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.
Highlights
Though target-oriented immunotherapy is an important direction in the treatment of cancer, small chemical molecules are still widely used as anticancer drugs in clinical cancer therapy
Since suppression of neurogenesis is thought to be a mechanism underlying MTX/5-FU-induced impairment of cognitive processes mediated by the hippocampus, we examined new cell production in the dentate gyrus to determine if PAN-811 is capable of counteracting this suppressive effect
The results show that PAN-811 prevents cognitive deficits resulting from chemotherapy with MTX/5-FU in our model and preserves neurogenesis in the dentate gyrus
Summary
Though target-oriented immunotherapy is an important direction in the treatment of cancer, small chemical molecules are still widely used as anticancer drugs in clinical cancer therapy. The anticancer drugs methotrexate (MTX) and 5-fluorouracil (5-FU) are antimetabolites that function in suppression of cell mitosis and proliferation, and are commonly used in clinical treatment of various cancers, such as breast cancer. Both MTX and 5-FU can pass the blood-brain barrier (BBB) in amounts that are sufficient to cause cognitive impairment [2, 9,10,11], possibly by increasing oxidative stress (OS) [10, 12, 13]. The results show that PAN-811 prevents cognitive deficits resulting from chemotherapy with MTX/5-FU in our model and preserves neurogenesis in the dentate gyrus
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