iloprost and Diabetic-Neuropathies

We have investigated the relationship between cyclic nucleotides and nerve function in the sciatic nerve of rats made diabetic with streptozotocin. Cyclic AMP (cAMP) content in the sciatic nerves of diabetic rats was significantly (P < 0.05) lower than in those of normal rats, while cyclic GMP content did not differ between the two groups. Administration of the stable prostacyclin analogue iloprost or dibutyryl cyclic AMP (dbcAMP) significantly (P < 0.05) restored the cAMP content in the sciatic nerves and motor nerve conduction velocity, which reflects nerve function. There was a positive correlation between cAMP content in the sciatic nerves and motor nerve conduction velocity in both normal and diabetic rats. Endoneurial preparations of sciatic nerves obtained from normal rats were incubated in Krebs-Ringer bicarbonate buffer containing D-glucose (30 or 5.5 mmol/l). Cyclic AMP accumulation was significantly (P < 0.05) suppressed in the buffer containing 30 mmol D-glucose/l compared with that containing 5.5 mmol/l. Iloprost (P < 0.05) and dbcAMP (P < 0.01) increased cAMP accumulations in the tissues incubated in buffer containing both 5.5 and 30 mmol D-glucose/l. When non-metabolizing hexoses, such as L-glucose or 3-O-methylglucose instead of D-glucose were used, cAMP accumulations at 30 mmol hexose/l were not significantly different from those at 5.5 mmol/l. Cyclic AMP phosphodiesterase activity in the sciatic nerves of diabetic rats did not change compared with that in nerves from normal rats. Although not significant, mean ATP content in the sciatic nerves of diabetic rats was about 30% lower than that in nerves of normal rats.(ABSTRACT TRUNCATED AT 250 WORDS)

Topics: Adenylyl Cyclases; Animals; Bucladesine; Colforsin; Culture Techniques; Cyclic AMP; Diabetes Mellitus, Experimental; Diabetic Neuropathies; Glucose; Iloprost; Male; Motor Neurons; Neural Conduction; Rats; Rats, Wistar; Sciatic Nerve

The effects of the prostacyclin analogue iloprost on nerve function were examined in streptozotocin-diabetic rats. Rats were treated either with iloprost from induction of diabetes over 2 months in a preventive experiment, or for 1 month following a 1 month untreated period of diabetes in a reversal experiment. One and 2 months untreated diabetic control, non-diabetic control, and iloprost-treated non-diabetic groups were also used. Diabetes of 1 month duration caused a 21% (P < 0.001) reduction in sciatic motor conduction velocity and a 14% (P < 0.001) deficit in saphenous sensory conduction. This was not significantly changed over a subsequent month without treatment. Diabetic rats given iloprost treatment in both preventive and reversal studies had motor and sensory conduction velocities not significantly different from those of non-diabetic controls, but greater than for untreated diabetes (P < 0.01). Iloprost treatment did not have a significant effect on nerve conduction in non-diabetic rats. The time taken for sciatic nerve compound action potential amplitude to be reduced by 80% under hypoxic conditions in vitro was progressively elevated by 19% and 57% after 1 and 2 months diabetes respectively. Iloprost treatment significantly attenuated this for both preventive (47%, P < 0.001) and reversal (50%, P < 0.001) studies. There was no effect on hypoxic resistance for non-diabetic rats. In the preventive group there was a 28% increase in sciatic nerve endoneurial capillary density (P < 0.001), a lesser effect (16%, P < 0.05) in the reversal group, and no effect in non-diabetic rats.(ABSTRACT TRUNCATED AT 250 WORDS)

Topics: Action Potentials; Animals; Diabetes Mellitus, Experimental; Diabetic Neuropathies; Iloprost; Male; Motor Neurons; Neural Conduction; Neurons, Afferent; Oxygen Consumption; Rats; Rats, Sprague-Dawley; Sciatic Nerve; Streptozocin

