Research Project
6789196
DESCRIPTION (provided by applicant): Ischemia/hypoxia is a significant contributor to neurodegeneration. Both focal/localized and/or global ischemia can induce considerable neuronal injury. A typical case of focal ischemia is ischemic stroke in which the transport of oxygen and glucose to localized regions of the brain is halted by blockage of an artery rendering focal neurological deficits such as weakness or paralysis. Currently, more than 4 million people in the United States are living with the consequences of stroke. Global ischemia occurs in various conditions, including intracerebral hemorrhage due to hypertension and subarachnoid hemorrhage, and associates with cardiac arrest hypotension, closed head injury, drowning, strangulation, and open-heart surgery. For instance, hypoxia may cause significant cognitive decline following an otherwise normal coronary artery bypass graft (CABG) operation. Approximately 500,000 CABG procedures are performed in the U.S. each year. The neurodegenerative-signaling cascade initiated by ischemia is complicated, involving glutamate release and glutamate receptor activation, intracellular Ca 2. accumulation, free radical production, and consequent necrosis and apoptosis (MacGregor et al., 2003). Neuredegeneration is a multi-step process, and while ischemia is the initiating event, the process may continue for several hours to several days even after reperfusion. As such, drugs capable of protecting neurons may be of value prior to, during and long after the initiating event. Our recent results demonstrate that PAN-811, a bioavailable small molecule (MW: 195) currently in phase II clinical trials for the treatment of patients with cancer, can efficiently block hypoxia-induced neurodegeneration. Although the mechanism of action of PAN-811 remains unclear and is one aspect of the proposed work, one possible mechanism is via metal ion chelation. Ca++, Fe++ and thus reactive oxygen species (ROS) are generally increased during neurodegeneration, as such PAN-811 may act to reduce ROS via Ca++ Fe++ chelation. However, this is clearly not the only effect of PAN-811 as we have noted that PAN-811 also suppresses H202-induced neuronal cell death and associated oxidative damage. Here we propose to develop PAN-811 as a neuroprotectant for global and focal ischemia.
