Clozapine-induced agranulocytosis (CA) results from an increased rate of apoptosis of blood neutrophils and their promyeloid precursors (1) due to oxidative stress under clozapine treatment.
Besides uncoupling of the electron transport, the enzymes xanthine oxidase and NADPH oxidase are implicated in the pathogenesis of CA, because of their ability to generate reactive oxygen species. Since activation of both enzymes involves p38 mitogen-activated kinase (p38 MAPK) (2,3), inhibition of this common activator should prevent neutrophils from CA.
Indeed, inhibition of p38 MAPK by the specific inhibitor SB203580 decreased apoptosis induction by clozapine (100µM) to background levels (4%). Since SB203580 influences radical production, it is more effective than radical scavengers. At present, several clinical trials confirm the high selectivity and good bioavailibility of p38 MAPK inhibitors. Based on our in vitro results, one can speculate that these p38 MAPK inhibitors will be interesting tools in preventing CA.
1 Loeffler S et al. Pharmacopsychiatry 2003; 35:37–41
2Kayyali US et al., J. Biol. Chem. 2001; 276:14359–14365
3Yamamori T et al. Biochem Biophys Res Commun. 2002;293:1571–1578
