Insulin-sensitizing antihyperglycaemic medications are associated with better outcome in patients with diabetes undergoing cardiac stress testing.

BACKGROUND: There are several treatment modalities available for diabetes; however, the effects of the different medications on coronary artery disease are less understood. The purpose of this study was to evaluate the correlation of insulin-sensitizing therapy with the outcome of stress myocardial perfusion testing and to compare it with conventional therapy. METHODS: Of 417 patients referred to stress testing for evaluation of chest pain, 222 were identified as being treated with conventional therapy only (insulin and insulin secretagogues) and 195 as being treated with insulin sensitizers (metformin and thiazolidinediones (TZD)). Multivariate logistic regression models were used to correct for confounding factors and to determine the independent relation between treatment type and stress-test outcome. RESULTS: Ischaemia, infarction and the composite outcome were less frequent in the insulin-sensitizer group than in the conventional therapy group (odds ratio (OR) = 0.39, P = 0.025; OR = 0.32, P = 0.021 and OR = 0.38, P = 0.009, respectively). The subgroup analysis showed that treatment with metformin (n = 125) compared with conventional therapy was associated with less infarction or the composite outcome of ischaemia and/or ischaemia (OR = 0.18 (95% confidence interval (CI): 0.05-0.66), P = 0.010; OR = 0.34 (95%CI: 0.15-0.80), P = 0.014, respectively). Treatment with TZD (n = 43) was associated with a trend to less frequent ischaemia (OR = 0.18 (95%CI: 0.03-1.01), P = 0.051). CONCLUSION: The addition of insulin-sensitizing medications to the conventional diabetes therapy or their sole use was associated with decreased coronary artery disease or its severity in patients with diabetes as determined by stress myocardial perfusion study. Randomized prospective trials will be necessary to prove this benefit.

Differential mechanisms of neuroprotection by 17 beta-estradiol in apoptotic versus necrotic neurodegeneration.

The major goal of this study was to compare mechanisms of the neuroprotective potential of 17 beta-estradiol in two models for oxidative stress-independent apoptotic neuronal cell death with that in necrotic neuronal cell death in primary neuronal cultures derived from rat hippocampus, septum, or cortex. Neuronal apoptosis was induced either by staurosporine or ethylcholine aziridinium (AF64A), as models for necrotic cell death glutamate exposure or oxygen-glucose deprivation (OGD) were applied. Long-term (20 hr) pretreatment (0.1 microm 17 beta-estradiol) was neuroprotective in apoptotic neuronal cell death induced by AF64A (40 microm) only in hippocampal and septal neuronal cultures and not in cortical cultures. The neuroprotective effect was blocked by the estrogen antagonists ICI 182,780 and tamoxifen and the phosphatidylinositol 3-kinase (PI3-K) inhibitor LY294002. In glutamate and OGD-induced neuronal damage, long-term pretreatment was not effective. In contrast, short-term (1 hr) pretreatment with 17 beta-estradiol in the dose range of 0.5-1.0 microm significantly reduced the release of lactate dehydrogenase and improved morphology of cortical cultures exposed to glutamate or OGD but was not effective in the AF64A model. Staurosporine-induced apoptosis was not prevented by either long- or short-term pretreatment. The strong expression of the estrogen receptor-alpha and the modulation of Bcl proteins by 17 beta-estradiol in hippocampal and septal but not in cortical cultures indicates that the prevention of apoptotic, but not of necrotic, neuronal cell death by 17 beta-estradiol possibly depends on the induction of Bcl proteins and the density of estrogen receptor-alpha.

Temporary changes of the AP-1 transcription factor binding activity in the gerbil hippocampus after transient global ischemia, and ischemic tolerance induction.

Global forebrain ischemia of 5-min duration results in delayed neuronal death (DND) of CA1 neurons in the gerbil hippocampus. DND can be prevented by a preconditioning sublethal ischemic stimulus (2. 5 min), a phenomenon, known as ischemic tolerance induction. Striking evidence exists for the involvement of regulatory transcription factors encoded by immediate early genes (IEGs) in the fate of CA1 neurons. Here, we investigated by electrophoretic mobility shift assay (EMSA) the postischemic changes of the DNA binding activity of the Activator Protein-1 (AP-1) transcription factor complex after preconditioning, lethal ischemia, and after acquisition of an ischemic tolerant state. A short duration peak of AP-1 binding activity at 3 h of reperfusion was a hallmark of ischemic tolerance induction. The kinetics of this activation profile, i.e. the rapid linear increase between 1 and 3 h and a similar rapid decline at 6 or 12 h of reperfusion are prominent within the CA1 and CA3 region of all ischemic groups which are designated for neuronal survival. No changes in the c-Jun and ATF-2 immunoreactivity were observed in the CA1 region, however an increase in only c-Jun immunoreactivity occurred in concordance with the elevation of AP-1 binding in the CA3 region. The results clearly demonstrate a differential regulation of AP-1 binding activity in CA1 during and after acquisition of an ischemic tolerant state in contrast to ischemia leading to neuronal death. The early peak at 3 h of reperfusion in AP-1 binding affinity observed in the single 2.5 min and the ischemic tolerant groups suggests a protective role of early AP-1 activation, whereas failure of this initial activation may contribute to DND. Our data furthermore suggest, that elevation of the AP-1 binding activity in the CA1 and CA3 regions underlies a different regulatory mechanism in the gerbil hippocampus after ischemic stress.

Hyperbaric oxygenation induced tolerance against focal cerebral ischemia in mice is strain dependent.

SV129 or C57BL/6 mice were exposed to hyperbaric oxygenation (HBO, 5 days, 1 h every day, 100% O(2) at 3 atm absolute). One day after the 5th HBO session focal cerebral ischemia was induced. In SV129 mice, HBO induced tolerance against permanent focal cerebral ischemia (n=42, mean infarct volume reduction 27%, P=0.001), but not against transient (30 or 60 min) focal cerebral ischemia. In the C57BL/6 strain of mice, HBO did not induce tolerance against focal cerebral ischemia, even when the duration of ischemia or the HBO protocol were modified. For the first time we demonstrate that HBO can induce tolerance to focal cerebral ischemia, but this effect is strain dependent.

Ischemic tolerance in the brain.

Endogenous tolerance to cerebral ischemia is nature's strategy for neuroprotection. Exploring the physiologic and molecular mechanism of this phenomenon may give us new means of protection against ischemia and other degenerative disorders. This article reviews the currently available experimental methods to induce ischemic tolerance in the brain and gives a brief summary of the potential mode of action.