P3‐041: A POTENTIAL TRI‐THERAPY FOR ALZHEIMER'S DISEASE

Abstract

Cognitive symptoms in Alzheimer's disease (AD) are currently managed by moderately acting drugs which efficacy decreases fast over time. We previously showed that a combination of acamprosate and baclofen (PXT864) synergistically prevented cognitive impairments in AD mice. In this study, we investigated whether PXT864 could i) protect cognitive functions by synergizing with sub-therapeutic doses of donepezil (DNPz) to limit the occurrence of adverse events, or ii) rescue the efficacy of DNPz that is lost over time under therapeutic doses. We used the Aβ25-35 intracerebroventricular (ICV) injection mouse to model AD. First, PXT864 was tested in combination with sub-therapeutic doses of DNPz, both administered to mice before Aβ25-35 injection. Second, we modelized the loss of activity of DNPz treatment over time when initiated after Aβ25-35 ICV injection. Third, once DNPz effect was lost, we added PXT864 to DNPz and assessed the value of such tri-therapy. Efficacy was assessed by Y-maze and step-through passive avoidance cognitive tests. We found that combination of sub-therapeutic dose of PXT864 and DNPz yielded synergistic protection against Aβ-induced cognitive deficits. We then confirmed the declining efficacy of DNPz at a late stage of the disease in mice. Interestingly, adding PXT864 at that stage fully restored lost cognition in these animals that became all irresponsive to DNPz. These data highlight the importance of combinational strategies and suggest that PXT864 could be used either as a first line treatment or a second line treatment with a safe sub-therapeutic or even a full therapeutic dose of DNPz in Alzheimer's patients.