A multifunctional cytoprotective agent that reduces neurodegeneration after ischemia.
Cellular and molecular pathways underlying ischemic neurotoxicity are multifaceted and complex. Although many potentially neuroprotective agents have been investigated, the simplicity of their protective mechanisms has often resulted in insufficient clinical utility. We describe a previously uncharacterized class of potent neuroprotective compounds, represented by PAN-811, that effectively block both ischemic and hypoxic neurotoxicity. PAN-811 disrupts neurotoxic pathways by at least two modes of action. It causes a reduction of intracellular-free calcium as well as free radical scavenging resulting in a significant decrease in necrotic and apoptotic cell death. In a rat model of ischemic stroke, administration of PAN-811 i.c.v. 1 h after middle cerebral artery occlusion resulted in a 59% reduction in the volume of infarction. Human trials of PAN-811 for an unrelated indication have established a favorable safety and pharmacodynamic profile within the dose range required for neuroprotection warranting its clinical trial as a neuroprotective drug.
Jiang
Zhi-Gang
ZG
Panacea Pharmaceuticals, Inc., Gaithersburg, MD 20877, USA. zgjiang@panaceapharma.com
Lu
X-C May
XC
Nelson
Valery
V
Yang
Xiaofang
X
Pan
Weiying
W
Chen
Ren-wu
RW
Lebowitz
Michael S
MS
Almassian
Bijan
B
Tortella
Frank C
FC
Brady
Roscoe O
RO
Ghanbari
Hossein A
HA
D000818:Animals; D017209:Apoptosis; D015153:Blotting, Western; D002118:Calcium / Q000378:metabolism; D002540:Cerebral Cortex / Q000378:metabolism; D002614:Chelating Agents / Q000494:pharmacology; D018920:Coculture Techniques; D003342:Corpus Striatum / Q000378:metabolism; D053938:DNA Fragmentation; D004195:Disease Models, Animal; D004305:Dose-Response Relationship, Drug; D005452:Fluoresceins / Q000494:pharmacology; D016166:Free Radical Scavengers / Q000378:metabolism; D006801:Humans; D000860:Hypoxia; D020244:Infarction, Middle Cerebral Artery / Q000188:drug therapy*; D007511:Ischemia; D007770:L-Lactate Dehydrogenase / Q000378:metabolism; D008297:Male; D009336:Necrosis; D019636:Neurodegenerative Diseases / Q000188:drug therapy*; D009474:Neurons / Q000378:metabolism; D018696:Neuroprotective Agents / Q000494:pharmacology*; D011725:Pyridines / Q000494:pharmacology*; D051381:Rats; D017207:Rats, Sprague-Dawley; D017382:Reactive Oxygen Species; D013882:Thiosemicarbazones / Q000494:pharmacology*; D013997:Time Factors
D002614:Chelating Agents; D005452:Fluoresceins; D016166:Free Radical Scavengers; D018696:Neuroprotective Agents; D011725:Pyridines; D017382:Reactive Oxygen Species; D013882:Thiosemicarbazones; C078157:3-aminopyridine-2-carboxaldehyde thiosemicarbazone; C093616:6-carboxyfluorescein diacetate; D007770:L-Lactate Dehydrogenase; D002118:Calcium