Pathways Leading to Apoptotic Neurodegeneration Following Trauma to the Developing Rat Brain

Felderhoff‐Mueser, Ursula; Sifringer, Marco; Pesditschek, Stefanie; Kuckuck, Heike; Moysich, Axel; Bittigau, Petra; Ikonomidou, Chrysanthy

doi:10.1006/nbdi.2002.0521

Cited by 83 publications

(66 citation statements)

References 42 publications

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“…By 48 hrs after injury the number of apoptotic cells in the thalamus and cortex was largely reduced, and no caspase-3 positive neurons were detected by 7 days post-injury. These data demonstrate that, similar to rats (Felderhoff-Mueser et al, 2002;Bittigau et al, 2003), apoptotic cell death is the major contributor to post-traumatic neuronal degeneration in infant mice compared to the delayed, biphasic, and limited apoptosis in adults (Conti et al, 1998;Yakovlev and Faden, 2001;Raghupathi et al, 2002).…”

Section: Discussionmentioning

confidence: 64%

“…Accordingly, these two age groups have been widely used to model the neurodegenerative and neurophatological consequences of TBI in infants and toddlers (Adelson et al, 1996;Prins et al, 1996;Tong et al, 2002;Bittigau et al, 2003;Pullela et al, 2006;Huh et al, 2007). It has been shown that moderate to severe TBI in infant rats (P3-P14) resulted in initial excitotoxic/necrotic cell death at the impact site within 4-5 hours after impact, which was followed by disproportionally larger apoptotic cell death in the cortex and subcortical regions peaking at 24 hrs post-injury (Bittigau et al, 1999;Felderhoff-Mueser et al, 2002;Bittigau et al, 2003;Bayly et al, 2006b). However, post-traumatic apoptotic cell death declined significantly during the second postnatal week and was almost a non factor by P14 (Bittigau et al, 1999).…”

Section: Introductionmentioning

confidence: 99%

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Mild traumatic brain injury to the infant mouse causes robust white matter axonal degeneration which precedes apoptotic death of cortical and thalamic neurons

Dikranian

Cohen

Donald

et al. 2008

Experimental Neurology

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The immature brain in the first several years of childhood is very vulnerable to trauma. Traumatic brain injury (TBI) during this critical period often leads to neuropathological and cognitive impairment. Previous experimental studies in rodent models of infant TBI were mostly concentrated on neuronal degeneration, while axonal injury and its relationship to cell death have attracted much less attention. To address this, we developed a closed controlled head injury model in infant (P7) mice and characterized the temporospatial pattern of axonal degeneration and neuronal cell death in the brain following mild injury. Using amyloid precursor protein (APP) as marker of axonal injury we found that mild head trauma causes robust axonal degeneration in the cingulum/external capsule as early as 30 min post-impact. These levels of axonal injury persisted throughout a 24 hr period, but significantly declined by 48 hrs. During the first 24 hrs injured axons underwent significant and rapid pathomorphological changes. Initial small axonal swellings evolved into larger spheroids and clublike swellings indicating the early disconnection of axons. Ultrastructural analysis revealed compaction of organelles, axolemmal and cytoskeletal defects. Axonal degeneration was followed by profound apoptotic cell death in the posterior cingulate and retrosplenial cortex and anterior thalamus which peaked between 16 and 24 hrs post-injury. At early stages post-injury no evidence of excitotoxic neuronal death at the impact site was found. At 48 hrs apoptotic cell death was reduced and paralleled with the reduction in the number of APP-labeled axonal profiles. Our data suggest that early degenerative response to injury in axons of the cingulum and external capsule may cause disconnection between cortical and thalamic neurons, and lead to their delayed apoptotic death.

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Section: Discussionmentioning

confidence: 64%

Section: Introductionmentioning

confidence: 99%

Mild traumatic brain injury to the infant mouse causes robust white matter axonal degeneration which precedes apoptotic death of cortical and thalamic neurons

Dikranian

Cohen

Donald

et al. 2008

Experimental Neurology

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“…Marmigere et al, 2003), whereas LPS and stress activate glutamatergic (Karreman and Moghaddam, 1996;Glezer et al, 2003) and dopaminergic (Abekawa et al, 2000;Gamaro et al, 2003;Matsumoto et al, 2005) systems, which induces BDNF expression (Zafra et al, 1990(Zafra et al, , 1991Kuppers and Beyer, 2001). Although BDNF increases in pathological situations (Felderhoff-Mueser et al, 2002) and seems to exert a protective activity (TapiaArancibia et al, 2004), some evidence suggests that neurotrophins strengthen or may even cause neuronal damage under certain pathological conditions through the induction of NADPH-oxidase (Koh et al, 1995;Samdani et al, 1997;Kim et al, 2002). Thus, BDNF could be involved in the increase of the damage induced by inflammation in stressed animals.…”

