PAN-811 prevents chemotherapy-induced cognitive impairment and preserves neurogenesis in the hippocampus of adult rats.

Abstract

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.

• Authors: Zhi-Gang Jiang, Gordon Winocur, J Martin Wojtowicz, Olga Shevtsova, Steven Fuller, Hossein A Ghanbari
• Journal: PloS one (PLoS One) Vol. 13 Issue 1 Pg. e0191866 ( 2018) ISSN: 1932-6203 [Electronic] United States
• PMID: 29370277 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)

Chemical References

• Antineoplastic Agents
• Dcx protein, rat
• Doublecortin Protein
• Enzyme Inhibitors
• Neuroprotective Agents
• Pyridines
• Thiosemicarbazones
• 3-aminopyridine-2-carboxaldehyde thiosemicarbazone
• Ribonucleotide Reductases
• Fluorouracil
• Methotrexate

Topics

• Animals
• Antineoplastic Agents (administration & dosage, adverse effects)
• Cognitive Dysfunction (chemically induced, prevention & control)
• Dentate Gyrus (drug effects)
• Discrimination Learning (drug effects)
• Disease Models, Animal
• Doublecortin Protein
• Enzyme Inhibitors (pharmacology)
• Female
• Fluorouracil (administration & dosage, adverse effects)
• Hippocampus (drug effects, pathology, physiopathology)
• Humans
• Learning (drug effects)
• Methotrexate (administration & dosage, adverse effects)
• Neurogenesis (drug effects)
• Neuroprotective Agents (pharmacology)
• Pyridines (pharmacology)
• Rats
• Rats, Long-Evans
• Ribonucleotide Reductases (antagonists & inhibitors)
• Spatial Memory (drug effects)
• Thiosemicarbazones (pharmacology)