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.

Chemotherapy-Induced Cognitive Impairment and Hippocampal Neurogenesis: A Review of Physiological Mechanisms and Interventions

“…BrdU labelling of dividing cells one day prior to sacrifice confirmed the MTX + 5-FU induced impairment in neuronal proliferation lasting more than one month following the end of chemotherapy treatment [ 155 ]. Following behavioral testing, MTX + 5-FU treated rats were found to have a 25% reduction in DCX levels in the SGZ persisting for over three months following the start of treatment [ 155 , 157 , 158 ]. These findings are consistent with studies using multiple dosages of MTX [ 75 , 76 , 77 , 78 ] or 5-FU alone [ 89 , 90 , 93 , 94 , 95 , 97 ], and identify the long temporal window of neurogenic suppression and the complex cognitive domains disrupted by MTX + 5-FU combination therapy in otherwise healthy female animals.…”

Evaluation of a Novel Synthetic Peptide Derived from Cytolytic Mycotoxin Candidalysin

“…Chemotherapy is known to have adverse effects on brain function, causing dysfunctions in learning, memory, attention, motor activity, and executive function [ 50 , 51 ]. In addition, several studies show that tyrosine kinases, antimetabolites, microtubule inhibitors, and alkylating agents can induce neurotoxicity [ 52 , 53 , 54 ].…”

Neuroimaging based biotypes for precision diagnosis and prognosis in cancer-related cognitive impairment

“…Nguyen and Ehrlich described multiple other drugs that could potentially be repurposed for treating CRCI ( 160 ). Preclinical studies have evaluated several novel agents including PAN-811, a ribonucleotide reductase inhibitor ( 161 ), mesenchymal stem cells ( 162–164 ), functionalized mitochondria ( 165 ), dual leucine zipper kinase ( 166 ), histone deacetylase 6 inhibitor ( 167 ), KU-32, for mitochondrial repair ( 168 ), and astaxanthin, an antioxidant ( 169 ), among others. However, these treatments have yet to be translated into clinical studies.…”