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We investigated the interaction of genetic and environmental factors, treating midbrain neuronal cultures from PK\u2010KO and wild\u2010type (WT) mice with rotenone (ROT). ROT (0.025\u20130.1\u2003\u00b5<jats:sc>m<\/jats:sc>) produced a dose\u2010dependent selective reduction of tyrosine hydroxylase\u2010immunoreactive cells and of other neurons, as shown by the immunoreactivity to microtubule\u2010associated protein 2 in PK\u2010KO cultures, suggesting that the toxic effect of ROT involved dopamine and other types of neurons. Neuronal death was mainly apoptotic and suppressible by the caspase inhibitor t\u2010butoxycarbonyl\u2010Asp(OMe)\u2010fluoromethyl ketone (Boc\u2010D\u2010FMK). PK\u2010KO cultures were more susceptible to apoptosis induced by low doses of ROT than those from WT. ROT increased the proportion of astroglia and microglia more in PK\u2010KO than in WT cultures. Indomethacin, a cyclo\u2010oxygenase inhibitor, worsened the effects of ROT on tyrosine hydroxylase cells, apoptosis and astroglial (glial fibrillary acidic protein) cells. <jats:italic>N<\/jats:italic>\u2010nitro\u2010<jats:sc>l<\/jats:sc>\u2010arginine methyl ester, an inhibitor of nitric oxide synthase, increased ROT\u2010induced apoptosis but did not change tyrosine hydroxylase\u2010immunoreactive or glial fibrillary acidic protein area. Neither indomethacin nor <jats:italic>N<\/jats:italic>\u2010nitro\u2010<jats:sc>l<\/jats:sc>\u2010arginine methyl ester had any effect on the reduction by ROT of the mitochondrial potential as measured by 3\u2010(4,5\u2010dimethylthiazol\u20102\u2010yl)\u20102,5\u2010diphenyltetrazolium bromide. Microglial NADPH oxidase inhibition, however, protected against ROT. The roles of p38 MAPK and extracellular signal\u2010regulated kinase signaling pathways were tested by treatment with SB20358 and PD98059, respectively. These compounds were inactive in ROT\u2010naive cultures but PD98059 slightly increased cellular necrosis, as measured by lactate dehydrogenase levels, caused by ROT, without changing mitochondrial activity. SB20358 increased the mitochondrial failure and lactate dehydrogenase elevation induced by ROT. Minocycline, an inhibitor of microglia, prevented the dropout of tyrosine hydroxylase and apoptosis by ROT; the addition of microglia from PK\u2010KO to WT neuronal cultures increased the sensitivity of dopaminergic neurons to ROT. PK\u2010KO mice were more susceptible than WT to ROT and the combined effects of <jats:italic>Park\u20102<\/jats:italic> suppression and ROT reproduced the cellular events observed in Parkinson's disease. These events were prevented by minocycline.<\/jats:p>","DOI":"10.1111\/j.1471-4159.2006.03777.x","type":"journal-article","created":{"date-parts":[[2006,3,29]],"date-time":"2006-03-29T13:38:02Z","timestamp":1143639482000},"page":"934-946","source":"Crossref","is-referenced-by-count":128,"title":["Susceptibility to rotenone is increased in neurons from parkin null mice and is reduced by minocycline"],"prefix":"10.1111","volume":"97","author":[{"given":"M. J.","family":"Casarejos","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"J.","family":"Men\u00e9ndez","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"R. M.","family":"Solano","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"J. 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