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OBJECTIVES: The impairment of cognitive functions in diabetes mellitus (DM) is well known. Nitric oxide (NO)-guanyly cyclase (GC)-cyclic guanosine monophosphate (cGMP) pathway is an important role in cognitive functions, and, consequently, phosphodiesterase-5 (PDE-5) inhibitors as well as NO-GC activators are of considerable interest in the treatment of cognitive deficits. Therefore, we aimed to investigate the effects of YC-1 (3-5-hydroxymethyl-2-furyl)-1-benzyl-indazole), an NO-GC activator, and zaprinast, a PDE-5 inhibitor, on cognitive dysfunction in streptozotocin (STZ)-induced diabetic rats. METHODS: Male Wistar rats were divided into five groups (nine rats in each): Control, Vehicle (DMSO), Diabetic (50 mg/kg/i.p. streptozotocin), Diabetic-YC-1 (1 mg/kg/day/i.p., for 4 weeks), and Diabetic-Zaprinast (10 mg/kg/day/i.p., for 4 weeks) group. The Morris water maze, passive avoidance, locomotor activity, and foot shock sensitivity tests were applied to assess the effect of YC-1 and zaprinast on learning and memory. To explore the mechanisms of YC-1 and zaprinast on learning and memory performance, protein expressions of brain-derived neurotrophic factor (BDNF) in hippocampus were examined immunohistochemically. RESULTS: Thirty days after the induction of DM, rats exhibited severe learning and memory dysfunctions associated with decreased BDNF expression. Both chronic YC-1 and zaprinast treatment improved cognitive performance and hippocampal BDNF expression in diabetic rats. In the locomotor activity and foot shock sensitivity test, no significant differences were observed between the groups. Furthermore, hyperglycaemia did not affect cognition enhancement effects of YC-1 or zaprinast in diabetic rats. CONCLUSIONS: Our findings highlight the beneficial effects of nitric oxide-guanylyl cyclase activators and PDE-5 inhibitors to improve cognitive function in diabetes.

Diabetes is one of the risk factors for the development of vascular dementia (VD), leading to endothelial dysfunction and cognitive impairment. Resveratrol has been shown to have antioxidant, antiinflammatory, and neuroprotective effects. The previous studies have also reported that resveratrol improves cognitive and vascular endothelial functions in several pathological conditions. In the present study we aimed to evaluate the effect of resveratrol on cognitive and vascular endothelial function and to explore the mechanisms of its effects in the streptozotocin-induced diabetic rat model of VD. Male Wistar rats were divided into 3 groups (n = 10 in each group): Control, diabetes (DM), DM + resveratrol (DM + RSV) groups. Rats from the DM + RSV group received resveratrol (20 mg/kg/day, ip) for 4 weeks after induction of diabetes and then cognitive functions of the rats were tested by the Morris water maze and a passive avoidance tests. After behavioral tests, endothelial function of thoracic aorta (the endothelium-dependent and -independent vasorelaxant responses) was investigated. To explore the mechanisms of resveratrol, endothelial eNOS, aortic superoxide dismutase (SOD), NADPH oxidase, heme oxygenase-1 (HO-1) levels, TNF-α and IL-1β expressions; serum SOD and NADPH oxidase levels and, hippocampal BDNF, TNF-α and IL-1β expressions were measured. It was shown that DM resulted in severe learning and memory deficits associated with endothelial dysfunction, increased expression of TNF-α and IL-1β, increased oxidative stress levels and decreased expression of eNOS and BDNF. In contrast, resveratrol treatment improved the cognitive decline. It was also found that chronic treatment with resveratrol ameliorated the impaired vascular reactivity. Reveratrol significantly reversed diabetes-induced changes of protein expression. Our data suggest that resveratrol prevents memory deficits, endothelial dysfunction, increased oxidative stress, inflammation and impairment of neurotrophin expression in a VD rat model. Thus, the vasculoprotective and neuroprotective effects of resveratrol may be beneficial in DM patients.

Type 1 diabetes is clinically characterized as the loss of control of glucose homeostasis due to the reduced number of insulinproducing cells. Long-term glycemic control after implantation could be maintained by preserving the cell viability and tissue-specific functions during the process of microencapsulation. In this study, alginate solution was supplemented with platelet-rich plasma (PRP) to improve the viability and preserve the cell functions during the encapsulation of a beta cell line (BRIN-BD11). Cell viability was assessed and insulin secretion and insulin stimulation index were evaluated. eTh polymerization of alginate with PRP enhanced the viability up to 61% in the alginate microbeads. PRP supplementation to the alginate composition not only increased the number of viable cells by 1.95-fold, but the insulin secretion also improved by about 66%. eTh stimulation index, however, was not affected by the PRP supplementation.

Ischemia/reperfusion (I/R) injury represents a source of substantial morbidity and mortality in various statuses that is, coronary bypass, myocardial infarction, and so on. Oxygen free radicals, formed during I/R, have been proposed as one of the main causes of tissue injury and play important role in I/R injury. Leucocytes have been shown to play an important role in the development of tissue injury after I/R. Accordingly, numerous studies have shown that even short-time I/R-induced DNA damage can be investigated in human peripheral leucocytes using the alkaline single-cell gel-electrophoresis assay (comet assay). After ischaemia, the genotoxic damage detected in human peripheral leucocytes locally in the reperfused tissue results in numerical, morphologic and biochemical alterations of all circulating white blood cells in the human organism. It leads particularly to the release of substantial amounts of oxygen radicals and other reactive agents. Simultaneously, local ischaemia in the reperfused tissue is extended to the whole body systemically through these activated inflammatory cells and, possibly, results in secondary detectable tissue damage in endothelial cells of the systemic circulation inducing prolonged DNA damage even in the early reperfusion period. Thus, we aimed to investigate whether the I/R during the routinely practised operation causes DNA damage, since other published studies were on animal and in vitro models and did not exactly reflect the operation procedure in the clinic. We measured DNA damage (single-strand breaks, oxidised purines and pyrimidines) by modified alkaline comet assay using two bacterial enzymes (formamidopyrimidine glycosylase (Fpg), endonuclease III (EndoIII)), which recognise oxidised purines and pyrimidine bases, in patients who had lower extremity surgery. There was no statistically significant difference in DNA damage between time periods (before surgery, after I/R; T1, T2 and T3). According to our findings, we indicate that at the molecular level DNA is damaged due to the I/R during the routinely practised operation; however, this effect could not be determined phenotypically. Thus, we may suggest that the surgeons and anaesthetist/operation room personnel could be informed about that fact and encouraged to use antioxidants and/or apply prophylaxis. Our findings showed that I/R injury did not induce DNA damage. Further studies of this approach are needed. Crown Copyright (C) 2010 Published by Elsevier Ltd. All rights reserved.