Triptan Drugs, Natural Killer Cell Cytotoxicity, and Neutrophils Pro‐Matrix Metalloproteinase‐9 Secretion

Abstract

To study the effect of various triptan-like drugs, eg, avitriptan, naratriptan, and sumatriptan, as well as the benzopyran alnitidan, on the natural killer cell (NKC) activity of peripheral blood mononuclear cell (PBMC) samples and highly purified NKC (HPNKC) preparations. We also examined the possible role of these agents as immunomodulators by studying their effect upon the in vitro secretion of pro-matrix metalloproteinase-9 (pMMP-9) from whole blood and purified neutrophils samples. The pharmacological profile of a large number of triptan-like compounds has been extensively studied. However, relatively little is known of their interactions with cellular components of the immune system. Blood was obtained from nonsmoking, drug-free healthy individuals from the Blood Bank of the University of Chile main Clinical Hospital (J.J.A.). PBMC were separated by centrifugation and HPNKC acquired by an immunomagnetic isolation procedure. NKC cytotoxicity was assayed using (51)Cr-labeled K-562 cells as target. Addition of drugs and of effector cells (30 : 1, 50 : 1, and 70 : 1 ratio for PBMCs, and 5 : 1 for HPNKCs) was followed by incubation. Paired Student's t-test (2-tailed) was used to determine the significance of the specific (51)Cr release in controls vs drug-treated samples. Aliquots of whole blood or purified neutrophils were added test drug, incubated, centrifuged, and the supernatant analyzed by gelatine zymography. Gelatinolytic activity was visualized, and a digested zone at MW 92 kD indicated presence of pMMP-9. Area of proteolysis was estimated by densitometry; prestained standards were used to assess pMMP-9 molecular weight. Peripheral blood mononuclear cell's NKC cytotoxicity was consistently decreased after incubation with each and every one of the drugs tested. This result, observed for the 3 effector : target (E : T) cell ratios used, was relatively similar among the various compounds studied, and reached statistical significance only at E : T 70 : 1. Similar drug treatment failed, however, to produce significant changes in the cytotoxicity of HPNKC preparations, suggesting that modulation of the PBMC's NKC activity and that of HPNKC samples require different kinds of cell's derived signal. Incubation with either of the drugs tested failed to significantly alter (basal) nonstimulated pMPP-9 secretion by whole blood samples. However, basal pMMP-9 secretion by purified neutrophil preparations was significantly inhibited by alnitidan and sumatriptan, and not affected by naratriptan. Various drugs with a triptan-like chemical structure interact with cellular components of the innate immune system, resulting in an apparent indirect inhibition of NKC activity and direct inhibition of neutrophils pMMP-9 secretion. These results suggest that they may play a positive role in decreasing the severity of inflammatory processes. Whether this effect is part of triptans antimigraine mechanism of action, or just an added beneficial effect of their use for the reversal treatment of migraine headaches remains to be explored.