While neurons are considered radioresistant, astrocytes are sensitive to γ-irradiation. The mechanisms responsible for WBI-induced cognitive impairment remain obscure, and there are no effective treatments or prevention strategies.Īstrocytes are an abundant cell type in the brain and play critical roles in regulation of neuronal function and cerebral blood flow (CBF).
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WBI also leads to a progressive impairment of cognitive function in laboratory rodents, modeling the full clinical picture. WBI-induced cognitive impairment progresses to dementia in about 2 to 5% of long-term survivors. WBI causes progressive impairments in verbal and spatial memory, attention, novel problem-solving ability, and executive function in over 50% of surviving patients, which manifests months to years after treatment, compromising quality of life.
Although WBI is clinically effective in eliminating proliferating cancer cells, there is a growing concern regarding serious unwanted side effects and late toxicity profile in brain tissue. Over 200,000 cancer patients receive either partial large field or WBI every year in the USA for this indication. Incidence of brain involvement in patients with metastatic cancer is 10–40%. Whole brain irradiation (WBI, also known as whole brain radiation therapy or WBRT) remains an important treatment option for patients with both identifiable brain metastases and as a prophylaxis for microscopic malignancies. Our data show that WBI causes a long-lasting decrement in synaptic-evoked astrocyte Ca 2+ signals 12–15 months postirradiation, which may be an important contributor to cognitive decline seen after WBI. However, an electrical stimulation protocol used in long-term potentiation (theta burst), revealed attenuated astrocyte Ca 2+ responses in the astrocyte arbor and soma in WBI. Astrocytic Ca 2+ responses induced by bath administration of phenylephrine (detected with Rhod-2/AM) were also unaltered by WBI. We found that WBI did not affect astrocyte-to-astrocyte gap junctional coupling. To test the integrity of astrocyte-to-astrocyte gap junctional coupling postWBI, astrocytes were loaded with Alexa-488-hydrazide by patch-based dye infusion, and the increase of fluorescence signal in neighboring astrocyte cell bodies was assessed with 2-photon microscopy in acute slices of the sensory-motor cortex. Mice were subjected to a clinically relevant protocol of fractionated WBI, and 12 to 15 months after irradiation, we confirmed persistent cognitive impairment compared to controls. We tested the hypothesis that WBI-induced cognitive impairment associates with persistent impairment of astrocytic Ca 2+ signaling and/or gap junctional coupling. Hallmarks of astrocyte function are the ability to generate stimulus-induced intercellular Ca 2+ signals and to move metabolic substrates through the connected astrocyte network. Astrocytes play critical roles in the regulation of neuronal activity, brain metabolism, and cerebral blood flow, and while neurons are considered radioresistant, astrocytes are sensitive to γ-irradiation.
WBI promotes progressive cognitive dysfunction in over half of surviving patients, yet, the underlying mechanisms remain obscure. Whole brain irradiation (WBI) therapy is an important treatment for brain metastases and potential microscopic malignancies.
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