N. Makkonen et al., DIFFERENT EFFECTS OF 3 BISPHOSPHONATES ON NITRIC-OXIDE PRODUCTION BY RAW-264 MACROPHAGE-LIKE CELLS IN-VITRO, The Journal of pharmacology and experimental therapeutics, 277(2), 1996, pp. 1097-1102
The macrophage-suppressive properties of three bisphosphonates were ev
aluated by studying their effect on nitric oxide (NO) production by ac
tivated RAW 264 macrophage-like cells. The cells were activated with 1
0 mu g/ml of lipopolysaccharide, and NO was determined as nitrite in t
he cell culture supernatant. The effect of the drugs on inducible NO s
ynthase was determined by Western blot analysis. As free drugs, clodro
nate and pamidronate inhibited NO secretion in a dose-dependent manner
, whereas alendronate had no effect. Liposome encapsulation enhanced t
he effect of clodronate by a factor of 7, but the potency of pamidrona
te weakened slightly when encapsulated in liposomes. The inducible NO
synthase expression inside the cells was also decreased by liposomal c
lodronate. In contrast to pamidronate, clodronate could affect the NO
secretion when given to the cells simultaneously with lipopolysacchari
de, and the inhibitory action was still seen when the drug was added 2
h after lipopolysaccharide induction. The viability of the cells was
not affected by free or liposomal clodronate, whereas pamidronate show
ed considerable cytotoxicity. This study shows the different actions o
f these three bisphosphonates on NO production by macrophages and sugg
ests that liposomal clodronate is the most promising bisphosphonate as
an anti-inflammatory agent, whereas aminobisphosphonates do not posse
ss anti-inflammatory properties.