SBIR-STTR Award

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.

Thesaurus Terms:
cerebral ischemia /hypoxia, chemical structure function, drug design /synthesis /production, drug screening /evaluation, neuroprotectant, pharmacokinetics, small molecule apoptosis, calcium ion, chelating agent, chemical binding, free radical oxygen, hypoglycemia, iron, neural degeneration, neurotoxicology behavior test, electroencephalography, laboratory rat, spectrometry, tissue /cell culture

Ischemia/hypoxia is a significant contributor to neurodegeneration. A typical case is ischemic stroke. Currently, more than 4 million people in the U.S are living with the consequences of stroke. Stroke has become the third leading cause of death in this country, a major cause of long-term disability, and a significant burden on public health worldwide. The clinical significance of cerebral ischemia is compounded by the lack of effective neuroprotective treatments that directly inhibit ischemic neuronal death. Therefore development of novel neuroprotectants is a top priority for the prevention and treatment of ischemic diseases. In phase I of this work we identified a novel class of neuroprotective compounds, the the alpha(N)- heterocyclic carboxaldehyde thiosemicarbazones (HCTs), including PAN-811. Panacea Pharmaceuticals, Inc. has licensed the used of this compound and maintains intellectual property rights for its use in neuroprotective therapy. PAN-811 fully blocks hypoxic and ischemic neuronal cell death at a dose of 1 uM in vitro, and reduces infarct volume by up to 59% in the middle cerebral artery occlusion (MCAo) rat model of stroke. It manifests dual mechanistic functions including both Ca2+ -chelation and free radical-scavenging. Our goal is the development of PAN-811 as a clinically available neuroprotective drug, thus, this phase II grant proposal is aimed at the completion of the requisite preclinical studies. A further pharmacologic study of PAN-811 focusing on its neuroprotective mechanism in reference to necrotic and/or apoptotic cell death is proposed. We will also extend our studies with the MCAo model to optimize the route of administration, compare bolus delivery with infusion, further study dosing effects, and determine the window of therapeutic opportunity. Outcomes will initially be measured by evaluating total infarct volume but will include behavioral testing after more complete establishment of these parameters. PAN-811 is currently in phase II clinical trials for another indication, cancer, by Vion Pharmaceuticals, Inc. As such, much is already known about the human toxicology and pharmacokinetics of PAN-811. If the administration route changes to gain maximum efficacy, the toxicity and pharmacokinetics of PAN-811 will be re-evaluated prior to clinical trial. At the end of the phase II period, we expect to submit an IND application to the FDA to use PAN-811 for the treatment of transient ischemic stroke and initiate phase Ib clinical trials