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Developing new therapies for stroke is urgently needed, as this disease is the leading cause of death and disability worldwide, and the existing treatment is only available for a small subset of patients. The interruption of blood flow to the brain during ischemic stroke launches multiple immune responses, characterized by infiltration of peripheral immune cells, the activation of brain microglial cells, and the accumulation of immune mediators. Copper is an essential trace element that is required for many critical processes in the brain. Copper homeostasis is disturbed in chronic neurodegenerative diseases and altered in stroke patients, and targeted copper delivery has been shown to be protective against chronic neurodegeneration. This study was undertaken to assess whether the copper bis(thiosemicarbazone) complex, Cu II (atsm), is beneficial in acute brain injury, in preclinical mouse models of ischemic stroke. We demonstrate that the copper complex Cu II (atsm) protects neurons from excitotoxicity and N2a cells from OGD in vitro, and is protective in permanent and transient ischemia models in mice as measured by functional outcome and lesion size. Copper delivery in the ischemic brains modulates the inflammatory response, specifically affecting the myeloid cells. It reduces CD45 and Iba1 immunoreactivity, and alters the morphology of Iba1 positive cells in the ischemic brain. Cu II (atsm) also protects endogenous microglia against ischemic insult and reduces the proportion of invading monocytes. These results demonstrate that the copper complex Cu II (atsm) is an inflammation-modulating compound with high therapeutic potential in stroke and is a strong candidate for the development of therapies for acute brain injury.

The purpose of this study was to evaluate the effects of exhaustive exercise (marathon run) on different lipid peroxidation measurements, including copper-induced serum lipids and VLDL + LDL oxidation susceptibility, and on plasma total antioxidative capacity (TRAP), muscular damage and plasma antioxidants in healthy moderately trained male (n = 21) and female (n = 25) volunteers. Blood samples were taken before and just after the 42-km run. In women, baseline levels of several antioxidative compounds (serum albumin and uric acid, plasma free thiols and blood glutathione) were lower, resulting in 21.5% lower plasma total antioxidative capacity and 70.3% higher serum oxidation susceptibility, compared to men. To compare effects in men and women, the exercise-induced variable changes were adjusted for their baseline levels. After this adjustment, there were no statistically significant differences between the genders in the extent of muscular damage (serum creatine kinase, (CK)), or in the change in serum lipids or VLDL + LDL oxidation susceptibility, or that of plasma antioxidative capacity. A possible beneficial effect of exercise was that serum HDL cholesterol levels increased significantly in both genders, but especially in women. In the group of pooled genders (n=46), the increases in serum CK and in plasma lactate were 190% (95% CI, 133% to 246%) and 109% (95% CI, 65% to 175%), respectively. On the basis of our lipid peroxidation and TRAP measurements, uric acid was observed to be the most important plasma antioxidant. The effect of exercise was to decrease the oxidation susceptibility of serum lipids by 24.8% (95% CI 13.4% to 36.2%) and to elevate plasma TRAP by 14.6% (95% CI, 11.4% to 17.7%). Nonetheless, the oxidation susceptibility of the VLDL + LDL fraction increased by 11.0% (95% CI, 1.9% to 20.2%). Our results suggest that there are no gender-based differences in exhaustive exercise-induced lipid peroxidation or muscular damage. Secondly, even though exhaustive exercise can increase plasma/serum total resistance towards oxidation, the oxidation resistance of the atherogenic lipoprotein fraction might be diminished. On the basis of these results, several in vitro measurements of lipid peroxidation assessing both water and lipid soluble plasma fractions are needed if a true perspective of the plasma redox status is to be obtained.

To test the effects of combined coenzyme Q10 (Q10) and d-alpha-tocopheryl acetate supplementation on exercise-induced oxidative stress and muscular damage we conducted a double-blind study in 37 moderately trained male marathon runners. These were randomly allocated to receive either an antioxidant cocktail: 90 mg of Q10 and 13.5 mg of d-alpha-tocopheryl acetate daily (18 men) or placebo (19 men) for three weeks before a marathon (42km) run. Just before the run, plasma Q10 was 282% (p < 0.0001) and plasma vitamin E 16% (p < 0.007) higher in the supplemented group, than in the placebo group. Also the proportion of plasma ubiquinol of total Q10, an indication of plasma redox status in vivo, was significantly higher in the supplemented group. Furthermore, the susceptibility of the VLDL + LDL fraction, to copper-induced oxidation, was significantly reduced in the supplemented group, compared to the placebo group. The exercise increased lipid peroxidation significantly in both study groups, as assessed by the elevated proportion LDL of LDL and the increased susceptibility of lipoproteins to copper induced oxidation. However, the supplementation had no effect on lipid peroxidation or on the muscular damage (increase in serum creatine kinase activity or in plasma lactate levels) induced by exhaustive exercise. Plasma ascorbate, Q10, whole blood glutathione and serum uric acid concentrations increased during the exercise, elevating significantly the TRAP value of plasma by 10.3% and the proportion of plasma ubiquinol of total Q10 by 4.9%. These results suggest that even though exercise increases plasma lipid peroxidation, it also elevates the antioxidative capacity of plasma, as assessed by the increased plasma TRAP and the proportion of Q10H2 of total Q10. However, prior supplementation with small doses of Q10 and d-alpha-tocopheryl acetate neither attenuates the oxidation of lipoproteins nor muscular damage induced by exhaustive exercise such as encountered in a marathon run.