Molecular neurobiology
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Molecular neurobiology · Dec 2016
Traumatic Brain Injury Increases the Expression of Nos1, Aβ Clearance, and Epileptogenesis in APP/PS1 Mouse Model of Alzheimer's Disease.
To test the hypothesis that an amyloidogenic genetic background predisposes to worsening of post-TBI outcome, we investigated whether traumatic brain injury (TBI) in amyloid precursor protein (APP)/PS1 mice aggravates epileptogenesis and/or enhances somatomotor and cognitive impairment. To elaborate the mechanisms of worsening outcomes, we studied changes in the expression of genes involved in APP processing and Tau pathways in the perilesional cortex, ipsilateral thalamus, and ipsilateral hippocampus 16 weeks post-TBI. Mild (mTBI) or severe TBI (sTBI) was triggered using controlled cortical impact in 3-month-old APP/PS1 mice and wild-type (Wt) littermates. ⋯ Motor impairment correlated (p < 0.001) with the increased cortical expression of genes encoding proteins related to β-amyloid (Aβ) clearance, including Clu (r = 0.83), Abca1 (r = 0.78), A2m (r = 0.76), Apoe (r = 0.70), and Ctsd (r = 0.63). Immunohistochemical analysis revealed a focal reduction in Aβ load lateral to lesion core in APP/PS1-sTBI mice compared to APP/PS1-sham mice (p < 0.05). The present study provides the first comprehensive evidence of exacerbated epileptogenesis and its molecular mechanisms in Alzheimer's disease (AD)-related genetic background after TBI.
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Molecular neurobiology · Dec 2016
Meta AnalysisEfficacy of Progesterone for Acute Traumatic Brain Injury: a Meta-analysis of Randomized Controlled Trials.
Progesterone, a steroid hormone, has been shown to have multifactorial neuroprotective effects in a variety of animal models of acute traumatic brain injury (TBI). Translation to humans showed positive effects in previous phase II trials, but unfortunately, negative results were observed in two recent phase III trials. The present study focuses on the efficacy of progesterone on acute TBI based on the published data of randomized controlled trials (RCTs). ⋯ Sensitivity analysis showed that all the outcomes were stable after excluding Shakeri (Clin Neurol Neurosurg 115: 2019-2022, 2013) or Wright (N Engl J Med 371: 2457-2466, 2014) trials. The quality of the evidence was varied from high to low. In conclusion, progesterone has no significant improvement in the functional recovery and mortality rate after acute TBI.
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Molecular neurobiology · Dec 2016
Topological Reorganization of the Default Mode Network in Irritable Bowel Syndrome.
The aim of this study was to investigate the topological reorganization of the brain default mode network (DMN) in patients with irritable bowel syndrome (IBS) using resting-state functional magnetic resonance imaging (rs-fMRI). With approval by our ethics committee, rs-fMRI was prospectively performed in 31 IBS patients (25 male, 27 ± 8 years) and 32 healthy controls (25 male, 29 ± 9 years). The DMN was determined by unbiased seed-based functional connectivity (FC) analysis and then parcellated into several subregions. ⋯ Inclusion of anxiety and depression as covariates abolished FC between ORBsupmed and precuneus and some E glob differences. The average DMN FC was positively correlated with average E glob (r = 0.47, P = 0.008) and negatively correlated with symptom severity score (r = -0.37, P = 0.04) in IBS patients. In conclusion, IBS patients showed topological reorganization of the DMN to a non-optimized regularity configuration, which may partly be ascribed to high levels of anxiety and depression.
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Molecular neurobiology · Dec 2016
GSK-3β inhibitor TWS119 attenuates rtPA-induced hemorrhagic transformation and activates the Wnt/β-catenin signaling pathway after acute ischemic stroke in rats.
Hemorrhagic transformation (HT) is a devastating complication for patients with acute ischemic stroke who are treated with tissue plasminogen activator (tPA). It is associated with high morbidity and mortality, but no effective treatments are currently available to reduce HT risk. Therefore, methods to prevent HT are urgently needed. ⋯ In addition, Western blot analysis showed that TWS119 increased the protein expression of β-catenin, claudin-3, and ZO-1 while suppressing the expression of GSK-3β. These results suggest that TWS119 reduces rtPA-induced HT and attenuates blood-brain barrier disruption, possibly through activation of the Wnt/β-catenin signaling pathway. This study provides a potential therapeutic strategy to prevent tPA-induced HT after acute ischemic stroke.
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Molecular neurobiology · Dec 2016
bFGF Protects Against Blood-Brain Barrier Damage Through Junction Protein Regulation via PI3K-Akt-Rac1 Pathway Following Traumatic Brain Injury.
Many traumatic brain injury (TBI) survivors sustain neurological disability and cognitive impairments due to the lack of defined therapies to reduce TBI-induced blood-brain barrier (BBB) breakdown. Exogenous basic fibroblast growth factor (bFGF) has been shown to have neuroprotective function in brain injury. The present study therefore investigates the beneficial effects of bFGF on the BBB after TBI and the underlying mechanisms. ⋯ Both the in vivo and in vitro effects are related to the activation of the downstream signaling pathway, PI3K/Akt/Rac-1. Inhibition of the PI3K/Akt or Rac-1 by specific inhibitors LY294002 or si-Rac-1, respectively, partially reduces the protective effect of bFGF on BBB integrity. Overall, our results indicate that the protective role of bFGF on BBB involves the regulation of tight junction proteins and RhoA in the TBI model and OGD-induced HBMECs injury, and that activation of the PI3K/Akt /Rac-1 signaling pathway underlies these effects.