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Institute for Advanced Simulation (IAS)

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Seminar by Prof. Peter Wipf

University of Pittsburgh, Pittsburgh (USA)

08 Oct 2015 11:00
08 Oct 2015 12:00
Lecture room 2009, Jülich GRS building (16.15)

Mitochondria are crucial suppliers of ATP, providing the cell with energy. They also are the source of many carbohydrate, protein, and lipid building blocks and secondary messengers. Upon aging, cellular stress, genetic damage, or by radiation or reperfusion injury, damaged brain mitochondria produce bursts of oxygen radicals that can directly attack vital lipid, protein and DNA constituents. Mitochondria are also at the convergence of critical cell death pathways and are powerful mediators of inflammation.
Central to these potentially pathologic mechanisms is the supraphysiologic generation of reactive oxygen species (ROS), which overwhelms the natural balance within cells maintained by superoxide dismutase, catalase, and glutathione. While some ROS initiate the activation of host defenses, triggering stem cell renewal, differentiation and proliferation, immune response and glucose signaling, sustained high levels of ROS can cause irreversible intracellular damage.
Accumulation of damaged cellular components can contribute to neurodegeneration and to aging, in particular by accumulation of ROS-triggered DNA damage and neuronal death. Oxidation of the mitochondria-specific cardiolipin has a pivotal role in the execution of the cell death program. XJB-5-131 is a bifunctional preclinical drug candidate that prevents cardiolipin oxidation. It is comprised of an electron and ROS scavenger covalently linked to a mitochondrial targeting moiety. We and others have suggested that the failure of dietary antioxidants in clinical trials is due their inability to scavenge ROS at the site of production. XJB-5-131’s efficacy is due to its localization to these membranes, the primary site of ROS generation. This preclinical agent has shown therapeutic potential in several rodent models where it was found to offset brain degenerative processes, including traumatic brain injury and age-related cardial dysfunction.
Most relevant to the lecture topic, XJB-5-131 delivers superb outcome in a 26-month HdhQ150 mouse model of Huntington’s Disease (HD) and a PND17 rat model of cardiac arrest (CA) induced ischemia-reperfusion.