Vindeburnol Induces Neuroprotection in Rat Traumatic Brain Injury via Adrenergic Receptor Antagonism

Introduction/Objective: Traumatic Brain Injury (TBI) causes substantial neurological deficits and remains a major therapeutic challenge. This study aimed to evaluate the neuroprotective properties of Vindeburnol (VIND), a semi-synthetic derivative of vincamine, and to identify its potential molecular targets and optimal dosing regimen for post-traumatic treatment. Methods: Radioligand binding assays were used to determine VIND affinity for 22 CNS receptors, 7 ion channels, and 1 enzyme at a concentration of 10 μM. The in vivo neuroprotective effect was studied in a rat model of TBI induced by controlled cortical impact. VIND was administered intraperitoneally at doses of 10 or 20 mg/kg daily or every other day for 10 days. Neurological recovery was assessed using the beam-walking and limb-placement tests, and brain lesion volume was quantified by MRI on day 14. Results: VIND showed strong inhibition of radioligand binding at α1- and α2-adrenergic receptors (74% and 84.1%, respectively). In vivo, the most pronounced neuroprotective effect was observed at 20 mg/kg every other day, resulting in approximately a twofold reduction in lesion volume (88.7 ± 6.5 mm3 vs 179.4 ± 19.3 mm3 in saline-treated TBI rats, p < 0.001) and a significant improvement in neurological outcomes. The 10 mg/kg dose showed a non-significant trend towards neuroprotection. Discussion: The neuroprotective effect of VIND is likely mediated by the inhibition of excessive adrenergic receptor activation, resulting in improved neuronal survival and functional recovery. These findings highlight adrenergic modulation as a promising therapeutic mechanism for mitigating post-traumatic brain damage. Conclusion: Vindeburnol demonstrated significant neuroprotective efficacy in a rat model of TBI and may represent a promising pharmacological candidate for post-traumatic neuroprotection.