3-aminopyridine-2-carboxaldehyde-thiosemicarbazone and Disease-Models--Animal

Topics: Animals; Biomarkers, Tumor; Bone Neoplasms; Disease Management; Disease Models, Animal; Disease Susceptibility; Gene Expression Regulation, Neoplastic; Humans; Mice; Molecular Targeted Therapy; Prognosis; Pyridines; Ribonucleoside Diphosphate Reductase; Sarcoma, Ewing; Thiosemicarbazones; Xenograft Model Antitumor Assays

Chemotherapy-induced cognitive impairment (CICI) occurs in a substantial proportion of treated cancer patients, with no drug currently available for its therapy. This study investigated whether PAN-811, a ribonucleotide reductase inhibitor, can reduce cognitive impairment and related suppression of neurogenesis following chemotherapy in an animal model. Young adult rats in Chemo and Chemo+PAN-811 groups received 3 intraperitoneal (i.p.) injections of methotrexate (MTX) and 5-fluorouracil (5-FU), and those in Saline and Saline+PAN-811 groups received equal volumes of physiological saline at 10-day intervals. PAN-811 in saline was delivered through i.p. injection, 10 min following each saline (Saline+PAN-811 group) or MTX/5-FU (Chemo+PAN-811 group) treatment, while equal volumes of saline were delivered to Saline and Chemo groups. Over Days 31-66, rats were administered tests of spatial memory, nonmatching-to-sample rule learning, and discrimination learning, which are sensitive to dysfunction in hippocampus, frontal lobe and striatum, respectively. On Day 97, neurogenesis was immnunohistochemically evaluated by counting doublecortin-positive (DCX+) cells in the dentate gyrus (DG). The results demonstrated that the Chemo group was impaired on the three cognitive tasks, but co-administration of PAN-811 significantly reduced all MTX/5-FU-induced cognitive impairments. In addition, MTX/5-FU reduced DCX+ cells to 67% of that in Saline control rats, an effect that was completely blocked by PAN-811 co-administration. Overall, we present the first evidence that PAN-811 protects cognitive functions and preserves neurogenesis from deleterious effects of MTX/5-FU. The current findings provide a basis for rapid clinical translation to determine the effect of PAN-811 on CICI in human.

Topics: Animals; Antineoplastic Agents; Cognitive Dysfunction; Dentate Gyrus; Discrimination Learning; Disease Models, Animal; Doublecortin Protein; Enzyme Inhibitors; Female; Fluorouracil; Hippocampus; Humans; Learning; Methotrexate; Neurogenesis; Neuroprotective Agents; Pyridines; Rats; Rats, Long-Evans; Ribonucleotide Reductases; Spatial Memory; Thiosemicarbazones

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.

Topics: Animals; Apoptosis; Blotting, Western; Calcium; Cerebral Cortex; Chelating Agents; Coculture Techniques; Corpus Striatum; Disease Models, Animal; DNA Fragmentation; Dose-Response Relationship, Drug; Fluoresceins; Free Radical Scavengers; Humans; Hypoxia; Infarction, Middle Cerebral Artery; Ischemia; L-Lactate Dehydrogenase; Male; Necrosis; Neurodegenerative Diseases; Neurons; Neuroprotective Agents; Pyridines; Rats; Rats, Sprague-Dawley; Reactive Oxygen Species; Thiosemicarbazones; Time Factors