Treating Parkinson's Disease via Activation of BDNF/TrkB Signaling Pathways and Inhibition of Delta-Secretase

Parkinson's disease (PD) is the second most common neurodegenerative disease with motor disorders as the key clinical features. BDNF/TrkB neurotrophic signalings are progressively reduced, whereas delta-secretase, a protease that cleaves alpha-synuclein (alpha-Syn) at N103 and promotes its aggregation and neurotoxicity, is gradually escalated in PD patient brains, associated with dopaminergic neuronal loss in the Substantia Nigra. Here, we show that stimulation of deficient BDNF/TrkB signalings with its small molecular agonist CF3CN displays the promising therapeutic effect, and blockade of delta-secretase with an optimal specific inhibitor #11A exhibits marked therapeutic effect, and combination of both demonstrates additive restorative efficacy in MPTP-induced human SNCA transgenic PD mice. Upon oral administration, CF3CN robustly activates TrkB-mediated neurotrophic pathway in the brains of SNCA mice and decreases alpha-Syn N103 cleavage by delta-secretase, and #11A strongly blocks delta-secretase and reduces alpha-Syn N103 fragmentation, increasing TH-positive dopaminergic neurons. The mixture of CF3CN and #11A shows the maximal TH and dopamine levels with demonstrable BDNF as compared to negligible BDNF in vehicle-treated MPTP/SNCA mice, leading to the climaxed motor functions. Notably, both compounds possess the appropriate in vivo PK profiles. Hence, our findings support that CF3CN and #11A are promising therapeutic pharmaceutical agents for treating PD.

Automated summary

Parkinson's disease is a common neurodegenerative disease characterized by motor disorders. Stimulation of deficient BDNF/TrkB signalings and blockade of delta-secretase show promising therapeutic effects in PD, and their combination enhances the restorative efficacy. This study is significant for the discovery of potential therapeutic agents for PD.