Proteins released from degenerating neurons are surrogate markers for acute brain damage

Siman, Robert; McIntosh, Tracy K.; Soltesz, Kristie; Chen, Zhaoming; Neumar, Robert W.; Roberts, Veronica

doi:10.1016/j.nbd.2004.03.016

Cited by 157 publications

(152 citation statements)

References 47 publications

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“…miR-711 appears to be sufficient for neuronal cell death, as indicated by decreased survival in neurons treated with miR-711 mimics. Administration of miR-711 hairpin inhibitors attenuated etoposide-induced neuronal apoptosis-resulting in reductions in PUMA, Bim and mitochondria permeabilization, as well as decreased markers of caspase-dependent (caspase-3, PARP and α-fodrin cleavage) 22 and -independent (AIF nuclear translocation) 11 cell death. The specificity of these actions is demonstrated by the lack of effects of miR-711 hairpin inhibitors on other pro-apoptotic Bcl2 family members such as Noxa, Bid or Bax (data not shown).…”

Section: Mir-711 Activates Neuronal Apoptosis B Sabirzhanov Et Almentioning

confidence: 99%

“…Western blot demonstrated that neurons transfected with miR-711 hairpin inhibitor displayed reduced levels of the cleaved fragment of caspase-3, cleaved poly-(ADP-ribose) polymerase (PARP), and attenuated the decrease of the full length uncleaved fragment of α-fodrin (240 kDa) after etoposide treatment (Figures 2a and f-h). miR-711 hairpin inhibitor reduced the levels of both calpain-dependent (150/145 kDa) and caspase-dependent cleavage (150/120 kDa) 22 fragments of α-fodrin (Figures 2a, i and j).…”

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confidence: 99%

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miR-711 upregulation induces neuronal cell death after traumatic brain injury

et al. 2015

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Traumatic brain injury (TBI) is a leading cause of mortality and disability. MicroRNAs (miRs) are small noncoding RNAs that negatively regulate gene expression at post-transcriptional level and may be key modulators of neuronal apoptosis, yet their role in secondary injury after TBI remains largely unexplored. Changes in miRs after controlled cortical impact (CCI) in mice were examined during the first 72 h using miR arrays and qPCR. One selected miR (711) was examined with regard to its regulation and relation to cell death; effects of miR-711 modulation were evaluated after CCI and using in vitro cell death models of primary cortical neurons. Levels of miR-711 were increased in the cortex early after TBI and in vitro models through rapid upregulation of miR-711 transcription (pri-miR-711) rather than catabolism. Increases coincided with downregulation of the pro-survival protein Akt, a predicted target of miR-711, with sequential activation of forkhead box O3 (FoxO3)a/glycogen synthase kinase 3 (GSK3)α/β, pro-apoptotic BH3-only molecules PUMA (Bcl2-binding component 3) and Bim (Bcl2-like 11 (apoptosis facilitator)), and mitochondrial release of cytochrome c and AIF. miR-711 and Akt (mRNA) co-immunoprecipitated with the RNA-induced silencing complex (RISC). A miR-711 hairpin inhibitor attenuated the apoptotic mechanisms and decreased neuronal death in an Aktdependent manner. Conversely, a miR-711 mimic enhanced neuronal apoptosis. Central administration of the miR-711 hairpin inhibitor after TBI increased Akt expression and attenuated apoptotic pathways. Treatment reduced cortical lesion volume, neuronal cell loss in cortex and hippocampus, and long-term neurological dysfunction. miR-711 changes contribute to neuronal cell death after TBI, in part by inhibiting Akt, and may serve as a novel therapeutic target.

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Section: Mir-711 Activates Neuronal Apoptosis B Sabirzhanov Et Almentioning

confidence: 99%

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confidence: 99%

miR-711 upregulation induces neuronal cell death after traumatic brain injury

et al. 2015

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“…While no such test currently exists, there are many efforts under way to identify TBI protein product biomarkers released by injured brain cells using cell biological and neuroproteomic approaches in serum and cerebrospinal fluid (CSF). [122][123][124] A validated and sensitive test would be especially important for mild TBI with suspected DAI, where typically there are no radiological findings. Identifying biomarkers to detect damage in mild TBI, however, has been very challenging, considering that CSF is not likely to be collected from this patient population and there is little perturbation of the blood-brain barrier that would allow biomarkers to reach the systemic circulation for routine blood analysis.…”

Section: Biomarkersmentioning

confidence: 99%

“…Among these, recent studies have suggested that aII-spectrin breakdown products SBDP150 and 145, produced by calpain cleavage, have been linked to acute neuronal necrosis, while SBDP120, produced by caspase 3, has been linked to apoptotic cell death cascades. 41,122,[125][126][127][128][129][130][131] While these aII-spectrin breakdown products have been discussed within the context of neuronal damage, it is important to note that they have been associated with both TAI/DAI and its downstream target deafferentation and synaptic loss. 38,51,[132][133][134] In addition to spectrin breakdown products, other potential markers of axonal injury include various phosphoforms of the neurofilament-H subunit as well as cleaved tau suggesting damage to the axon cytoskeleton.…”

