Post-stroke brain can be protected by modulating the lncRNA FosDT

Area of Science:

• Neuroscience
• Molecular Biology
• Genetics

Background:

• Stroke induces significant secondary brain damage.
• Fos downstream transcript (FosDT), a long noncoding RNA, is implicated in post-stroke neuronal injury.
• Previous studies indicated neuroprotective effects of FosDT knockdown or deletion.

Purpose of the Study:

• To evaluate the therapeutic potential of FosDT siRNA for stroke treatment.
• To assess the efficacy of FosDT siRNA across various rodent models and conditions.
• To elucidate the molecular mechanisms underlying FosDT's role in stroke.

Main Methods:

• Transient middle cerebral artery occlusion (MCAO) model in rodents.
• Administration of FosDT siRNA at different time points post-reperfusion.
• Assessment of motor function recovery using rotarod, beam walk, and adhesive removal tests.
• Measurement of infarct size.
• Investigation of molecular pathways involving REST and NF-κB.

Main Results:

• FosDT siRNA administration significantly improved motor function recovery and reduced infarct size in adult and aged rats of both sexes.
• Delayed administration of FosDT siRNA also demonstrated significant therapeutic benefits.
• FosDT siRNA enhanced functional recovery in both normal and diabetic mice.
• The transcription factor REST mediates FosDT-induced neuronal damage, while NF-κB regulates FosDT expression.

Conclusions:

• FosDT is a viable therapeutic target for mitigating secondary brain damage after stroke.
• FosDT siRNA exhibits a favorable therapeutic window and broad applicability across sex, age, species, and comorbidities.
• Targeting FosDT holds promise for enhancing post-stroke functional recovery.