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.