Minocycline blocks nitric oxide-induced neurotoxicity by inhibition p38 MAP kinase in rat cerebellar granule neurons

Minocycline, a semisynthetic second-generation tetracycline, was reported t o have neuroprotective effects in models of global and focal cerebral ische mia, the R6/2 mouse model of Huntington disease, as well as glutamate-induc ed neurotoxicity in mixed neuronal/glial cultures. It was suggested that ne uroprotective effects of minocycline resulted from inhibition of microglial /astroglial activation 'Proc. Natl. Acad. Sci. USA 95 1998 15769'. To deter mine whether or not minocycline is able to directly protect neurons against injury insults and to delineate its neuroprotective mechanism(s), we treat ed 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 fas hion. Consistent to other reports, NO was able to induce p38 MAP kinase pho sphorylation at 3-6 h and such an induction could be significantly inhibite d by minocycline. Furthermore, SB 203580, a p38 MAP kinase inhibitor, almos t completely attenuated NO-induced neuronal death of CGN as well. These res ults 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 neurodeg enerative models. (C) 2001 Elsevier Science Ireland Ltd. All rights reserve d.