Gene expression analysis in the hippocampus of Tg2576 mice after different treatments with HDAC and PDE inhibitors. Gene expression analysis in the hippocampus of Tg2576 mice after different treatments with HDAC and PDE inhibitors

The goal of this study was the identification of a novel mode of action for this unmet need. Pharmacological tool compounds: suberoylanilide hydroxamic acid (SAHA) and tadalafil, targeting histone deacetylases (HDAC) and phosphodiesterase 5 (PDE5) respectively, were utilized simultaneously for in-vitro and in-vivo Proof-of-Concept (PoC). A synergistic effect was observed in the amelioration of AD signs using the combination therapy in Tg2576 mice. Finally, a therapeutic agent, CM-414, inhibiting simultaneously HDAC2/6 and PDE5 was generated and tested in Tg2576 mice. CM-414 reversed cognitive impairment, reduced amyloid and tau pathology, and rescued dendritic spine density loss in the hippocampus in AD mice. Importantly, the effect obtained was present after a 4-weeks wash-out period.However, to obtain a compound with a safer profile we designed a new compound, CM-695, targeting HDAC6 and PDE9. CM-695 showed similar effect to that of CM-414 after chronic administration to Tg2576 although the effect was not mantained when CM-695 was no longer administered. Overall design: Comparisson of global gene expression profiling in aged Tg2576 mice hippocampi between diferent treatments and sacrificed 24 hours after the end of the treatment