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Potentially neuroprotective gene modulation in an in vitro model of mild traumatic brain injury

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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.

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Acknowledgments

We wish to thank the Wessex Medical Research Centre for funding this study and for their support to our research. We also wish to thank Ms. Kathryn Rasco for her technical assistance in the manuscript preparation.

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Authors and Affiliations

  1. Neuropharmacology and Neurobiology Section, School of Clinical and Experimental Medicine, College of Medical and Dental Sciences, University of Birmingham, Birmingham, UK

    Valentina Di Pietro & Antonio Belli

  2. Division of Clinical Neurosciences, School of Medicine, University of Southampton, Southampton, UK

    Valentina Di Pietro

  3. Institute of Biochemistry and Clinical Biochemistry, Catholic University of Rome, Rome, Italy

    Angela M. Amorini, Barbara Tavazzi & Giacomo Lazzarino

  4. Department of Neurosurgery, Department of Molecular and Medical Pharmacology, David Geffen School of Medicine at UCLA, UCLA Brain Injury Research Center, Los Angeles, CA, USA

    David A. Hovda

  5. Division of Neurosurgery, Department of Neurosciences Head and Neck Surgery, S. Camillo Hospital, Rome, Italy

    Stefano Signoretti

  6. Division of Pediatric Neurology, Department of Neurosurgery, David Geffen School of Medicine at UCLA, Mattel Children’s Hospital UCLA, UCLA Brain Injury Research Center, Los Angeles, CA, USA

    Christopher C. Giza

  7. Division of Neurotraumatology and Neuroradiology, Department of Biomedicine and Prevention, University of Rome Tor Vergata, Rome, Italy

    Roberto Vagnozzi

  8. Division of Biochemistry and Molecular Biology, Department of Biology, Geology and Environmental Sciences, University of Catania, Viale A. Doria 6, 95125, Catania, Italy

    Giuseppe Lazzarino

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  1. Valentina Di Pietro
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  2. Angela M. Amorini
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  3. Barbara Tavazzi
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  6. Christopher C. Giza
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  7. Giacomo Lazzarino
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  9. Giuseppe Lazzarino
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  10. Antonio Belli
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Correspondence to Giuseppe Lazzarino.

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Di Pietro, V., Amorini, A.M., Tavazzi, B. et al. Potentially neuroprotective gene modulation in an in vitro model of mild traumatic brain injury. Mol Cell Biochem 375, 185–198 (2013). https://doi.org/10.1007/s11010-012-1541-2

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  • DOI: https://doi.org/10.1007/s11010-012-1541-2

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