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

Neurotherapeutics, 2022 · DOI: 10.1007/s13311-022-01248-1 · Published: May 20, 2022

Simple Explanation

Parkinson’s disease (PD) is characterized by the progressive loss of dopaminergic neurons and reduced BDNF/TrkB signaling. This study explores treating PD by stimulating BDNF/TrkB signaling and blocking δ-secretase, an enzyme that promotes α-Syn aggregation. The researchers used a small molecule agonist CF3CN to stimulate BDNF/TrkB and an inhibitor #11A to block δ-secretase in MPTP-induced human SNCA transgenic PD mice. The goal was to see if either compound alone or in combination could restore dopamine levels and improve motor function. The findings suggest that both CF3CN and #11A, especially when combined, could be promising therapeutic agents for treating PD by protecting dopaminergic neurons and improving motor functions in PD mice.

Study Duration

5 weeks

Participants

Human SNCA transgenic PD mice

Evidence Level

Not specified

Key Findings

1
CF3CN activates the TrkB-mediated neurotrophic pathway and decreases α-Syn N103 cleavage, while #11A strongly blocks δ-secretase and reduces α-Syn N103 fragmentation, leading to increased dopaminergic neurons.
2
The combination of CF3CN and #11A resulted in the highest levels of TH and dopamine, along with demonstrable BDNF, leading to improved motor functions compared to vehicle-treated mice.
3
#11A and CF3CN additively restore the defective motor functions in SNCA/MPTP PD mice

Research Summary

This study investigates the therapeutic potential of activating BDNF/TrkB signaling and inhibiting δ-secretase in a mouse model of Parkinson's Disease (PD). The researchers used CF3CN, a TrkB agonist, and #11A, a δ-secretase inhibitor, to treat MPTP-induced human SNCA transgenic PD mice. The results indicate that both CF3CN and #11A, administered individually, offer protection to dopaminergic neurons from MPTP-induced degeneration, leading to increased dopamine levels. Notably, the combination of CF3CN and #11A demonstrated the most significant neuroprotective effect. The study concludes that CF3CN and #11A are promising therapeutic agents for PD, as they ameliorate α-Syn fragmentation and phosphorylation, escalate dopaminergic neuronal survival and dopamine levels, and restore motor functions in SNCA/MPTP PD mice.

Practical Implications

Potential New Therapeutics

CF3CN and #11A show promise as potential therapeutic agents for Parkinson's disease.

Combination Therapy

The combination of CF3CN and #11A may offer an enhanced therapeutic effect compared to individual treatments.

Disease-Modifying Strategies

The compounds may represent new disease-modifying strategies for treating PD by targeting specific pathological mechanisms.

Study Limitations

1
Study conducted on MPTP-induced human SNCA transgenic PD mouse model; results may not directly translate to human patients.
2
The brain permeability of #11A is not optimal compared to other derivatives.
3
Further research is needed to understand the long-term effects and safety profile of CF3CN and #11A.

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