal of Immunology, 2010, 185: 1230-1237.

引用

页码：1230 / 1237

页数：8

共 54 条

[51] NADPH oxidase mediates oxidative stress in the 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine model of Parkinson's disease [J].

Wu, DC ;

Teismann, P ;

Tieu, K ;

Vila, M ;

Jackson-Lewis, V ;

Ischiropoulos, H ;

Przedborski, S .

PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA, 2003, 100 (10) :6145-6150

[52] MTH1, an oxidized purine nucleoside triphosphatase, protects the dopamine neurons from oxidative damage in nucleic acids caused by 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine [J].

Yamaguchi, H ;

Kajitani, K ;

Dan, Y ;

Furuichi, M ;

Ohno, M ;

Sakumi, K ;

Kang, D ;

Nakabeppu, Y .

CELL DEATH AND DIFFERENTIATION, 2006, 13 (04) :551-563

[53] TNF-α knockout and minocycline treatment attenuates blood-brain barrier leakage in MPTP-treated mice [J].

Zhao, Chaohui ;

Ling, Zaodung ;

Newman, Mary B. ;

Bhatia, Ankush ;

Carvey, Paul M. .

NEUROBIOLOGY OF DISEASE, 2007, 26 (01) :36-46

[54] Oxidative Stress in Parkinson's Disease A Mechanism of Pathogenic and Therapeutic Significance [J].

Zhou, Chun ;

Huang, Yong ;

Przedborski, Serge .

MITOCHONDRIA AND OXIDATIVE STRESS IN NEURODEGENERATIVE DISORDERS, 2008, 1147 :93-104

← 1 2 3 4 5 6 →