Chemotherapy-Induced Cognitive Impairments: Targeting Neuroimmune Processes as Potential Treatments

Abstract

Chemotherapy has prolonged the survival rates of cancer patients. However, chemotherapy causes peripheral neuropathies and cognitive impairments. Isolating which chemotherapy agents are responsible for these behavioural changes is difficult. Patients are given regimens that contain several agents alongside hormone therapy and radiation. Animal models are useful to elucidate which class of agents have the most neurotoxic effect and can determine which neural mechanisms are vulnerable to chemotherapy. Animal models can also determine which pharmacological agents reduce neurotoxic side effects to restore normal functioning. The first aim of this thesis was to compose a systematic review of chemobrain in animal models. The second aim was to explore the effects of oxaliplatin (OXP) on cognition in rodents. The third aim was to determine whether ibudilast (IBU), a proven immune therapy and nicotinamide mononucleotide (NMN), a permeable nicotinamide adenine dinucleotide precursor can reduce OXP-induced neurotoxicity. The systematic review showed that across all chemotherapy regimens short term memory (STM) was profoundly impaired. Impairments were associated with disrupted neurogenesis, oxidative stress, inflammation and altered neuronal morphology. The most cytotoxic regimens were cisplatin and methotrexate + 5-fluorouracil with or without cyclophosphamide. These regimens produced impairments in STM, long term memory and executive control. Experiments demonstrated that one injection of IBU or consumption of NMN for 7 days reduced OXP-induced object recognition memory impairments in acute and chronic pre-clinical models of OXP-induced neurotoxicity. Furthermore, OXP-treated rats showed intact object recognition memory at least 7 days post NMN treatment cessation. One injection of IBU also prevented OXP-induced tactile allodynia. These experiments highlight the therapeutic potential of IBU and NMN in reducing the neurotoxic side effects of platinum chemotherapy agents.