Targeting ryanodine receptor type 2 to mitigate chemotherapy-induced neurocognitive impairments in mice

Abstract

Chemotherapy-induced cognitive dysfunction (chemobrain) is an important adverse sequela of chemotherapy. Chemobrain has been identified by the National Cancer Institute as a poorly understood problem for which current management or treatment strategies are limited or ineffective. Here, we show that chemotherapy treatment with doxorubicin (DOX) in a breast cancer mouse model induced protein kinase A (PKA) phosphorylation of the neuronal ryanodine receptor/calcium (Ca 2+ ) channel type 2 (RyR2), RyR2 oxidation, RyR2 nitrosylation, RyR2 calstabin2 depletion, and subsequent RyR2 Ca 2+ leakiness. Chemotherapy was furthermore associated with abnormalities in brain glucose metabolism and neurocognitive dysfunction in breast cancer mice. RyR2 leakiness and cognitive dysfunction could be ameliorated by treatment with a small molecule Rycal drug (S107). Chemobrain was also found in noncancer mice treated with DOX or methotrexate and 5-fluorouracil and could be prevented by treatment with S107. Genetic ablation of the RyR2 PKA phosphorylation site (RyR2-S2808A) also prevented the development of chemobrain. Chemotherapy increased brain concentrations of the tumor necrosis factor–α and transforming growth factor–β signaling, suggesting that increased inflammatory signaling might contribute to oxidation-driven biochemical remodeling of RyR2. Proteomics and Gene Ontology analysis indicated that the signaling downstream of chemotherapy-induced leaky RyR2 was linked to the dysregulation of synaptic structure–associated proteins that are involved in neurotransmission. Together, our study points to neuronal Ca 2+ dyshomeostasis via leaky RyR2 channels as a potential mechanism contributing to chemobrain, warranting further translational studies.

Systemic and targeted activation of Nrf2 reverses doxorubicin-induced cognitive impairments and sensorimotor deficits in mice

“…Several groups have identified chemotherapy-induced abnormalities in hippocampus and prefrontal cortex as underlying cognitive impairment. These include reduced numbers of neuronal spines and dendrites, lower neurogenesis, impaired myelination and persistent dysregulation of oligodendrocyte, astrocyte, and microglial function which are all crucial for health and plasticity of the central nervous system (Gibson, Nagaraja et al 2019, Nguyen and Ehrlich 2020, Liu, Reiken et al 2023. The mechanisms by which oncology drugs exert these cellular effects are varied due to differing therapeutic regimens and mechanisms of action between classes.…”