Molecular neurobiology
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Molecular neurobiology · Mar 2017
Protocatechualdehyde Protects Against Cerebral Ischemia-Reperfusion-Induced Oxidative Injury Via Protein Kinase Cε/Nrf2/HO-1 Pathway.
Oxidative stress is closely related to the pathogenesis of ischemic stroke. Protocatechualdehyde (PCA) is a phenolic acid compound that has the putative antioxidant activities. The present study was aimed to investigate the molecular mechanisms involved in the antioxidative effect of PCA against cerebral ischemia/reperfusion (I/R) injury. ⋯ The neuroprotection effect of PCA was abolished by knockdown of Nrf2 and HO-1. Moreover, knockdown of protein kinase Cε (PKCε) also blocked PCA-induced Nfr2 nuclear translocation, HO-1 expression, and neuroprotection. Taken together, these results provide evidences that PCA can protect against cerebral ischemia-reperfusion-induced oxidative injury, and the neuroprotective effect involves the PKCε/Nrf2/HO-1 pathway.
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Molecular neurobiology · Mar 2017
TREM2 Overexpression has No Improvement on Neuropathology and Cognitive Impairment in Aging APPswe/PS1dE9 Mice.
Previously, we showed that overexpression of triggering receptor expressed on myeloid cells 2 (TREM2), a microglia-specific immune receptor, in the brain of a middle-aged (7 months old) APPswe/PS1dE9 mice could ameliorate Alzheimer's disease (AD)-related neuropathology by enhancement of microglial amyloid-β (Aβ) phagocytosis. Since AD is an age-related neurodegenerative disorder, it is critical to assess the efficacy of TREM2 overexpression in aging animals with an advanced disease stage. In vivo, we employed a lentiviral strategy to overexpress TREM2 in the brain of aging (18 months old) APPswe/PS1dE9 mice, and observed its efficacy on AD-related neuropathology and cognitive functions. ⋯ Meanwhile, this phagocytic deficit in microglia from aging APPswe/PS1dE9 mice cannot be rescued by TREM2 overexpression. Taken together, our study shows that TREM2 overexpression fails to provide neuroprotection in aging APPswe/PS1dE9 mice, possibly attributing to deficits in microglial Aβ phagocytosis at the late-stage of disease progression. These findings indicate that TREM2-mediated protection in AD is at least partially dependent on the reservation of microglial phagocytic functions, emphasizing the importance of early therapeutic interventions for this devastating disease.
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Molecular neurobiology · Mar 2017
Combining Normobaric Oxygen with Ethanol or Hypothermia Prevents Brain Damage from Thromboembolic Stroke via PKC-Akt-NOX Modulation.
In a thromboembolic stroke model after reperfusion by recombinant tissue plasminogen activator (rt-PA), we aimed to determine whether therapeutic hypothermia (TH) and ethanol (EtOH) in combination with low concentration (60 %) of normobaric oxygen (NBO) enhanced neuroprotection, as compared to using each of these agents alone. We further aimed to elucidate a potential role of the NADPH oxidase (NOX), phosphorylated protein kinase B (Akt), and protein kinase C-δ (PKC-δ) pathway in oxidative stress and neuroprotection. In Sprague-Dawley rats, a focal middle cerebral artery (MCA) occlusion was induced by an autologous embolus in the following experimental groups: rt-PA treatment alone, rt-PA + NBO treatment, rt-PA + TH at 33 °C, rt-PA + EtOH, rt-PA + NBO + EtOH, rt-PA + NBO + TH, rt-PA + NOX inhibitor, rt-PA + EtOH + NOX inhibitor, or rt-PA + EtOH + Akt inhibitor. ⋯ The present study demonstrated that combining NBO with either TH or EtOH conferred similar neuroprotection via modulation of NOX activation. The results suggest a role of Akt in NOX activation and implicate an upstream PKC-δ pathway in the Akt regulation of NOX. It is possible to substitute EtOH for TH, thus circumventing the difficulties in clinical application of TH through the comparatively easier usage of EtOH as a potential stroke management.
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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.