EUK 207

The brain could be exposed to irradiation as part of a nuclear accident, radiological terrorism (dirty bomb scenario) or a medical radiological procedure. In the context of accidents or terrorism, there is considerable interest in compounds that can mitigate radiation-induced injury when treatment is initiated a day or more after the radiation exposure. As it will be challenging to determine the radiation exposure an individual has received within a relatively short time frame, it is also critical that the mitigating agent does not negatively affect individuals, including emergency workers, who might be treated, but who were not exposed. Alterations in hippocampus-dependent cognition often characterize radiation-induced cognitive injury. The catalytic ROS scavenger EUK-207 is a member of the class of metal-containing salen manganese (Mn) complexes that suppress oxidative stress, including in the mitochondria, and have been shown to mitigate radiation dermatitis, promote wound healing in irradiated skin, and mitigate vascular injuries in irradiated lungs. As the effects of EUK-207 against radiation injury in the brain are not known, we assessed the effects of EUK-207 on sham-irradiated animals and the ability of EUK-207 to mitigate radiation-induced cognitive injury. The day following irradiation or sham-irradiation, the mice started to receive EUK-207 and were cognitively tested 3 months following exposure. Mice irradiated at a dose of 15Gy showed cognitive impairments in the water maze probe trial. EUK-207 mitigated these impairments while not affecting cognitive performance of sham-irradiated mice in the water maze probe trial. Thus, EUK-207 has attractive properties and should be considered an ideal candidate to mitigate radiation-induced cognitive injury.

Association between amyloid-β (Aβ) toxicity, mitochondrial dysfunction, oxidative stress and neuronal damage has been demonstrated in the pathophysiology of Alzheimer's disease (AD). In the early stages of the disease, the defect in energy metabolism was found to be severe. This may probably due to the Aβ and ROS-induced declined activity of complexes in electron transport chain (ETC) as well as damages to mitochondrial DNA. Though clinically inconclusive, supplementation with antioxidants is reported to be beneficial especially in the early stages of the disease. A mild to moderate improvement in dementia is possible with therapy using antioxidants viz coenzyme Q10 (ubiquinone), α -lipoic acid, selenium, omega-3 fatty acids and vitamin E, emphasize their possible role as an adjuvant with the existing conventional treatment. Since mitochondrial dysfunction has been observed, a new therapeutic strategy called as 'Mitochondrial Medicine' which is aimed to maintain the energy production as well as to ameliorate the enhanced apoptosis of nerve cells, has been developed. Mitochondrial CoQ10, Szeto-Schiller peptide-31 and superoxide dismutase/ catalase mimetic, EUK-207 were the mitochondrial targeted agents demonstrated in experimental studies. This article discusses the mitochondrial impairment and the possible mitochondria targeted therapeutic intervention in AD.