title: Potentially neuroprotective gene modulation in an in vitro model of mild traumatic brain injury.
abstract: In this study, we investigated the hypothesis that mild traumatic brain injury (mTBI) triggers a controlled gene program as an adaptive response finalized to neuroprotection, similar to that found in hibernators and in ischemic preconditioning. A stretch injury device was used to produce an equi-biaxial strain field in rat organotypic hippocampal slice cultures at a specified Lagrangian strain of 10 % and a constant strain rate of 20 s(-1). After 24 h from injury, propidium iodide staining, HPLC analysis of metabolites and microarray analysis of cDNA were performed to evaluate cell viability, cell energy state and gene expression, respectively. Compared to control cultures, 10 % stretch injured cultures showed no change in viability, but demonstrated a hypometabolic state (decreased ATP, ATP/ADP, and nicotinic coenzymes) and a peculiar pattern of gene modulation. The latter was characterized by downregulation of genes encoding for proteins of complexes I, III, and IV of the mitochondrial electron transport chain and of ATP synthase; downregulation of transcriptional and translational genes; downregulation and upregulation of genes controlling the synthesis of glutamate and GABA receptors, upregulation of calmodulin and calmodulin-binding proteins; proper modulation of genes encoding for proapoptotic and antiapoptotic proteins. These results support the hypothesis that, following mTBI, a hibernation-type response is activated in non-hibernating species. Unlike in hibernators and ischemic preconditioning, this adaptive gene programme, aimed at achieving maximal neuroprotection, is not triggered by decrease in oxygen availability. It seems rather activated to avoid increase in oxidative/nitrosative stress and apoptosis during a transient period of mitochondrial malfunctioning.
authors.affiliation: Neuropharmacology and Neurobiology Section, School of Clinical and Experimental Medicine, College of Medical and Dental Sciences, University of Birmingham, Birmingham, UK.
authors.forename: Valentina
authors.initials: V
authors.lastname: Di Pietro
authors.forename: Angela M
authors.initials: AM
authors.lastname: Amorini
authors.forename: Barbara
authors.initials: B
authors.lastname: Tavazzi
authors.forename: David A
authors.initials: DA
authors.lastname: Hovda
authors.forename: Stefano
authors.initials: S
authors.lastname: Signoretti
authors.forename: Christopher C
authors.initials: CC
authors.lastname: Giza
authors.forename: Giacomo
authors.initials: G
authors.lastname: Lazzarino
authors.forename: Roberto
authors.initials: R
authors.lastname: Vagnozzi
authors.forename: Giuseppe
authors.initials: G
authors.lastname: Lazzarino
authors.forename: Antonio
authors.initials: A
authors.lastname: Belli
mesh_terms: D000244:Adenosine Diphosphate / Q000378:metabolism; D000255:Adenosine Triphosphate / Q000378:metabolism; D000818:Animals; D001930:Brain Injuries / Q000378:metabolism*; D002470:Cell Survival; D004734:Energy Metabolism; D005786:Gene Expression Regulation; D006624:Hippocampus / Q000378:metabolism* / Q000473:pathology; D008297:Male; D008928:Mitochondria / Q000378:metabolism; D058977:Molecular Sequence Annotation; D009419:Nerve Tissue Proteins / Q000235:genetics / Q000378:metabolism; D020411:Oligonucleotide Array Sequence Analysis; D051381:Rats; D017208:Rats, Wistar; D046509:Tissue Culture Techniques; D059467:Transcriptome
chemical_list: D009419:Nerve Tissue Proteins; D000244:Adenosine Diphosphate; D000255:Adenosine Triphosphate