Doxycycline is neuroprotective against nigral dopaminergic degeneration by a dual mechanism involving MMP-3.
In Parkinson disease (PD), the dopaminergic (DAergic) neurons in the substantia nigra undergo degeneration. While the exact mechanism for the degeneration is still not completely understood, neuronal apoptosis and inflammation are thought to play roles. We have recently obtained evidence that matrix metalloproteinase (MMP)-3 plays a crucial role in the apoptotic signal in DAergic cells as well as activation of microglia. The present study tested whether doxycycline might modulate MMP-3 and provide neuroprotection of DAergic neurons. Doxycycline effectively suppressed the expression of MMP-3 induced in response to cellular stress in the DAergic CATH.a cells. This was accompanied by protection of CATH.a cells as well as primary cultured mesencephalic DAergic neurons via attenuation of apoptosis. The active form of MMP-3, released under the cell stress condition, was also decreased in the presence of doxycycline. In addition, doxycycline led to downregulation of MMP-3 in microglial BV-2 cells exposed to lipopolysaccharide (LPS). This was accompanied by suppression of production of nitric oxide and TNF-alpha, as well as gene expression of iNOS, TNF-alpha, IL-1beta, and COX-2. In vivo, doxycycline provided neuroprotection of the nigral DAergic neurons following MPTP treatment, as assessed by tyrosine hydroxylase immunocytochemistry and silver staining, and suppressed microglial activation and astrogliosis as assessed by Iba-1 and GFAP immunochemistry, respectively. Taken together, doxycycline showed neuroprotective effect on DAergic system both in vitro and in vivo and this appeared to derive from anti-apoptotic and anti-inflammatory mechanisms involving downregulation of MMP-3.
Cho
Yuri
Y
Department of Biochemistry and Molecular Biology, University of Ulsan College of Medicine, 388-1 Pungnap-dong, Songpa-ku, Seoul 138-736, Korea.
Son
Hyo Jin
HJ
Kim
Eun-Mee
EM
Choi
Ji Hyun
JH
Kim
Sung Tae
ST
Ji
In Jung
IJ
Choi
Dong Hee
DH
Joh
Tong H
TH
Kim
Yoon Seong
YS
Hwang
Onyou
O
D015632:1-Methyl-4-phenyl-1,2,3,6-tetrahydropyridine / Q000494:pharmacology; D000818:Animals; D016923:Cell Death / Q000187:drug effects; D002478:Cells, Cultured; D004298:Dopamine / Q000378:metabolism*; D004305:Dose-Response Relationship, Drug; D004318:Doxycycline / Q000494:pharmacology*; D004797:Enzyme-Linked Immunosorbent Assay / Q000379:methods; D005260:Female; D015971:Gene Expression Regulation, Enzymologic / Q000187:drug effects; D020287:In Situ Nick-End Labeling / Q000379:methods; D007770:L-Lactate Dehydrogenase / Q000378:metabolism; D008297:Male; D019278:Matrix Metalloproteinase 3 / Q000235:genetics / Q000378:metabolism*; D051379:Mice; D008810:Mice, Inbred C57BL; D009419:Nerve Tissue Proteins / Q000378:metabolism; D009474:Neurons / Q000187:drug effects* / Q000648:ultrastructure; D018696:Neuroprotective Agents / Q000494:pharmacology*; D009573:Nitrites / Q000378:metabolism; D011247:Pregnancy; D051381:Rats; D017207:Rats, Sprague-Dawley; D016622:Silver Staining / Q000379:methods; D018709:Statistics, Nonparametric; D013378:Substantia Nigra / Q000166:cytology*; D014409:Tumor Necrosis Factor-alpha / Q000378:metabolism
D009419:Nerve Tissue Proteins; D018696:Neuroprotective Agents; D009573:Nitrites; D014409:Tumor Necrosis Factor-alpha; D015632:1-Methyl-4-phenyl-1,2,3,6-tetrahydropyridine; D007770:L-Lactate Dehydrogenase; D019278:Matrix Metalloproteinase 3; D004318:Doxycycline; D004298:Dopamine