Neuropharmacology · 2026
Peripheral alpha-2 antagonist vatinoxan improves dexmedetomidine-induced perivascular cerebrospinal fluid flow without affecting electroencephalogram activity in female rats.
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Antila Hanna, Jalonen Sonja C, Persson Niklas Daniel Åke, Peltoniemi Martta, Lohela Terhi J, Lilius Tuomas O
Аннотация
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.
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.