Cyclosporine A Accelerates Neurorecovery Transcriptional Trajectory in a Swine Model of Diffuse Traumatic Brain...

Area of Science:

• Neuroscience
• Genomics
• Traumatic Brain Injury Research

Background:

• Mild traumatic brain injury (mTBI) is a significant cause of morbidity in children, leading to persistent neurological, cognitive, and emotional deficits.
• The underlying transcriptional changes driving these long-term effects post-mTBI remain incompletely understood.
• Understanding gene expression alterations is crucial for developing effective therapeutic strategies.

Purpose of the Study:

• To investigate the transcriptional landscape of the brain following mild traumatic brain injury (mTBI) in a swine model.
• To characterize the temporal patterns of gene expression changes in distinct brain regions (frontal cortex and hippocampus + amygdala) at acute (1 day) and subacute (1 week) time points post-injury.
• To evaluate the potential neuroprotective and recovery-promoting effects of cyclosporine A (CsA) treatment on mTBI-induced transcriptional alterations.

Main Methods:

• Utilized formalin-fixed paraffin-embedded (FFPE) tissues from swine brains (N = 40) subjected to rapid non-impact head rotation (RNR) to model mTBI.
• Performed RNA sequencing to identify differentially expressed genes (DEGs) at 1 day and 1 week after injury.
• Classified DEGs into temporal patterns and analyzed shared gene ontology annotations to understand biological processes affected by mTBI.
• Administered cyclosporine A (CsA) treatment (20 mg/kg/day) starting 6 hours post-injury for 1 day to assess its impact on gene expression.

Main Results:

• Differentially expressed genes (DEGs) were more abundant at 1 week post-injury compared to 1 day, indicating evolving transcriptional responses.
• Gene ontology analysis revealed terms associated with neuronal distress at 1 day and neurorecovery at 1 week post-mTBI in both studied brain regions.
• CsA treatment significantly modulated DEGs, accelerating transcriptional profiles associated with neurorecovery in both the frontal cortex (466 DEGs) and hippocampus + amygdala (2794 DEGs).

Conclusions:

• Anatomic region and elapsed time significantly influence gene expression patterns following mTBI.
• The study highlights distinct temporal transcriptional signatures of neuronal distress and subsequent neurorecovery post-mTBI.
• Cyclosporine A (CsA) demonstrates potential as a therapeutic agent to promote neurorecovery after mTBI by modulating key transcriptional pathways.