Treatment with Actovegin® improves sensory nerve function and pathology in streptozotocin-diabetic rats via mechanisms involving inhibition of PARP activation.

BACKGROUND: Diabetic neuropathy is one of the most severe complications of diabetes, affecting approximately one-third of diabetic patients. We investigated the potential neuroprotective effect of Actovegin®, a deproteinized hemoderivative of calf blood, in an animal model of diabetic neuropathy. METHODS: A single intravenous injection of streptozotocin (STZ, 55 mg/kg) was used to induce experimental diabetes in male Sprague-Dawley rats. Actovegin® (200 or 600 mg/kg) was administered intraperitoneally from day 11 to day 40 post-STZ exposure. N-acetylcysteine (NAC) was used as a positive control and was added to drinking water (0.2 g/l) from day 2 until day 40. Measurements to assess efficacy included sensory nerve conduction velocity (SNCV), intraepidermal nerve fiber density (IENFD), and poly(ADP-ribose) content. RESULTS: A decrease (35%) in sensory nerve conduction velocity (SNCV) was seen in STZ-induced diabetic rats from day 10 post-STZ administration and persisted at days 25 and 39. At study completion (day 41), a decrease (32%) in intraepidermal nerve fiber density (IENFD) was found in hind-paw skin biopsies from STZ-rats. Reduced SNCV and IENFD were significantly ameliorated by both doses of Actovegin®. More-over, 600 mg/kg Actovegin® markedly decreased poly(ADP-ribose) polymerase (PARP) activity in sciatic nerves from STZ-diabetic rats as assessed by poly(ADP-ribose) content. CONCLUSION: Actovegin® improved several para-meters of experimental diabetic neuropathy via mechanisms involving suppression of PARP activation, providing a rationale for treatment of this disease in humans.

Non-Poisson distribution in time of small- and large-mode miniature end-plate potentials.

Minature end-plate potentials (MEPP's) were recorded from frog (Rana pipiens) sartorius muscle cells of 60--80 mum diam; MEPP frequency remained constant up to 3 h and was 100 times greater in 80-mum cells than in 6-mum cells. Rapid cooling or heating of preparations initiated or accentuated bursts of MEPP's. Records from cells under control conditions and from cells where the MEPP population had been reduced to the small mode showed many instances of small clusters of MEPP's occurring within 100-ms intervals, indicating quantal release interdependencies. Some small cells initially generated many large MEPP's 2 or more times the average amplitude and fewer small clusters. Analysis of the occurrence of both large- and small-mode MEPP's for both 1.0-s and 100-ms nonoverlapping bins demonstrated a highly significant deviation from a Poisson distribution with significance increasing with decreasing cell diameter and/or MEPP frequency. It is suggested that doublet MEPP's are generated from one release site and that large bursts results from the activity of several release sites, since the size of bursts decreases with cell diameter (junctional area). It is concluded that release characteristics are the same for large-mode (classical) and small-mode MEPP's and that the occurrence of MEPP's is not Poisson.