Preclinical Characterization of Vindeburnol: Pharmacokinetics, Safety, and Cognitive-Enhancing Properties

Cognitive impairment is a common symptom of many psychiatric
disorders and can significantly reduce the patients' quality
of life. Vindeburnol, a synthetic derivative of eburnamine–vincamine
alkaloids, has shown potential in models of depression and neurodegeneration;
however, its comprehensive properties and molecular mechanisms of
action have remained unexplored. We conducted a comprehensive preclinical
assessment of vindeburnol, including a subchronic toxicity study (20
and 80 mg/kg/day, orally, 14 days), pharmacokinetic analysis (40 mg/kg),
behavioral tests for memory and learning, and transcriptomic profiling
of the locus coeruleus (LC) in mice. Vindeburnol demonstrated a good
safety profile at 20 mg/kg, while the 80 mg/kg dose caused 20% mortality
and hepatotoxicity. The compound exhibited high oral bioavailability
(75%) and a long half-life (7.58 h). Behavioral analysis revealed
a specific improvement in episodic memory in the novel object recognition
test without affecting motor activity. Transcriptomic analysis of
the LC identified 10 differentially expressed genes, including the
upregulation of Npas3 and Cfap69, key regulators of neurogenesis and
synaptic plasticity, and the downregulation of genes associated with
neuroinflammation (Ctss, Hspa1b). Our study is the first to comprehensively
characterize vindeburnol as a promising compound with proven procognitive
effects. The data reveal its unique mechanism of action, which promotes
neuroplasticity and counteracts pathological processes by modulating
key transcriptional programs in the locus coeruleus, supporting its
further investigation as a potential neurotropic agent.