Traumatic Brain Injury Increased IGF-1B mRNA and Altered IGF-1 Exon 5 and Promoter Region Epigenetic Characteristics in the Rat Pup Hippocampus

Schober, Michelle E.; Ke, Xingrao; Xing, Bohan; Block, Benjamin; Requena, Daniela F.; McKnight, Robert A.; Lane, Robert H.

doi:10.1089/neu.2011.2276

Cited by 37 publications

(28 citation statements)

References 59 publications

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“…In the CNS, the potential role for this interaction is less well documented. Both IGF and IGFBPs are present after TBI [1,2,4] and the differentiation of cerebellar granular cells [25] and motor neurons are dependent on vitronectin [24]. Our findings of vitronectin as favorable compared to the control (Figure 2 and Figure 4) was thus not unexpected.…”

Section: Discussionsupporting

confidence: 56%

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Neurite Growth and Polarization on Vitronectin Substrate after in Vitro Trauma is not Enhanced after IGF Treatment

et al. 2018

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Following traumatic brain injuries (TBI), insulin-like growth factor (IGF) is cortically widely upregulated. This upregulation has a potential role in the recovery of neuronal tissue, plasticity, and neurotrophic activity, though the molecular mechanisms involved in IGF regulation and the exact role of IGF after TBI remain unclear. Vitronectin (VN), an extracellular matrix (ECM) molecule, has recently been shown to be of importance for IGF-mediated cellular growth and migration. Since VN is downregulated after TBI, we hypothesized that insufficient VN levels after TBI impairs the potential beneficial activity of IGF. To test if vitronectin and IGF-1/IGFBP-2 could contribute to neurite growth, we cultured hippocampal neurons on ± vitronectin-coated coverslips and them treated with ± IGF-1/IGF binding protein 2 (IGFBP-2). Under same conditions, cell cultures were also subjected to in vitro trauma to investigate differences in the posttraumatic regenerative capacity with ± vitronectin-coated coverslips and with ± IGF-1/IGFBP-2 treatment. In both the control and trauma situations, hippocampal neurons showed a stronger growth pattern on vitronectin than on the control substrate. Surprisingly, the addition of IGF-1/IGFBP-2 showed a decrease in neurite growth. Since neurite growth was measured as the number of neurites per area, we hypothesized that IGF-1/IGFBP-2 contributes to the polarization of neurons and thus induced a less dense neurite network after IGF-1/IGFBP-2 treatment. This hypothesis could not be confirmed and we therefore conclude that vitronectin has a positive effect on neurite growth in vitro both under normal conditions and after trauma, but that addition of IGF-1/IGFBP-2 does not have a positive additive effect.

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Section: Discussionsupporting

confidence: 56%

“…The insulin-like growth factor system (IGFs) is one example of growth factors that show widespread cortical upregulation following traumatic brain injury (TBI) [1,2]. This family of growth factors is developmentally regulated and displayed in specific regions of the brain, which suggests explicit physiological roles [3].…”

Section: Introductionmentioning

confidence: 99%

Neurite Growth and Polarization on Vitronectin Substrate after in Vitro Trauma is not Enhanced after IGF Treatment

et al. 2018

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“…33 In a controlled cortical impact model of TBI, Schober and colleagues examined hippocampi from 17 day old rat pups and found increased IGF-1B messenger ribonucleic acid (mRNA) expression associated with increased methylation at P1, as well as increased histone modifications associated with gene activation at P2 and exon5/ESE, along with differential methylation in the exon 5ESE regions. 34 While limited in scope, these studies implicate epigenetic modifications as part of the brain's response to traumatic injury. In the present study, we performed large-scale DNA methylation profiling of blast-related injury using our animal model of blast overpressure and identified DNA methylation perturbations associated with blast-related TBI.…”

