Minocycline prevents nigrostriatal dopaminergic neurodegeneration in the MPTP model of Parkinson's disease

^*Departments of Pharmacology and Toxicology, Indiana University School of Medicine, Indianapolis, IN 46202; ^†Department of Neurology, Philipps-University, Marburg, 35033 Germany; ^‡Neuroscience Discovery Research, Lilly Research Laboratories, Eli Lilly and Company, Indianapolis, IN 46285; and ^§Department of Pathology, Indiana University, Indianapolis, IN 46202

Edited by Solomon H. Snyder, The Johns Hopkins University School of Medicine, Baltimore, MD, and approved August 24, 2001 (received for review July 5, 2001)

Abstract

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.

Footnotes

↵ ¶ To whom reprint requests should be addressed. E-mail: Paul_Steven_M{at}Lilly.com.
This paper was submitted directly (Track II) to the PNAS office.
Abbreviations:

MPTP,

1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine;

MPP+,

1-methyl-4-phenylpyridinium;

SNpc,

substantia nigra pars compacta;

CGN,

cerebellar granule neurons;

RMN,

rostral mesencephalic neurons;

iNOS,

inducible NO synthase;

nNOS,

neuronal NO synthase;

DOPAC,

3,4-dihydroxyphenylacetic acid;

HVA,

homovanilic acid;

MAPK,

mitogenactivated protein kinase;

TH,

tyrosine hydroxylase;

MAO,

monoamine oxidase;

SNP,

sodium nitroprusside