{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,4]],"date-time":"2026-10-04T16:32:57Z","timestamp":1791131577187,"version":"4.1.0"},"reference-count":36,"publisher":"National Academy of Sciences","issue":"25","content-domain":{"domain":["www.pnas.org"],"crossmark-restriction":true},"short-container-title":["Proc. Natl. Acad. Sci. U.S.A."],"published-print":{"date-parts":[[2001,12,4]]},"abstract":"<jats:p>\n                    Parkinson's disease is a chronic neurodegenerative disorder\n characterized by the loss of dopamine neurons in the substantia nigra,\n decreased striatal dopamine levels, and consequent extrapyramidal motor\n dysfunction. We now report that minocycline, a semisynthetic\n tetracycline, recently shown to have neuroprotective effects in animal\n models of stroke\/ischemic injury and Huntington's disease, prevents\n nigrostriatal dopaminergic neurodegeneration in the\n 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) mouse model of\n Parkinson's disease. Minocycline treatment also blocked dopamine\n depletion in the striatum as well as in the nucleus accumbens after\n MPTP administration. The neuroprotective effect of minocycline is\n associated with marked reductions in inducible NO synthase (iNOS) and\n caspase 1 expression.\n                    <jats:italic>In vitro<\/jats:italic>\n                    studies using primary\n cultures of mesencephalic and cerebellar granule neurons (CGN) and\/or\n glia demonstrate that minocycline inhibits both\n 1-methyl-4-phenylpyridinium (MPP\n                    <jats:sup>+<\/jats:sup>\n                    )-mediated iNOS expression\n and NO-induced neurotoxicity, but MPP\n                    <jats:sup>+<\/jats:sup>\n                    -induced\n neurotoxicity is inhibited only in the presence of glia. Further,\n minocycline also inhibits NO-induced phosphorylation of p38\n mitogen-activated protein kinase (MAPK) in CGN and the p38 MAPK\n inhibitor, SB203580, blocks NO toxicity of CGN. Our results suggest\n that minocycline blocks MPTP neurotoxicity\n                    <jats:italic>in vivo<\/jats:italic>\n                    by\n indirectly inhibiting MPTP\/MPP\n                    <jats:sup>+<\/jats:sup>\n                    -induced glial iNOS\n expression and\/or directly inhibiting NO-induced neurotoxicity, most\n likely by inhibiting the phosphorylation of p38 MAPK. Thus, NO appears\n to play an important role in MPTP neurotoxicity. Neuroprotective\n tetracyclines may be effective in preventing or slowing the progression\n of Parkinson's and other neurodegenerative diseases.\n                  <\/jats:p>","DOI":"10.1073\/pnas.251341998","type":"journal-article","created":{"date-parts":[[2002,7,26]],"date-time":"2002-07-26T10:35:07Z","timestamp":1027679707000},"page":"14669-14674","update-policy":"https:\/\/doi.org\/10.1073\/pnas.cm10313","source":"Crossref","is-referenced-by-count":652,"title":["Minocycline prevents nigrostriatal dopaminergic neurodegeneration in the MPTP model of Parkinson's disease"],"prefix":"10.1073","volume":"98","author":[{"given":"Yansheng","family":"Du","sequence":"first","affiliation":[{"name":"Departments of Pharmacology and Toxicology, Indiana University\r School of Medicine, Indianapolis, IN 46202; Department of\r Neurology, Philipps-University, Marburg, 35033 Germany;\r Neuroscience Discovery Research, Lilly Research\r Laboratories, Eli Lilly and Company, Indianapolis, IN 46285; and\r Department of Pathology, Indiana University,\r Indianapolis, IN 46202"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Zhizhong","family":"Ma","sequence":"additional","affiliation":[{"name":"Departments of Pharmacology and Toxicology, Indiana University\r School of Medicine, Indianapolis, IN 46202; Department of\r Neurology, Philipps-University, Marburg, 35033 Germany;\r Neuroscience Discovery Research, Lilly Research\r Laboratories, Eli Lilly and Company, Indianapolis, IN 46285; and\r Department of Pathology, Indiana University,\r Indianapolis, IN 46202"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Suizhen","family":"Lin","sequence":"additional","affiliation":[{"name":"Departments of Pharmacology and Toxicology, Indiana University\r School of Medicine, Indianapolis, IN 46202; Department of\r