Dying neurons in thalamus of asphyxiated term newborns and rats are autophagic

Ginet, Vanessa; Pittet, Marie P.; Rummel, Coralie; Osterheld, Maria‐Chiara; Meuli, Reto; Clarke, Peter G. H.; Puyal, Julien; Truttmann, Anita C.

doi:10.1002/ana.24257

Cited by 45 publications

(57 citation statements)

References 58 publications

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“…ADC values were lower in the thalamus than in the basal ganglia, and were increased in both areas during the first week after birth. It has been shown that restricted diffusion corresponds to cytotoxic edema and therefore irreversible lesions with neuronal cell death [19].…”

Section: Discussionmentioning

confidence: 99%

MRI Changes in the Thalamus and Basal Ganglia of Full-Term Neonates with Perinatal Asphyxia

et al. 2018

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Background: Magnetic resonance imaging (MRI) is the standard neuroimaging technique to assess perinatal asphyxia-associated brain injury in full-term infants. Diffusion-weighted imaging (DWI) is most informative when assessed during the first week after the insult. Objectives: To study the DWI abnormalities of the thalamus and basal ganglia in full-term infants with perinatal asphyxia. Methods: Fifty-five (near) term infants (normothermia n = 23; hypothermia n = 32) with thalamus and/or basal ganglia injury were included. MRI findings were assessed visually and quantitatively calculating apparent diffusion coefficient (ADC) values. Thalamus/basal ganglia ADC ratios were calculated to analyze the differences between these areas. Infants with an early MRI (days 1–3) or later MRI (days 4–7) were compared. Results: Isolated extensive thalamic injury was seen early, and focal thalamic and basal ganglia injury was seen later. On the early MRI, visual assessment underestimated abnormalities in the basal ganglia (59% abnormal vs. 90% abnormal on quantitative assessment; p = 0.015), suggesting the need for quantitative assessment. In infants treated with hypothermia, the thalamus/basal ganglia ADC ratio was lower. Conclusions: Both visual analysis and quantitative evaluation of cerebral MRI after perinatal asphyxia are needed, especially during the first few days after birth. Timing of ADC changes is influenced by therapeutic hypothermia.

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Section: Discussionmentioning

confidence: 99%

MRI Changes in the Thalamus and Basal Ganglia of Full-Term Neonates with Perinatal Asphyxia

et al. 2018

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“…23, 24 Selective KO of Atg7 in neuronally committed cells shows that basal levels of autophagy are required for normal neuron survival, 16, 25 and autophagy is a protective mechanism in response to numerous stresses. 26, 27 Overactivated autophagy induces autophagic cell death, 28 and genetic inhibition of autophagy prevents hypoxia–ischemia-induced neuronal cell death in multiple brain regions. 18 Autophagy has also been shown to be involved in irradiation-induced cell death in cancer cells, 29, 30 and autophagy inhibitors can enhance radiosensitivity in gliomas; 31 however, it is still unknown if inhibition of autophagy works to prevent irradiation-induced neural stem and progenitor cell death in the juvenile brain.…”

Section: Discussionmentioning

confidence: 99%

Inhibition of autophagy prevents irradiation-induced neural stem and progenitor cell death in the juvenile mouse brain

Wang

Zhou

et al. 2017

Cell Death Dis

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Radiotherapy is an effective tool in the treatment of malignant brain tumors. However, damage to brain stem and progenitor cells constitutes a major problem and is associated with long-term side effects. Autophagy has been shown to be involved in cell death, and the purpose of this study was to evaluate the effect of autophagy inhibition on neural stem and progenitor cell death in the juvenile brain. Ten-day-old selective Atg7 knockout (KO) mice and wild-type (WT) littermates were subjected to a single 6Gy dose of whole-brain irradiation. Cell death and proliferation as well as microglia activation and inflammation were evaluated in the dentate gyrus of the hippocampus and in the cerebellum at 6 h after irradiation. We found that cell death was reduced in Atg7 KO compared with WT mice at 6 h after irradiation. The number of activated microglia increased significantly in both the dentate gyrus and the cerebellum of WT mice after irradiation, but the increase was lower in the Atg7 KO mice. The levels of proinflammatory cytokines and chemokines decreased, especially in the cerebellum, in the Atg7 KO group. These results suggest that autophagy might be a potential target for preventing radiotherapy-induced neural stem and progenitor cell death and its associated long-term side effects.

