A Novel In Vitro Model to Investigate Chemotherapy-Related Cognitive Impairment

Abstract

Chemobrain is a debilitating cognitive impairment that affects many cancer patients who receive chemotherapeutics, with no readily available pharmacological treatments. A novel and robust in vitro model for chemobrain was established with ReN CX cells to aid in the discovery of a meaningful intervention. Utilization of neuronal stem cells and proper differentiation techniques in 96-well microplates permitted the in vitro analysis of chemobrain in a high throughput format. Immunofluorescent staining and high-content imaging were used to measure chemotherapy-induced axon degeneration and assess cell state quantitatively through an image analysis pipeline. Concentrations of paclitaxel, cisplatin, and vincristine needed to induce an axonal phenotypic change in the chemobrain model were determined through titration. A chemotherapy-induced peripheral neuropathy model that STE20 kinase inhibitors confer neuroprotection against paclitaxel-induced peripheral neuropathy. STE20 kinase inhibitors were tested on the neurons and at titrated concentrations of paclitaxel, cisplatin, and vincristine for neuroprotection against chemotherapy-induced axon degeneration. It was determined that GNE-495 promotes neurogenesis with increased neurite outgrowth in a dose-dependent manner, as well as prosetin at concentrations that did not induce neurotoxicity. Furthermore, the STE20 kinase inhibitors provided statistically significant neuroprotection from some chemotherapeutics. The establishment of the chemobrain model and the therapeutic potential of the STE20 kinase inhibitors are an important step in the research of chemobrain.