Section: Biomarkersmentioning

confidence: 99%

Therapy Development for Diffuse Axonal Injury

Smith

Hicks

Povlishock

2013

Journal of Neurotrauma

171

146

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Diffuse axonal injury (DAI) remains a prominent feature of human traumatic brain injury (TBI) and a major player in its subsequent morbidity. The importance of this widespread axonal damage has been confirmed by multiple approaches including routine postmortem neuropathology as well as advanced imaging, which is now capable of detecting the signatures of traumatically induced axonal injury across a spectrum of traumatically brain-injured persons. Despite the increased interest in DAI and its overall implications for brain-injured patients, many questions remain about this component of TBI and its potential therapeutic targeting. To address these deficiencies and to identify future directions needed to fill critical gaps in our understanding of this component of TBI, the National Institute of Neurological Disorders and Stroke hosted a workshop in May 2011. This workshop sought to determine what is known regarding the pathogenesis of DAI in animal models of injury as well as in the human clinical setting. The workshop also addressed new tools to aid in the identification of this axonal injury while also identifying more rational therapeutic targets linked to DAI for continued preclinical investigation and, ultimately, clinical translation. This report encapsulates the oral and written components of this workshop addressing key features regarding the pathobiology of DAI, the biomechanics implicated in its initiating pathology, and those experimental animal modeling considerations that bear relevance to the biomechanical features of human TBI. Parallel considerations of alternate forms of DAI detection including, but not limited to, advanced neuroimaging, electrophysiological, biomarker, and neurobehavioral evaluations are included, together with recommendations for how these technologies can be better used and integrated for a more comprehensive appreciation of the pathobiology of DAI and its overall structural and functional implications. Lastly, the document closes with a thorough review of the targets linked to the pathogenesis of DAI, while also presenting a detailed report of those target-based therapies that have been used, to date, with a consideration of their overall implications for future preclinical discovery and subsequent translation to the clinic. Although all participants realize that various research gaps remained in our understanding and treatment of this complex component of TBI, this workshop refines these issues providing, for the first time, a comprehensive appreciation of what has been done and what critical needs remain unfulfilled.

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“…rons Cerebral cortical neurons were prepared from embryonic day 17 Sprague-Dawley rats as described previously [12,13] .…”

Section: Primary Culture and Treatment Of Cerebral Cortical Neu-mentioning

confidence: 99%

Glutamate enhances the surface distribution and release of Munc18 in cerebral cortical neurons

et al. 2010

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Objective Munc18 is considered as an intracellular protein that plays an important role in exocytosis of neurotransmitters. Previous studies have demonstrated the presence of autoantibodies against Munc18 in a subgroup of Rasmussen's encephalitis patients. However, the machinery of Munc18 autoimmunity is still elusive. The present study was aimed to investigate Munc18 release from primary cultured neurons, Munc18 distribution on the outer plasma membrane of neurons, and the neurotoxicity of Munc18 antibody. Methods The cerebral cortical neurons from embryonic day 17 SpragueDawley rats were prepared and cultured in neurobasal medium. The proteins in culture medium were precipitated with 10% trichloroacetic acid, and analyzed by immunoblotting. The proteins on neuronal surface were biotinylated with EZ-Link-sulfo-NHS-LC-Biotin, and collected with avidin-conjugated agarose beads followed by immunoblotting analysis. For cell surface immunofluorescent staining, the living neurons were labeled with anti-Munc18 antibody at 4 °C. Neuronal injury was assessed by lactate dehydrogenase(LDH) release. Results Munc18 was detected in culture medium by immunoblotting analysis.After treatment with 50 μmol/L glutamate for 1 h, Munc18 content in medium was increased. Meanwhile, β-actin and syntaxin1were not detected in culture medium, and LDH release was not significantly increased. Moreover, glutamate enhanced Munc18 distribution on outer plasma membrane. Living neuron staining also demonstrated the localization of Munc18 on neuronal surface after glutamate treatment, especially at contacting regions between neurons. Glutamate-induced increase of surface Munc18 distribution was suppressed by NMDA receptor antagonist MK801, but not by AMPA receptor antagonist NBQX. Moreover, compared with c-Fos antibody, Munc18 antibody could induce neuronal injury, when culture medium contained the components of serum. Conclusion A portion of Munc18 can be released from neurons or distributed on neuronal surface, which can be enhanced by glutamate treatment via activation of NMDA receptors. Besides, Munc18 antibody-induced neuronal injury depends on the serum components.

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Proteins released from degenerating neurons are surrogate markers for acute brain damage

Cited by 157 publications

References 47 publications

miR-711 upregulation induces neuronal cell death after traumatic brain injury

miR-711 upregulation induces neuronal cell death after traumatic brain injury

Therapy Development for Diffuse Axonal Injury

Glutamate enhances the surface distribution and release of Munc18 in cerebral cortical neurons

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