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“…Later, in both rat and mouse models of perinatal HI, ultrastructural studies revealed numerous autophagosomes and autolysosomes in the cytosol of dying neurons (Ginet et al, 2009; Koike et al, 2008; Zhu et al, 2005). In P7 hypoxic‐ischemic rat pups, our group showed that an LC3‐II increase was already detectable as soon as 6 h after the insult and peaked at around 24 h (Ginet et al, 2014a; Ginet et al, 2009). Autophagic flux enhancement was suggested by an increase in both LC3‐positive dots and lysosomal markers (LAMP1, cathepsins) and activity (acid phosphatase, β‐hexosaminidase) that can occur in the same dying neurons (Ginet et al, 2009).…”

Section: Autophagy Mediated Cell Death In Neonatal Himentioning

confidence: 94%

“…Few studies have addressed the functional role of enhanced autophagy in neonatal cerebral HI models until now. All the studies suggest that enhanced autophagy plays a role in the apoptotic pathway since dying neurons can express both autophagic and apoptotic features (Carloni et al, 2008; Ginet et al, 2014a; Ginet et al, 2009; Koike et al, 2008) and since autophagy inhibition decreases apoptotic markers such as caspase‐3 activation (Carloni et al, 2008; Koike et al, 2008). Interestingly, we showed that autophagy could mediate apoptosis in primary cortical neurons cultures treated with classical apoptotic stimuli (Grishchuk et al, 2011).…”

Section: Autophagy Mediated Cell Death In Neonatal Himentioning

confidence: 99%

Neuronal death after perinatal cerebral hypoxia‐ischemia: Focus on autophagy—mediated cell death

Descloux

Ginet²,

Clarke³

et al. 2015

Intl J of Devlp Neuroscience

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Neonatal hypoxic-ischemic encephalopathy is a critical cerebral event occurring around birth with high mortality and neurological morbidity associated with long-term invalidating sequelae. In view of the great clinical importance of this condition and the lack of very efficacious neuroprotective strategies, it is urgent to better understand the different cell death mechanisms involved with the ultimate aim of developing new therapeutic approaches. The morphological features of three different cell death types can be observed in models of perinatal cerebral hypoxia-ischemia: necrotic, apoptotic and autophagic cell death. They may be combined in the same dying neuron. In the present review, we discuss the different cell death mechanisms involved in neonatal cerebral hypoxia-ischemia with a special focus on how autophagy may be involved in neuronal death, based: (1) on experimental models of perinatal hypoxia-ischemia and stroke, and (2) on the brains of human neonates who suffered from neonatal hypoxia-ischemia.

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Dying neurons in thalamus of asphyxiated term newborns and rats are autophagic

Abstract: These results show for the first time that autophagy is enhanced in severe HIE in dying thalamic neurons of human newborns, as in rats. Experimental neuroprotective strategies targeting autophagy could thus be a promising lead to follow for the development of future therapeutic approaches.

Cited by 45 publications

References 58 publications

MRI Changes in the Thalamus and Basal Ganglia of Full-Term Neonates with Perinatal Asphyxia

MRI Changes in the Thalamus and Basal Ganglia of Full-Term Neonates with Perinatal Asphyxia

Inhibition of autophagy prevents irradiation-induced neural stem and progenitor cell death in the juvenile mouse brain

Neuronal death after perinatal cerebral hypoxia‐ischemia: Focus on autophagy—mediated cell death

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