Section: Discussionmentioning

confidence: 99%

Stress Increases Vulnerability to Inflammation in the Rat Prefrontal Cortex

Pablos¹,

Villarán²,

Argüelles³

et al. 2006

J. Neurosci.

193

176

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Inflammation could be involved in some neurodegenerative disorders that accompany signs of inflammation. However, because sensitivity to inflammation is not equal in all brain structures, a direct relationship is not clear. Our aim was to test whether some physiological circumstances, such as stress, could enhance susceptibility to inflammation in the prefrontal cortex (PFC), which shows a relative resistance to inflammation. PFC is important in many brain functions and is a target for some neurodegenerative diseases. We induced an inflammatory process by a single intracortical injection of 2 g of lipopolysaccharide (LPS), a potent proinflammogen, in nonstressed and stressed rats. We evaluated the effect of our treatment on inflammatory markers, neuronal populations, BDNF expression, and behavior of several mitogen-activated protein (MAP) kinases and the transcription factor cAMP response element-binding protein. Stress strengthens the changes induced by LPS injection: microglial activation and proliferation with an increase in the levels of the proinflammatory cytokine tumor necrosis factor-␣; loss of cells such as astroglia, seen as loss of glial fibrillary acidic protein immunoreactivity, and neurons, studied by neuronal-specific nuclear protein immunohistochemistry and GAD67 and NMDA receptor 1A mRNAs expression by in situ hybridization. A significant increase in the BDNF mRNA expression and modifications in the levels of MAP kinase phosphorylation were also found. In addition, we observed a protective effect from RU486 [mifepristone (11␤-[p-(dimethylamino)phenyl]-17␤-hydroxy-17-(1-propynyl)estra-4,9-dien-3-one)], a potent inhibitor of the glucocorticoid receptor activation. All of these data show a synergistic effect between inflammation and stress, which could explain the relationship described between stress and some neurodegenerative pathologies.

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“…Classical apoptosis may proceed by the intrinsic and/or extrinsic pathway (16)(17)(18). In the intrinsic pathway, mitochondria are induced to release a number of factors, leading to the formation of the apoptosome, which is comprised of the adapter protein Apaf-1, cytochrome c and caspase-9 (19,20). The extrinsic pathway, is believed to be based on death receptor-dependent recruitment of the adaptor protein, Fas-associated death domain (FADD), which, in turn, promotes dimerization and subsequent activation of caspase-8 (21).…”

Section: Discussionmentioning

confidence: 99%

Use of a novel sonosensitizer in sonodynamic therapy of U251 glioma cells in vitro

Chen

Song

et al. 2011

Experimental and Therapeutic Medicine

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Abstract. The aim of the present study was to investigate the effect of ZnPcS 2 P 2 -meditated sonodynamic therapy (SDT) on U251 human glioma cells and to identify its underlying biological mechanism. The growth inhibition rate was determined by MTT assay. The apoptotic rate was examined by flow cytometry. Fine structures were observed with transmission electron microscopy (TEM). Generation of reactive oxygen species (ROS) was detected spectrophotometrically. Caspase-3, -8 and -9 expression was detected by Western blot analysis. The growth inhibition rate of U251 human glioma cells indicated that ZnPcS 2 P 2 -meditated SDT had a better growth inhibition rate of tumor cells at a concentration of 5.0 µg/ml ZnPcS 2 P 2 , at a 4-h incubation time with ZnPcS 2 P 2 , and at 6 h re-incubation following SDT. At 6 h after SDT, the growth inhibition rate of cells was significantly higher compared to other groups, apoptosis could be detected in SDT by flow cytometry. TEM examination revealed morphological features of apoptosis or necrosis. Furthermore, caspase-3, -8 and -9 expression following SDT was found to be increased by Western blot analysis. Finally, generation of ROS in cells was also elevated. In conclusion, ZnPcS 2 P 2 -SDT is capable of inducing U251 cell apoptosis or necrosis and has satisfying antitumor effects. The mechanism of ZnPcS 2 P 2 -meditated SDT involves ROS generation in U251 cells, which initiates subsequent apoptosis through the mitochondrial and death receptor pathways.

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Pathways Leading to Apoptotic Neurodegeneration Following Trauma to the Developing Rat Brain

Cited by 83 publications

References 42 publications

Mild traumatic brain injury to the infant mouse causes robust white matter axonal degeneration which precedes apoptotic death of cortical and thalamic neurons

Mild traumatic brain injury to the infant mouse causes robust white matter axonal degeneration which precedes apoptotic death of cortical and thalamic neurons

Stress Increases Vulnerability to Inflammation in the Rat Prefrontal Cortex

Use of a novel sonosensitizer in sonodynamic therapy of U251 glioma cells in vitro

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