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Abstract:

Many recent studies demonstrate the importance of fluid movement within the central nervous system on brain function and homeostasis. Our lab focuses on ependymal cells that display motile cilia, which protrude into the cerebral spinal fluid (CSF) and beat at up to 60 Hz. While the presence of motile ependymal cilia is well documented, the function and influence of these cells on fluid movement in the brain remains elusive. To examine the function of motile cilia, we identified FDA-approved compounds capable of impairing or enhancing cilia motility as a “side effect.” These compounds were administered intraventricularly, and the effects on drug accumulation in the brain, neuropathologies, and toxicity were quantified. Administering cilia inhibitors in conjunction with temozolomide, the standard of care chemotherapy for malignant brain tumors, results in a 40-fold increase in the concentration of temozolomide in the brain, which conveys a significant survival benefit for animals bearing orthotopic brain tumors. Importantly, this treatment is well-tolerated, with no additional adverse events observed in the co-treatment group compared to treatment with temozolomide alone. On the other hand, enhancing the beat frequency of ependymal cilia appears to increase the clearance of compounds and metabolites from the brain. Administering a motile cilia stimulator after a traumatic brain injury (TBI) results in increased tightening of the blood-brain barrier post-injury, quicker recovery post-injury, and improved cognition compared to controls. Taken together, these data indicate that ependymal cilia motility is a novel, targetable feature that can adjuvant current interventions for brain disease by altering fluid flux within the central nervous system.

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