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It has been hypothesized that advanced Maillard reaction in vivo could explain some of the age- and diabetes-related changes. Furthermore, involvement of the Maillard reaction with Alzheimer's disease has also been suggested, as advanced glycation end products, such as pyrraline and pentosidine, were demonstrated to localize in lesions of the disease. Although aminoguanidine has been studied extensively and established as an inhibitor of the Maillard reaction, other candidates have not been investigated thoroughly. In the present study, we examined the inhibitory effect of tenilsetam [(+/-)-3-(2-thienyl)-2-piperazinone], an antidementia drug, on the Maillard reaction. Tenilsetam inhibited glucose- and fructose-induced polymerization of lysozyme in a concentration-dependent manner in vitro. Reduced enzymatic digestibility of collagen incubated with 100 mM glucose for 4 weeks was also restored to a control level by coincubation with 100 mM tenilsetam. To determine whether tenilsetam inhibits the Maillard reaction in vivo, streptozotocin-induced diabetic rats were treated with tenilsetam (50 mg/kg x day). Elevated levels of advanced glycation end-product-derived fluorescence and pyrraline in renal cortex and aorta of diabetic rats were suppressed by the administration of tenilsetam for 16 weeks. These inhibitory effects of this agent on advanced glycation in diabetic rats suggested its potential therapeutic role in controlling diabetic complications.

Chronic hyperglycemia has adverse effects on B cell function. We investigated the possible role of advanced glycosylation end products (AGEs) in glucotoxicity. Rat islets were cultured at different glucose concentrations for 1–6 weeks in RPMI 1640. Culture was performed with or without aminoguanidine (AG), which is known to prevent AGE formation in other tissues. AGE-associated fluorescence (370 nm excitation and 440 nm emission) progressively increased during 6 weeks of culture at 38 mm, but not at 11 or 5.5 mm, glucose. The increase in fluorescence was significantly inhibited by AG. The effects of AG on insulin secretion were tested directly after the culture period as well as after a wash-out period of continued culture at 11 mm glucose in the absence of AG. The presence of AG during culture for 1 week at 38 mm glucose failed to affect basal release at 3.3 mm glucose or stimulated release at 27 mm glucose. AG was ineffective whether tested directly after the culture period or after wash-out. When the s...

Nitric Oxide (NO) is now recognized as a mediator of several biological functions. In the present study we examined the effects of NO synthase (NOS) inhibitors on the ovulatory process in vivo, and whether this effect can be reversed by a NO generator. Immature eCG-hCG treated rats were injected intraperitonealy (ip) or unilaterally into the periovarian sac (intrabursal injection; ib) with inhibitors of the inducible form of NOS. Aminoguanidine (AG) suppressed ovulation in a dose-dependent manner, reaching a 54% inhibition at a dose of 20 mg/kg when injected ip (p < 0.001 vs. saline control). Likewise, local ib administration inhibited ovulation from the treated ovary; thus a dose of 2 mg/kg resulted in 48% inhibition, as compared to the contralateral ovary (p < 0.01). Similar results were obtained whether AG was administered 2 h prior to the stimulation of ovulation by hCG or deferred up to 4 h afterwards. An additional NOS inhibitor, NG-methyl-L-arginine (L-NMA) suppressed ovulation, albeit to a lower extent. Intrabursal administration of L-NMA (0.1 and 1 mg/kg) resulted in 34% and 32% inhibition, respectively (p < 0.05 vs. the saline treated control). The same doses of NG-methyl-D-arginine (D-NMA) did not inhibit ovulation significantly compared to the saline treated control. When sodium nitroprusside (0.5 mg/kg), a NO generator, was injected concomitantly with AG, it completely reversed its inhibitory action on ovulation. Thus, we have demonstrated the ability of NOS inhibitors to suppress hCG-induced ovulation in the rat in vivo. The specificity of this effect is confirmed by the ability of a NO generator to reverse the inhibitory action of AG. In conclusion, the ovarian NO/NOS system seems to be necessary for follicle rupture during ovulation.