Minocycline prevents nigrostriatal dopaminergic neurodegeneration in the MPTP model of Parkinson's disease.
Parkinson's disease is a chronic neurodegenerative disorder characterized by the loss of dopamine neurons in the substantia nigra, decreased striatal dopamine levels, and consequent extrapyramidal motor dysfunction. We now report that minocycline, a semisynthetic tetracycline, recently shown to have neuroprotective effects in animal models of stroke/ischemic injury and Huntington's disease, prevents nigrostriatal dopaminergic neurodegeneration in the 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) mouse model of Parkinson's disease. Minocycline treatment also blocked dopamine depletion in the striatum as well as in the nucleus accumbens after MPTP administration. The neuroprotective effect of minocycline is associated with marked reductions in inducible NO synthase (iNOS) and caspase 1 expression. In vitro studies using primary cultures of mesencephalic and cerebellar granule neurons (CGN) and/or glia demonstrate that minocycline inhibits both 1-methyl-4-phenylpyridinium (MPP(+))-mediated iNOS expression and NO-induced neurotoxicity, but MPP(+)-induced neurotoxicity is inhibited only in the presence of glia. Further, minocycline also inhibits NO-induced phosphorylation of p38 mitogen-activated protein kinase (MAPK) in CGN and the p38 MAPK inhibitor, SB203580, blocks NO toxicity of CGN. Our results suggest that minocycline blocks MPTP neurotoxicity in vivo by indirectly inhibiting MPTP/MPP(+)-induced glial iNOS expression and/or directly inhibiting NO-induced neurotoxicity, most likely by inhibiting the phosphorylation of p38 MAPK. Thus, NO appears to play an important role in MPTP neurotoxicity. Neuroprotective tetracyclines may be effective in preventing or slowing the progression of Parkinson's and other neurodegenerative diseases.
Du
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Y
Departmens of Pharmacology and Toxicology, Indiana University School of Medicine, Indianapolis, IN 46202, USA.
Ma
Z
Z
Lin
S
S
Dodel
R C
RC
Gao
F
F
Bales
K R
KR
Triarhou
L C
LC
Chernet
E
E
Perry
K W
KW
Nelson
D L
DL
Luecke
S
S
Phebus
L A
LA
Bymaster
F P
FP
Paul
S M
SM
D000818:Animals; D020170:Caspase 1 / Q000378:metabolism; D002478:Cells, Cultured; D004298:Dopamine / Q000378:metabolism; D006801:Humans; D007093:Imidazoles / Q000494:pharmacology; D020267:MPTP Poisoning / Q000188:drug therapy* / Q000517:prevention & control*; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D008911:Minocycline / Q000494:pharmacology*; D020928:Mitogen-Activated Protein Kinases / Q000037:antagonists & inhibitors / Q000378:metabolism; D008995:Monoamine Oxidase / Q000378:metabolism; D009410:Nerve Degeneration / Q000517:prevention & control*; D009474:Neurons / Q000187:drug effects / Q000378:metabolism; D018696:Neuroprotective Agents / Q000494:pharmacology*; D009569:Nitric Oxide / Q000378:metabolism; D019001:Nitric Oxide Synthase / Q000378:metabolism; D052247:Nitric Oxide Synthase Type II; D020734:Parkinsonian Disorders / Q000139:chemically induced / Q000188:drug therapy* / Q000517:prevention & control*; D010766:Phosphorylation; D011725:Pyridines / Q000494:pharmacology; D014793:Visual Cortex / Q000187:drug effects; D048051:p38 Mitogen-Activated Protein Kinases
D007093:Imidazoles; D018696:Neuroprotective Agents; D011725:Pyridines; D009569:Nitric Oxide; C496319:NOS2 protein, human; D019001:Nitric Oxide Synthase; D052247:Nitric Oxide Synthase Type II; C496317:Nos2 protein, mouse; D008995:Monoamine Oxidase; D020928:Mitogen-Activated Protein Kinases; D048051:p38 Mitogen-Activated Protein Kinases; D020170:Caspase 1; D008911:Minocycline; C093642:SB 203580; D004298:Dopamine