Peripheral alpha-2 antagonist vatinoxan improves dexmedetomidine-induced perivascular cerebrospinal fluid flow without affecting electroencephalogram activity in female rats

Background The glymphatic concept represents a brain-wide perivascular fluid network contributing to brain metabolite clearance. Dexmedetomidine, a sedative α 2 -adrenergic receptor agonist, enhances perivascular cerebrospinal fluid (CSF) flow by reducing central noradrenergic tone and inducing sleep-like electroencephalogram (EEG) slow-wave activity. Concurrently, α 2 -adrenergic agonists modulate peripheral physiological functions, possibly influencing the central glymphatic dynamics. Utilizing peripherally restricted α 2 -adrenergic antagonist vatinoxan, we evaluated the role of physiological parameters on the glymphatic-enhancing properties of dexmedetomidine. Methods The effects of vatinoxan on the EEG spectral signature of dexmedetomidine and physiological parameters were investigated in female Sprague-Dawley rats. The whole-body distribution of intracisternally infused radiolabeled CSF tracer technetium-99m-labeled diethylenetriaminepentaacetic acid ([ 99 ᵐTc]Tc-DTPA) was quantified utilizing single-photon emission computed tomography (SPECT). Results While vatinoxan had no influence on the EEG spectral signature of dexmedetomidine sedation, it alleviated the peripheral effects, such as peripheral vasoconstriction, hyperglycemia, diuresis, and hyperosmolality. Vatinoxan created a unique CSF tracer distribution pattern by elevating the cortical tracer availability, quantified as area under the time–activity curve (AUC 0-91 ), by 36% (AUC 0–91 ratio, 1.36; 95% CI, 1.0–1.8), increasing the maximum tracer concentration (C max ) in the intracranial space by 39% (C max ratio, 1.39; 95% CI, 1.06–1.81), and decreasing the tracer availability in the spinal canal by 25% (AUC 0–91 ratio, 0.75; 95% CI, 0.66–0.85). Simultaneously, vatinoxan promoted the tracer egress from the CNS by 360% (AUC 0–91 ratio, 4.6; 95% CI, 2.7–7.8). Conclusions Antagonism of peripheral α 2 -adrenergic receptors with vatinoxan during dexmedetomidine sedation enhances perivascular CSF influx, irrespective of slow-wave activity.