Neurology, Philipps-University, Marburg, 35033 Germany;\r Neuroscience Discovery Research, Lilly Research\r Laboratories, Eli Lilly and Company, Indianapolis, IN 46285; and\r Department of Pathology, Indiana University,\r Indianapolis, IN 46202"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Richard C.","family":"Dodel","sequence":"additional","affiliation":[{"name":"Departments of Pharmacology and Toxicology, Indiana University\r School of Medicine, Indianapolis, IN 46202; Department of\r Neurology, Philipps-University, Marburg, 35033 Germany;\r Neuroscience Discovery Research, Lilly Research\r Laboratories, Eli Lilly and Company, Indianapolis, IN 46285; and\r Department of Pathology, Indiana University,\r Indianapolis, IN 46202"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Feng","family":"Gao","sequence":"additional","affiliation":[{"name":"Departments of Pharmacology and Toxicology, Indiana University\r School of Medicine, Indianapolis, IN 46202; Department of\r Neurology, Philipps-University, Marburg, 35033 Germany;\r Neuroscience Discovery Research, Lilly Research\r Laboratories, Eli Lilly and Company, Indianapolis, IN 46285; and\r Department of Pathology, Indiana University,\r Indianapolis, IN 46202"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Kelly R.","family":"Bales","sequence":"additional","affiliation":[{"name":"Departments of Pharmacology and Toxicology, Indiana University\r School of Medicine, Indianapolis, IN 46202; Department of\r Neurology, Philipps-University, Marburg, 35033 Germany;\r Neuroscience Discovery Research, Lilly Research\r Laboratories, Eli Lilly and Company, Indianapolis, IN 46285; and\r Department of Pathology, Indiana University,\r Indianapolis, IN 46202"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Lazarose C.","family":"Triarhou","sequence":"additional","affiliation":[{"name":"Departments of Pharmacology and Toxicology, Indiana University\r School of Medicine, Indianapolis, IN 46202; Department of\r Neurology, Philipps-University, Marburg, 35033 Germany;\r Neuroscience Discovery Research, Lilly Research\r Laboratories, Eli Lilly and Company, Indianapolis, IN 46285; and\r Department of Pathology, Indiana University,\r Indianapolis, IN 46202"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Eyassu","family":"Chernet","sequence":"additional","affiliation":[{"name":"Departments of Pharmacology and Toxicology, Indiana University\r School of Medicine, Indianapolis, IN 46202; Department of\r Neurology, Philipps-University, Marburg, 35033 Germany;\r Neuroscience Discovery Research, Lilly Research\r Laboratories, Eli Lilly and Company, Indianapolis, IN 46285; and\r Department of Pathology, Indiana University,\r Indianapolis, IN 46202"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Ken W.","family":"Perry","sequence":"additional","affiliation":[{"name":"Departments of Pharmacology and Toxicology, Indiana University\r School of Medicine, Indianapolis, IN 46202; Department of\r Neurology, Philipps-University, Marburg, 35033 Germany;\r Neuroscience Discovery Research, Lilly Research\r Laboratories, Eli Lilly and Company, Indianapolis, IN 46285; and\r Department of Pathology, Indiana University,\r Indianapolis, IN 46202"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"David L. G.","family":"Nelson","sequence":"additional","affiliation":[{"name":"Departments of Pharmacology and Toxicology, Indiana University\r School of Medicine, Indianapolis, IN 46202; Department of\r Neurology, Philipps-University, Marburg, 35033 Germany;\r Neuroscience Discovery Research, Lilly Research\r Laboratories, Eli Lilly and Company, Indianapolis, IN 46285; and\r Department of Pathology, Indiana University,\r Indianapolis, IN 46202"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Susan","family":"Luecke","sequence":"additional","affiliation":[{"name":"Departments of Pharmacology and Toxicology, Indiana University\r School of Medicine, Indianapolis, IN 46202; Department of\r Neurology, Philipps-University, Marburg, 35033 Germany;\r Neuroscience Discovery Research, Lilly Research\r Laboratories, Eli Lilly and Company, Indianapolis, IN 46285; and\r Department of Pathology, Indiana University,\r Indianapolis, IN 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