Phosphodiesterase 5 inhibitors for drug repositioning in a mouse model of chemotherapy-induced cognitive impairment

Abstract

Given the constant progress in cancer diagnostics and therapeutic interventions, the life expectancy of cancer patients, including breast cancer, which ranks as the second most prevalent cancer among women in our country, has been steadily increasing. In fact, the 5-year survival rate for breast cancer now surpasses 90%, prompting a surge in interest regarding the patients' quality of life. Among the various factors influencing quality of life, cognitive function stands out as a significant component. Studies indicate that approximately 35-70% of breast cancer patients experience cognitive impairments subsequent to undergoing antineoplastic therapy, commonly referred to as Chemotherapy-Induced Cognitive Impairment (CICI) or "chemobrain." The principal culprit behind cognitive impairments in cancer patients is believed to be certain chemotherapeutic agents, such as Paclitaxel (PTX). While the precise mechanisms underlying the onset of cognitive impairments due to cancer treatments remain elusive, several proposed mechanisms include oxidative stress, disruption of the blood-brain barrier, and heightened inflammatory responses. The objectives of this research endeavor were twofold: 1) to establish a CICI rodent model utilizing PTX, the quintessential chemotherapeutic agent implicated in breast cancer-induced cognitive impairments, and 2) to propose a novel therapeutic approach for CICI by activating Nitric Oxide Synthase and accumulating cGMP using a PDE5 inhibitor, known for its anti-inflammatory and antioxidant effects. The use of PDE5 inhibitors is advantageous owing to their widespread application in the treatment of erectile dysfunction, offering favorable pharmacokinetic properties and a favorable side effect profile. To achieve these objectives, PTX was intraperitoneally administered to 8-month-old rodents, followed by a battery of behavioral experiments encompassing the Open Field Test, Novel Object Recognition Test, and Morris Water Maze. Preliminary findings revealed a mild proclivity towards cognitive impairments in PTX-treated animals compared to those subjected to sham injections, although the effect magnitude was not substantial. Additionally, assessment of protein levels demonstrated a heightened inclination towards inflammation and oxidative stress in the PTX-treated group. However, the administration of a PDE5 inhibitor as a therapeutic intervention for ameliorating cognitive impairments failed to restore performance in the behavioral experiments. Moreover, at the protein level, the PDE5 inhibitor did not significantly mitigate the inflammation and oxidative stress observed in the CICI model, despite an evident tendency towards increased inflammation and oxidative stress in the CICI model compared to the sham treatment group. Consequently, it is postulated that while inflammation and oxidative stress may contribute to the mechanism underlying PTX-induced cognitive impairments, the PDE5 inhibitor did not exert sufficient inhibitory effects in this context. These findings may be attributed to the possibility of relatively mild cognitive impairments in the CICI model employed in this study, as well as potential inadequacies in the dosage or administration method of the PDE5 inhibitor. As our research centers on investigating therapeutic agents for cancer patients, future investigations may involve modeling with rodents harboring cancer cells and exploring alternative strategies, such as modifying the dosage or administration method of the PDE5 inhibitor. In summary, this study successfully established a CICI rodent model induced by antineoplastic therapy and assessed the potential of PDE5 inhibitors as a novel treatment option. Although the efficacy of the PDE5 inhibitor was not fully evident in this study, it is anticipated that further research and subsequent refinements will lead to advancements in this field.