Minocycline blocks nitric oxide-induced neurotoxicity by inhibition p38 MAP kinase in rat cerebellar granule neurons.
Minocycline, a semisynthetic second-generation tetracycline, was reported to have neuroprotective effects in models of global and focal cerebral ischemia, the R6/2 mouse model of Huntington disease, as well as glutamate-induced neurotoxicity in mixed neuronal/glial cultures. It was suggested that neuroprotective effects of minocycline resulted from inhibition of microglial/astroglial activation 'Proc. Natl. Acad. Sci. USA 95 1998 15769'. To determine whether or not minocycline is able to directly protect neurons against injury insults and to delineate its neuroprotective mechanism(s), we treated cultured rat cerebellar granule neurons (CGN) with nitric oxide (NO) in the presence or absence of minocycline. We found that minocycline protected neurons against NO-induced neuronal death in a concentration-dependent fashion. Consistent to other reports, NO was able to induce p38 MAP kinase phosphorylation at 3-6 h and such an induction could be significantly inhibited by minocycline. Furthermore, SB 203580, a p38 MAP kinase inhibitor, almost completely attenuated NO-induced neuronal death of CGN as well. These results suggest that minocycline is able to block NO-induced neurotoxicity in CGN by inhibiting NO-induced phosphorylation of p38 MAP kinase. Our finding may explain the neuroprotective mechanism of minocycline in those neurodegenerative models.
Lin
S
S
Department of Pharmacology and Toxicology, Indiana University School of Medicine, 635 Barnhill Dr, Indianapolis, IN 46202, USA.
Zhang
Y
Y
Dodel
R
R
Farlow
M R
MR
Paul
S M
SM
Du
Y
Y
D000818:Animals; D000900:Anti-Bacterial Agents / Q000494:pharmacology*; D015153:Blotting, Western; D016923:Cell Death; D002478:Cells, Cultured; D002531:Cerebellum / Q000166:cytology / Q000201:enzymology / Q000378:metabolism*; D004791:Enzyme Inhibitors / Q000494:pharmacology*; D008911:Minocycline / Q000494:pharmacology*; D020928:Mitogen-Activated Protein Kinases / Q000037:antagonists & inhibitors*; D009474:Neurons / Q000166:cytology / Q000187:drug effects* / Q000201:enzymology; D018696:Neuroprotective Agents / Q000494:pharmacology*; D009569:Nitric Oxide / Q000378:metabolism*; D020030:Nitric Oxide Donors / Q000494:pharmacology; D009599:Nitroprusside / Q000494:pharmacology; D010766:Phosphorylation; D051381:Rats; D017207:Rats, Sprague-Dawley; D048051:p38 Mitogen-Activated Protein Kinases
D000900:Anti-Bacterial Agents; D004791:Enzyme Inhibitors; D018696:Neuroprotective Agents; D020030:Nitric Oxide Donors; D009599:Nitroprusside; D009569:Nitric Oxide; D020928:Mitogen-Activated Protein Kinases; D048051:p38 Mitogen-Activated Protein Kinases; D008911:Minocycline