Pharmacokinetic and safety of a novel pleiotropic compound in C57BL/6J mice with potential therapeutic interest in Alzheimer’s disease
Résumé
Several therapeutic targets have been identified to counteract the cognitive decline of Alzheimer's disease (AD). One of the recent approaches, which takes account the multifactorial origin of AD, is pleiotropic drugs. Multi-targeted directed ligands are designed to target different molecular causes involved in the pathogenesis of AD. A novel compound, acting as a prodrug and able of both selectively inhibiting butyrylcholinesterase and secondarily interacting with serotonin subtype 4 receptor, has therefore been developed. The first step of the project was to assess pharmacological screening and determine the pharmacokinetic profile of this compound in 3-month-old male and female C57BL/6J mice. The compound was administrated either through classical oral route or via intranasal administration. Although it requires a galenic formulation, intranasal administration offers a better central distribution through the blood-brain barrier. Actually, our pharmacokinetic study showed similar concentrations in plasma and brain following oral administration at 3 mg/kg (1h post-administration) and intranasal administration at 0.3 mg/kg (30 min post-administration). Given the pharmacokinetic results, further experiments should explore behavioral effect at lower doses after intranasal administration. Pharmacological screening and actimetry did not show adverse effects and changes in locomotor activity at 1 mg/kg and 10 mg/kg after oral administration in both male and female mice. Besides, ex vivo efficacy of this compound to modulate hippocampal synaptic plasticity is currently investigated. Afterwards, ability of this compound to reverse cognitive deficits both in a pharmacologic (scopolamine-induced) model and in transgenic mice model (5XFAD) will be undergone.