Clozapine prevents apoptosis and enhances receptor-dependent respiratory burst in human neutrophils
Vargas, F.; Rivas, C.; Perdomo, H.; Rivas, A.; Ojeda, L.E.; Velásquez, M.; Correia, H.; Hernández, A.; Fraile, G.
Die Pharmazie 60(5): 364-368
2005
ISSN/ISBN: 0031-7144 PMID: 15918587 Document Number: 590925
The present study was undertaken to determine if the antipsychotic drug clozapine (CLZ) in the concentration range 2-50 mu M can rescue polymorphonuclear cells (PIVINs) from undergoing apoptosis. Our results indicate that 20 mu M CLZ can rescue PMNs both from UVB-accelerated (28.0% vs. 45.9% for control without CLZ; P < 0.05) and from spontaneous (35.8% vs. 57.6%; P < 0.05) apoptosis whereas 50 mu M CLZ could rescue PMNs from spontaneous (34.3% vs. 57.6%; P < 0.05) apoptosis only. Furthermore, since apoptosis has been reported to involve the impairment of PMN function, we evaluated the effects of CLZ on respiratory burst in UVB-irradiated and in unirradiated PIVINs. When 20 or 50 mu M CLZ-pretreated PMNs were aged in a culture during 4 h, the luminol-dependent chemiluminescence (CL) response was 3-fold (P < 0.01) and 2.5-fold (P < 0.05) increased, respectively, by subsequent exposure to serum opsonized zymosan (OZ). When 50 mu M-pretreated PMNs were either UVB-irradiated or unirradiated, the CL response was 2.6-fold (P < 0.05) and 3.3-fold (P < 0.05) increased, respectively, after subsequent exposure to formyl-methionyl-leucyl-phenylaianine (fMLP). In contrast, the degree of enhancement was negligible upon subsequent exposure to ionomycin or phorbol myristate acetate (PMA). When incubation times were extended up to 22 h, the CL response induced by OZ in 20 mu M CLZ-treated PIVINs had a 4.9-fold increase (P < 0.001). This priming effect could be reverted when 20 mu M CLZ-treated PMNs (aged 4 In in culture) were coincubated for 5 min with the protein tyrosine kinase inhibitor genistein as well as with the phosphaticlylinositol 3-kinase (PI3-K) inhibitor wortmannin. These findings suggest that CLZ primes respiratory burst and prevents PMN apoptosis as a consequence of tyrosine phosphorylation- and P13-K activation-dependent signal transduction pathways.