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

• Published in: PloS one 2018-01, Vol.13 (1), p.e0191866-e0191866
• Main Authors: Jiang, Zhi-Gang, Winocur, Gordon, Wojtowicz, J Martin, Shevtsova, Olga, Fuller, Steven, Ghanbari, Hossein A
• Format: Article
• Language: English
• Subjects: 5-Fluorouracil; Animal cognition; Animal models; Animals; Antineoplastic Agents - administration & dosage; Antineoplastic Agents - adverse effects; Biology and Life Sciences; Cancer therapies; Chemotherapy; Cognitive ability; Cognitive Dysfunction - chemically induced; Cognitive Dysfunction - prevention & control; Cognitive tasks; Dentate gyrus; Dentate Gyrus - drug effects; Discrimination learning; Discrimination Learning - drug effects; Disease Models, Animal; Doublecortin protein; Drugs; Enzyme Inhibitors - pharmacology; Female; Fluorouracil - administration & dosage; Fluorouracil - adverse effects; Frontal lobe; Hippocampus; Hippocampus - drug effects; Hippocampus - pathology; Hippocampus - physiopathology; Humans; Impairment; Laboratories; Learning; Learning - drug effects; Medicine and Health Sciences; Memory; Memory tasks; Methotrexate; Methotrexate - administration & dosage; Methotrexate - adverse effects; Neostriatum; Neurogenesis; Neurogenesis - drug effects; Neuroprotective Agents - pharmacology; Neurotoxicity; Pharmaceuticals; Physiology; Pyridines - pharmacology; Quality of life; Rats; Rats, Long-Evans; Reductase; Reductases; Ribonucleotide Reductases - antagonists & inhibitors; Social Sciences; Spatial analysis; Spatial discrimination learning; Spatial memory; Spatial Memory - drug effects; Thiosemicarbazones - pharmacology; Young adults
• ISSN: 1932-6203; 1932-6203
• DOI: 10.1371/journal.pone.0191866

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.