Pharmacological or genetic depletion of senescent astrocytes prevents whole brain irradiation‐induced impairment of neurovascular coupling responses protecting cognitive function in mice

Abstract

Whole brain irradiation (WBI, also known as whole brain radiation therapy or WBRT) is a mainstream therapy for patients with identifiable brain metastases and as a prophylaxis for microscopic malignancies. WBI accelerates brain aging, causing progressive cognitive dysfunction in ~50% of surviving patients, thus compromising quality of life. The mechanisms responsible for this WBI side effect remain obscure, and there are no effective treatments or prevention strategies. Here, we test the hypothesis that WBI induces astrocyte senescence, which contributes to impaired astrocytic neurovascular coupling (NVC) responses and the genesis of cognitive decline. To achieve this goal, we used transgenic p16‐3MR mice, which allows the detection and selective elimination of senescent cells. We subjected these mice to a clinically relevant protocol of fractionated WBI (5 Gy twice weekly for 4 weeks). WBI‐treated and control mice were tested for spatial memory performance (radial arm water maze), astrocyte‐dependent NVC responses (whisker‐stimulation‐induced increases in cerebral blood flow, assessed by laser speckle contrast imaging), NVC‐related gene expression, astrocytic release of eicosanoid gliotransmitters and the presence of senescent astrocytes (by flow cytometry, immunohistochemistry and gene expression profiling) at 6 months post‐irradiation. WBI induced senescence in astrocytes, which associated with NVC dysfunction and impaired performance on cognitive tasks. To establish a causal relationship between WBI‐induced senescence and NVC dysfunction, se‐nescent cells were depleted from WBI‐treated animals (at 3 months post‐WBI) by genetic (ganciclovir treatment) or pharmacological (treatment with the BCL‐2/BCL‐xL inhibitor ABT263/Navitoclax, a known senolytic drug) means. In WBI treated mice, both treatments effectively eliminated senescent astrocytes, rescued NVC responses and improved cognitive performance. Our findings suggest that the use of senolytic drugs can be a promising strategy for preventing the cognitive impairment associated with WBI.Support or Funding InformationThis work was supported by grants the Oklahoma Center for the Advancement of Science and Technology, the Oklahoma Shared Clinical and Translational Resources (OSCTR) program funded by the National Institute of General Medical Sciences (GM104938), the NIA‐supported Geroscience Training Program in Oklahoma (T32AG052363), the Oklahoma Nathan Shock Center (P30AG050911), the Cellular and Molecular GeroScience CoBRE (1P20GM125528, sub#5337), and the NIGMS supported Center of Biomedical Research Excellence (CoBRE).