Fingolimod Effects on Motor Function and BDNF-TrkB Signaling in a Huntington's Mouse Model Are...

Area of Science:

• Neuroscience
• Pharmacology
• Genetics

Background:

• Huntington's Disease (HD) involves striatal neuron degeneration and motor/cognitive decline.
• Impaired brain-derived neurotrophic factor (BDNF) signaling via Tropomyosin receptor kinase B (TrkB) contributes to neuronal loss in HD.
• Fingolimod, an MS drug, may promote BDNF expression and neurotrophic support.

Purpose of the Study:

• To investigate if fingolimod, initiated presymptomatically, increases striatal BDNF and protects against motor dysfunction in HD.
• To examine fingolimod's effects on BDNF-TrkB signaling in the striatum at different HD disease stages.

Main Methods:

• Utilized the R6/2 mouse model of HD.
• Administered fingolimod chronically during the presymptomatic phase (age 4 weeks) and acutely during the symptomatic phase (age 7 weeks).
• Assessed locomotor deficits, limb clasping, and striatal BDNF-TrkB signaling.

Main Results:

• Chronic fingolimod in presymptomatic R6/2 mice did not improve motor deficits and worsened limb clasping.
• Presymptomatic fingolimod acutely decreased striatal BDNF-TrkB signaling dose-dependently.
• Acute fingolimod in symptomatic R6/2 mice increased striatal BDNF-TrkB signaling dose-dependently.

Conclusions:

• Fingolimod's effects on striatal BDNF-TrkB signaling and motor behavior in HD are complex and disease-stage dependent.
• Initiating fingolimod during the presymptomatic phase is not neuroprotective in the R6/2 HD model.
• Timing of fingolimod administration is critical for potential therapeutic benefit in HD drug trials, including S1P modulator trials.