Transcriptomics of traumatic brain injury: gene expression and molecular pathways of different grades of insult in a rat organotypic hippocampal culture model.
Traumatic brain injury (TBI) is the one of the most common forms of head trauma, and it remains a leading cause of death and disability. It is known that the initial mechanical axonal injury triggers a complex cascade of neuroinflammatory and metabolic events, the understanding of which is essential for clinical, translational, and pharmacological research. These can occur even in mild TBI, and are associated with several post-concussion manifestations, including transiently heightened vulnerability to a second insult. Recent studies have challenged the tenet that ischemia is the ultimate modality of tissue damage following TBI, as metabolic dysfunction can develop in the presence of normal perfusion and before intracranial hypertension. In order to elucidate the cellular and molecular changes occurring in TBI as a direct result of neuronal injury and in the absence of ischemic damage, we performed a microarray analysis of expressed genes and molecular interaction pathways for different levels of severity of trauma using an in-vitro model. A stretch injury, equivalent to human diffuse axonal injury, was delivered to rat organotypic hippocampal slice cultures, and mRNA levels following a 10% (mild) and 50% (severe) stretch were compared with controls at 24 h. More genes were differentially expressed following 10% stretch than 50% stretch, indicating the early activation of complex cellular mechanisms. The data revealed remarkable differential gene expression following mTBI, even in the absence of cell damage. Pathway analysis revealed that molecular interactions in both levels of injury were similar, with IL-1beta playing a central role. Additional pathways of neurodegeneration involving RhoA (ras homolog gene family, member A) were found in 50% stretch.
Di Pietro
Valentina
V
Division of Clinical Neurosciences, University of Southampton School of Medicine, Southampton, SO16 6YD, United Kingdom.
Amin
Daven
D
Pernagallo
Salvatore
S
Lazzarino
Giuseppe
G
Tavazzi
Barbara
B
Vagnozzi
Roberto
R
Pringle
Ashley
A
Belli
Antonio
A
D000818:Animals; D001930:Brain Injuries / Q000235:genetics* / Q000503:physiopathology*; D015870:Gene Expression; D020869:Gene Expression Profiling; D006624:Hippocampus / Q000503:physiopathology*; D020411:Oligonucleotide Array Sequence Analysis; D009924:Organ Culture Techniques; D051381:Rats; D017208:Rats, Wistar; D020133:Reverse Transcriptase Polymerase Chain Reaction; D014158:Transcription, Genetic