Temozolomide in combination with cranial radiation therapy after surgery is standard of care treatment for glioblastoma. However, cognitive impairment is a serious and common side effect of chemoradiation which significantly reduces patient quality of life. In the current study, we tested the effects of nasally administered human bone marrow-derived mesenchymal stem cells (hMSC) in restoring cognitive function after chemoradiation. Adult C57BL/6J mice were treated with chemotherapy (33 mg/kg temozolomide) and cranial irradiation (20 Gy delivered to the whole brain in 10 daily fractions) or sham. We administered one million hMSC nasally 5 and 7 days after the last chemoradiation treatment. Twenty-one days after the second hMSC administration, puzzle box test (PBT) and novel object/place recognition test (NOPRT) were performed to measure executive functioning and memory, respectively. After completion of behavioral testing, resting-state functional magnetic resonance imaging (fMRI) was acquired to measure functional connectivity. Chemoradiation decreased executive function and impaired memory, as measured by the PBT and the NOPRT. Additionally, chemoradiation caused a decrease in global functional connectivity in the brain, as shown by resting-state fMRI. Both cognitive function and functional connectivity were restored by nasal hMSC treatment.Our data suggest that treatment with hMSC restores cognitive function and functional brain damage that has occurred as a result of chemoradiation. Nasal hMSC treatment may represent a realistic therapeutic strategy for the treatment of chemoradiation-induced cognitive impairment.
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