Section: Introductionmentioning

confidence: 99%

Neuronal DNA Methylation Profiling of Blast-Related Traumatic Brain Injury

Haghighi

Chen

et al. 2015

Journal of Neurotrauma

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Long-term molecular changes in the brain resulting from blast exposure may be mediated by epigenetic changes, such as deoxyribonucleic acid (DNA) methylation, that regulate gene expression. Aberrant regulation of gene expression is associated with behavioral abnormalities, where DNA methylation bridges environmental signals to sustained changes in gene expression. We assessed DNA methylation changes in the brains of rats exposed to three 74.5 kPa blast overpressure events, conditions that have been associated with long-term anxiogenic manifestations weeks or months following the initial exposures. Rat frontal cortex eight months post-exposure was used for cell sorting of whole brain tissue into neurons and glia. We interrogated DNA methylation profiles in these cells using Expanded Reduced Representation Bisulfite Sequencing. We obtained data for millions of cytosines, showing distinct methylation profiles for neurons and glia and an increase in global methylation in neuronal versus glial cells ( p < 10 -7 ). We detected DNA methylation perturbations in blast overpressure-exposed animals, compared with sham blast controls, within 458 and 379 genes in neurons and glia, respectively. Differentially methylated neuronal genes showed enrichment in cell death and survival and nervous system development and function, including genes involved in transforming growth factor b and nitric oxide signaling. Functional validation via gene expression analysis of 30 differentially methylated neuronal and glial genes showed a 1.2 fold change in gene expression of the serotonin N-acetyltransferase gene (Aanat) in blast animals ( p < 0.05). These data provide the first genome-based evidence for changes in DNA methylation induced in response to multiple blast overpressure exposures. In particular, increased methylation and decreased gene expression were observed in the Aanat gene, which is involved in converting serotonin to the circadian hormone melatonin and is implicated in sleep disturbance and depression associated with traumatic brain injury.

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“…In addition, these clinical studies were begun between 18 and 180 weeks post-injury. 26,58 The full benefit of AChE inhibition, as seen in the present study, may be achieved in the acute and subacute periods, when tissue remodeling is still underway. AChE inhibition reverses the cerebral ischemia present in acute TBI, which may be a key factor in the reduction of lesion size, and it enhances perfusion, an index of activation, on the contralateral symmetrical side, which may indicate a beneficial effect on functional compensation.…”

Section: Discussionmentioning

confidence: 67%

“…In fact, many authors have demonstrated molecular and fine morphological alterations in the hippocampus following a primary cortical impact injury. [45][46][47][48]58 Selective manipulation of the central cholinergic system induces a profound deficit in water maze performance, 49 making this methodology suitable for the assessment of cholinergic dysfunction. The brain's cholinergic system is profoundly altered by cerebral cortex impact injury.…”

Section: Discussionmentioning

confidence: 99%

Acetylcholinesterase Inhibition Interacts with Training To Reverse Spatial Learning Deficits after Cortical Impact Injury

Scremin

Norman

Roch

et al. 2012

Journal of Neurotrauma

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Cholinergic mechanisms are known to play a key role in cognitive functions that are profoundly altered in traumatic brain injury (TBI). The present investigation was designed to test the ability of continuous administration, starting at the time of injury, of physostigmine (PHY), an acetylcholinesterase (AChE) inhibitor that crosses the blood-brain barrier (BBB), to ameliorate the alterations of learning and memory induced by cerebral cortex impact injury in rats under isoflurane anesthesia. Learning and memory were assessed with the Morris water maze implemented during days 7-11 (WM1), and days 21-25 post-TBI (WM2), with four trials per day for 3 days, followed by target reversal and 2 additional days of training. These groups of Sprague-Dawley male rats were used: TBI treated with PHY at 3.2 μmol/kg/day (TBI-PHY3.2), or 6.4 μmol/kg/day (TBI-PHY6.4), by subcutaneous osmotic pumps, or TBI and no injury (Sham) treated with saline. AChE activity was measured in brain tissue samples of non-traumatized animals that received PHY at the doses used in the TBI animals. In WM1 tests, PHY3.2 improved learning within sessions, but not between sessions, in the recall of the target position, while PHY6.4 had no significant effects. In WM2 tests, PHY improved within- and between-sessions performance at both dose levels. We found that continuous AChE inhibition interacted with repeated training on the water maze task to completely reverse the deficits seen in learning and memory induced by TBI. The PHY treatment also reduced the amount of brain tissue loss as measured using cresyl violet staining.

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Traumatic Brain Injury Increased IGF-1B mRNA and Altered IGF-1 Exon 5 and Promoter Region Epigenetic Characteristics in the Rat Pup Hippocampus

Cited by 37 publications

References 59 publications

Neurite Growth and Polarization on Vitronectin Substrate after in Vitro Trauma is not Enhanced after IGF Treatment

Neurite Growth and Polarization on Vitronectin Substrate after in Vitro Trauma is not Enhanced after IGF Treatment

Neuronal DNA Methylation Profiling of Blast-Related Traumatic Brain Injury

Acetylcholinesterase Inhibition Interacts with Training To Reverse Spatial Learning Deficits after Cortical Impact Injury

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