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 α2-adrenergic receptor agonist, enhances perivascular cerebrospinal fluid (CSF) flow by reducing central noradrenergic tone and inducing sleep-like electroencephalogram (EEG) slow-wave activity. Concurrently, α2-adrenergic agonists modulate peripheral physiological functions, possibly influencing the central glymphatic dynamics. Utilizing peripherally restricted α2-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 ([99ᵐTc]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 (AUC0-91), by 36 % (AUC0-91 ratio, 1.36; 95 % CI, 1.0-1.8), increasing the maximum tracer concentration (Cmax) in the intracranial space by 39 % (Cmax ratio, 1.39; 95 % CI, 1.06-1.81), and decreasing the tracer availability in the spinal canal by 25 % (AUC0-91 ratio, 0.75; 95 % CI, 0.66-0.85). Simultaneously, vatinoxan promoted the tracer egress from the CNS by 360 % (AUC0-91 ratio, 4.6; 95 % CI, 2.7-7.8).

CONCLUSIONS

Antagonism of peripheral α2-adrenergic receptors with vatinoxan during dexmedetomidine sedation enhances perivascular CSF influx, irrespective of slow-wave activity.