Reduction in primary nonfunction of syngeneic islet transplants with nordihydroguaiaretic acid, a lipoxygenase inhibitor

To study the effectiveness of a lipoxygenase inhibitor, nordihydroguaiareti c acid (NDGA), in the reduction of primary nonfunction, an insufficient num ber of syngeneic islets were transplanted underneath the renal capsule with NDGA administered daily for 4 weeks. After transplantation of the 150 isle ts, the decrement of blood glucose levels was significantly faster in the m ice that had received NDGA than in the mice that had received no drug at al l or dimethyl sulfoxide (DMSO) (p < 0.005, p < 0.05). The mean duration of temporary posttransplant hyperglycemia was 22.3 +/- 3.2 (n = 10), 35.9 +/- 2.3 (n = 14), and 33.7 +/- 4.1 (n = 6) days fur the respective groups. The diabetic mice that received 300 islets had their blood glucose levels decre ase faster than those that received 150 islets (19.7 +/- 1.6 vs. 35.9 +/- 2 .3 days, n = 14, p < 0.0001). There was no significant difference in the bl ood glucose reducing effect between the mice that received 150 islets with NDGA and the mice that received 300 islets [22.3 +/- 3.2 (n = 10) vs. 19.7 +/- 1.6 (n = 14) days, p > 0.05]. The insulin content of the graft from the mice treated with 150 islets and NDGA (3.02 +/- 0.24 mug, ii = 4) was high er than that from the mice that received 150 islets but no treatment (1.10 +/- 0.26 mug; n = 15, p < 0.005) or that had been treated with DMSO (1.21 /- 0.30 mug, n = 4, p < 0.05). The insulin content of the pancreas remnant had no significant differences among the three groups. The net glucose-stim ulated insulin secretion was 0.82 +/- 0.14 vs. 0.20 +/- 0.10 mu IU/islet x 60 min n = 8, p < 0.005) and 0.59 +/- 0.08 vs. 0.04 +/- 0.02 mu IU/islet x 60 min (n = 8, p < 0.0001) for islets cultured without NDGA vs, with NDGA a t 1 and 2 weeks, respectively. However, the insulin content of the cultured islets was similar between the two groups fur up to 2 weeks of incubation (at 1 week: 0.71 +/- 0.01 vs. 0.67 +/- 0.04 ng/islet, n = 8, p > 0.05; at 2 weeks: 0.71 +/- 0.02 vs. 0.80 +/- 0.07 ng/islet, it = 8, p > 0.05). Serum leukotriene B4 (LTB4) concentrations before and between the fifth and seven th days after transplantation were determined. For diabetic mice that recei ved 150 islets, serum LTB4 levels were 25,835 +/- 3,335 and 27,631 +/- 3,13 6 pg/ml (n = 4, p > 0.05). For diabetic mice that received 150 islets and N DGA, the corresponding figures were 22,301 +/- 2,706 pg/ml and 27,530 +/- 2 ,190 pg/ml (n = 8, p > 0.05). The graft histology revealed viable islet cel ls and networks of close vascular structures around the islets and did not reveal microscopic differences among the samples of all four groups. In con clusion, our data revealed that daily administration of NDGA for 4 weeks en hanced isoislet engraftment and preserved three times more mass of the isle t beta cells in the isografts. This result indicates that NDGA reduces prim ary nonfunction of islet syngeneic grafts in diabetic mice.