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.

Malnutrition, zinc supplementation and catch-up growth: changes in insulin-like growth factor I, its binding proteins, bone formation and collagen turnover.

OBJECTIVE: Zinc may be a limiting factor in restricting catch-up growth in severely malnourished children. This study had two aims: (i) to examine the effect of different zinc supplementation regimens on IGF-I, its binding proteins and on markers of bone and collagen turnover in severely malnourished children and (ii) to investigate mechanisms underlying catch-up growth by examining changes in these markers during nutritional rehabilitation, their inter-relationships and their relationships with ponderal and linear growth. DESIGN: Double-blind randomized intervention study of three regimens of oral zinc supplementation. PATIENTS: One hundred and forty-one children, aged 6-36 months, mean (SD) age 15.4 (8.7) months, with day 1 weight-for-height SD score (whz) -2.6 (0.93) and height-for-age SD score (haz) -3.79 (1.29). MEASUREMENTS: Weight, height, lower leg length (by knemometry) at 15-day intervals from day 1 to day 90 of nutritional rehabilitation. Blood collection on days 1, 15 and 30 for IGF-I, IGFBP3, IGFBP2, bone alkaline phosphatase (BAP, osteoblast marker), procollagen type I C-terminal propeptide (PICP, marker of type I collagen synthesis), procollagen type III N-terminal propeptide (P3NP, marker of soft tissue type III collagen synthesis) and type I collagen telopeptide (ICTP, marker of type I collagen breakdown). RESULTS: There was early rapid weight gain during refeeding, whereas height gain occurred later in the trial. IGF-I, IGFBP3, BAP, PICP and P3NP were low or very low on day 1 compared to well-nourished age-matched European children, and all increased within 15 days (P < 0.001), with PICP and P3NP reaching levels higher than European norms. IGFBP2 and ICTP were high on day 1 and decreased over the same period (P < 0.001). There were no differences in anthropometric outcome or marker responses among zinc regimens. Day 1 whz was correlated with BAP, PICP and P3NP (P < 0.001). Changes in IGF-I, IGFBP3, BAP, PICP and P3NP over 30 days correlated with ponderal growth (whz change) over the same period (all P < 0.01). However, changes in these markers over 30 days correlated better with lower leg growth (all P < 0.01) and linear growth (haz change, P < 0.01 for PICP and P3NP, P < 0.05 for IGFBP3) measured over 90 compared with 30 days. At most time points, there were strong positive correlations (i) among IGF-I, IGFBP3, BAP, PICP and P3NP (P < 0.01) and (ii) between IGFBP2 and ICTP (P < 0.01). Conversely, IGFBP2 was negatively correlated with IGF-I, IGFBP3, BAP, PICP and P3NP at most time points (P < 0.01). CONCLUSIONS: We found no difference among zinc regimens in growth, IGF-I and its binding proteins or markers of bone and collagen turnover. Severe malnutrition was associated with low rates of bone and collagen synthesis and high rates of collagen degradation, and nutritional rehabilitation was associated with full or partial 'normalization' of the markers studied. Early weight gain and subsequent linear growth were associated with early increments in IGF-I, IGFBP3 and markers of bone and collagen formation. The study of these markers has provided additional insights into the mechanisms of the effects of malnutrition and refeeding on growth.

Coaction of blue light and light absorbed by phytochrome in control of glutamine synthetase gene expression in Scots pine (Pinus sylvestris L.) seedlings.

The level of plastidic glutamine synthetase (GS; EC 6.3.1.2) in the cotyledonary whorl of the Scots pine (Pinus sylvestris L.) seedling was previously reported to be regulated by light. In the present paper we report on the control by light of the GS transcript level. A full-length GS cDNA clone of Scots pine was isolated (pGS1), sequenced and employed to measure GS transcript levels. Using dichromatic light treatments it was found that the transcript level is regulated by phytochrome. The strong specific effect of blue light is to be attributed to an increase of the responsiveness to phytochrome. Since no direct correlation between the transcript level and the rate of GS protein synthesis was observed, it was concluded that GS gene expression is only coarsely regulated at the level of transcript accumulation. Synthesis of GS protein is by itself light-dependent (light-mediated fine tuning of gene expression). This control at the translational level is also exerted via phytochrome with blue light determining the responsiveness of the process toward phytochrome. If the level of the far-red absorbing form of phytochrome (Pfr) is kept very low, blue light is not capable of bringing about synthesis of GS protein.