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Abstract
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.