PGE1 has been found to improve the symptoms of diabetic neuropathy. We considered that a PGI2 derivative may also have a similar action and therefore studied its effect in diabetic rats. Iloprost was administered intraperitoneally to streptozotocin-induced diabetic rats at a dose of 10 micrograms/kg/day for a month. The changes in nerve conduction velocity (NCV) were measured in the tail. One day after the last dose of iloprost, both sciatic nerves were removed from each rat, homogenized, and extracted with 6% TCA. The sorbitol and myo-inositol concentrations were determined by a combination of HPLC and an enzymatic method. Cyclic AMP (cAMP) levels were determined by RIA, and Na+, K+ ATPase activity was assessed by the enzyme cycling method of Greene and Lattimer. Iloprost was found to improve the NCV in the diabetic rats. The sorbitol content was not affected by iloprost, but the myo-inositol content was higher in the iloprost group than in the untreated group, although the difference was not statistically significant. The Na+, K+ ATPase activity and cAMP content were significantly higher in the iloprost group than in the untreated group. These findings suggest the possibility that the cAMP-dependent protein kinase (A-kinase) system has an important influence on improvement in Na+, K+ ATPase activity.

Topics: Animals; Blood Glucose; Body Weight; Cyclic AMP; Diabetes Mellitus, Experimental; Diabetic Neuropathies; Iloprost; Inositol; Male; Neural Conduction; Protein Kinases; Rats; Rats, Wistar; Sciatic Nerve; Sodium-Potassium-Exchanging ATPase; Sorbitol

The effects of a stable prostacyclin analog, Iloprost, and aldose reductase inhibitors (ONO-2235 and isoliquiritigenin) were studied to elucidate the role of cAMP in diabetic neuropathy in relation to polyol metabolism. In in vivo experiments, the cAMP and myoinositol contents in sciatic nerves and motor nerve conduction velocity were significantly reduced in diabetic rats. Iloprost significantly restored the reduced cAMP content in sciatic nerves and improved motor nerve conduction velocity in diabetic rats. However, the contents of sorbitol or myoinositol in sciatic nerves were not affected by Iloprost in diabetic rats. On the other hand, aldose reductase inhibitors significantly reduced the sorbitol content and increased the cAMP and myoinositol contents in the sciatic nerves of diabetic rats. The motor nerve conduction velocity was also slightly but significantly improved by treatment with aldose reductase inhibitors. There was a negative correlation between cAMP and sorbitol in the sciatic nerves of diabetic rats treated with aldose reductase inhibitors and a positive correlation between cAMP and motor nerve conduction velocity. In in vitro experiments, Iloprost significantly increased cAMP, but did not affect the sorbitol content in sciatic nerves. Aldose reductase inhibitors inhibited sorbitol accumulation and increased cAMP in sciatic nerves. Our data suggest that polyol pathway activation somehow results in cAMP reduction in sciatic nerves and that the reduction of cAMP in peripheral nerves may be closely related to the pathogenesis of diabetic neuropathy.

Topics: Aldehyde Reductase; Animals; Blood Glucose; Chalcone; Chalcones; Cyclic AMP; Cyclic GMP; Diabetes Mellitus, Experimental; Diabetic Neuropathies; Iloprost; Inositol; Male; Neural Conduction; Rats; Rats, Inbred WKY; Rhodanine; Sciatic Nerve; Sorbitol; Thiazolidines

Iloprost, a stable prostacyclin analog, was evaluated clinically for its ability to ameliorate the symptoms of peripheral neuropathy associated with diabetes. In an open, nonrandomized trial, 13 diabetic patients with neuropathy but without proliferative retinopathy received an intravenous infusion of Iloprost at a dose of 10 micrograms, at a rate of 0.1 micrograms/kg/h, twice daily for two weeks. The administration of Iloprost relieved the majority of such subjective symptoms as pain, numbness or sensation of cold and to a lesser extent, such autonomic symptoms as dizziness. In contrast, there was little evidence of objective improvement, e.g., in motor nerve conduction velocity. Iloprost treatment significantly inhibited the platelet aggregation rate stimulated by collagen in vitro. In the one patient tested, thermography revealed an increase in skin temperature by more than 2 degrees C. Side effects associated with Iloprost included headache (3 patients) or aggravation of pain in the extremities (2 patients) and could be ameliorated by slowing the infusion rate or by discontinuing the drug (one patient). Iloprost appears to be safe and effective for relieving the symptoms of diabetic neuropathy. Our results provide the rationale for a double-blind, clinical trial in larger populations of diabetics with peripheral neuropathy.

Topics: Aged; Diabetic Neuropathies; Female; Humans; Iloprost; Infusions, Intravenous; Male; Middle Aged; Platelet Aggregation