Enhanced cognitive protection through the combination of Amylovis-201, an anti-amyloidogenic agent with sigma-1 receptor agonist activity, and environmental enrichment in mice.

内容摘要

Amylovis-201 (CNEURO-201) shows strong neuroprotective activity in Alzheimer's disease (AD) models due to its anti-Aβ aggregating properties and sigma-1 receptors (S1R) agonist activity. The drug is neuroprotective in transgenic rodent models of AD that could translate into disease-modifying effects by both protecting neuronal and glial viability and actively decreasing amyloid aggregation. The individual vulnerability to the neurodegenerative process in AD is highly dependent on the "cognitive reserve," understood as the efficacy of brain plasticity throughout lifetime events. We aimed to determine whether Amylovis-201 efficacy in AD could be potentiated through stimulation of cognitive reserve. We combined Amylovis-201 administration with an experimental model of environmental enrichment (EE), using training on the Hamlet device. We analyzed the potentiating effects of the combination on brain plasticity and the development of resilience against memory deficits in a pharmacological AD model. We implemented a combined protocol with repeated per os (PO) administration of Amylovis-201 (0.1 and 1 mg/kg) and EE over 2 weeks (5 days/week), consisting of a 4-hour exploration of the Hamlet, a complex environment mimicking a small village with five functionalized houses. The combination of EE and low dose (0.1 mg/kg PO) of Amylovis-201 had an additive effect on hippocampal neurogenesis. It also protected mice against scopolamine (0.5 mg/kg IP)-induced spatial working memory deficits in the Y-maze and, at 0.1 or 1 mg/kg PO, against Aβ25-35-induced memory deficits. As EE is known to increase S1R expression, the combination of EE and Amylovis-201 had major effects on brain plasticity and neuroprotection.