Could dexmedetomidine be repurposed as a glymphatic enhancer?

Cerebrospinal fluid (CSF) flows through the central nervous system (CNS) via the glymphatic pathway to clear the interstitium of metabolic waste. In preclinical studies, glymphatic fluid flow rate increases with low central noradrenergic tone and slow-wave activity during natural sleep and general anesthesia. By contrast, sleep deprivation reduces glymphatic clearance and leads to intracerebral accumulation of metabolic waste, suggesting an underlying mechanism linking sleep disturbances with neurodegenerative diseases. The selective α2-adrenergic agonist dexmedetomidine is a sedative drug that induces slow waves in the electroencephalogram, suppresses central noradrenergic tone, and preserves glymphatic outflow. As recently developed dexmedetomidine formulations enable self-administration, we suggest that dexmedetomidine could serve as a sedative-hypnotic drug to enhance clearance of harmful waste from the brain of those vulnerable to neurodegeneration. The brain clears itself of harmful metabolic waste through the glymphatic system to several egress routes, including the meningeal lymphatic vessels, and onward to cervical lymph nodes.In rodents, glymphatic flow declines in the awake state and increases with slow-wave activity in electroencephalography during non-rapid eye movement (NREM) sleep.Declining glymphatic function could be an underlying link between chronic sleep disturbance and neurodegeneration.Dexmedetomidine is a widely used and studied sedative agent that promotes NREM sleep in humans. Further, it has neuroprotective and anti-neuroinflammatory properties. In rodents, dexmedetomidine enhances the glymphatic clearance of intraparenchymal tracers from the rodent brain.Due to its mechanisms of action, safety, and ease of use through several noninvasive administration routes, dexmedetomidine should be studied as a self-administered sedative-hypnotic drug in outpatient care. It may be the best available sedative glymphatic enhancer and may prove to attenuate neurodegeneration in long-term use.