Targeted activation of Nrf2 at sites of oxidative stress reverses doxorubicin-induced cognitive impairments in mice.

While cancer survivorship has increased due to advances in treatments, chemotherapy often carries long-lived neurotoxic side effects which reduce quality of life. Commonly affected domains include memory, executive function, attention, and processing speed, known as chemotherapy-induced cognitive impairment or "chemobrain". Oxidative stress and neuroimmune signaling in the brain have been mechanistically linked to the deleterious effects of chemotherapy on cognition. With this in mind, we tested if activation of the master regulator of antioxidant response nuclear factor E2-related factor 2 (Nrf2) using compound 1c or diroximel fumarate (DRF) would restore cognitive function after doxorubicin treatment. Compound 1c is a prodrug which locally releases the Nrf2 activator monomethyl fumarate (MMF) specifically at sites of oxidative stress, while DRF systemically releases MMF. Compound 1c and DRF both reversed doxorubicin-induced deficits in executive function, and spatial and working memory, across male and female mice. Nrf2 activators decreased malonaldehyde and protein carbonyl levels induced by doxorubicin in the hippocampus. Consistently, 1c increased nuclear translocation (activation) of Nrf2 in the hippocampus after doxorubicin treatment, whereas DRF indiscriminately activated Nrf2 in the hippocampus of vehicle-treated mice as well. Therapeutic actions of compound 1c and DRF were lost in Nrf2 knockout mice, confirming Nrf2 as the therapeutic target. Nrf2 activators reversed doxorubicin-induced loss of synaptic protein PSD95 and restored microglial morphology in the hippocampus while there was no significant effect of the drug treatment on adult neurogenesis. These results demonstrate the therapeutic potential of Nrf2 activators to reverse doxorubicin-induced cognitive impairments, and associated structural, phenotypic, and molecular changes in the hippocampus. The localized release of MMF by 1c at sites of oxidative stress has the potential to diminish unwanted effects of fumarates while reversing CICI induced by doxorubicin.