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Neuroprotection by selective neuronal deletion of Atg7 in neonatal brain injury.

Xie C, Ginet V, Sun Y, Koike M, Zhou K, Li T, Li H, Li Q, Wang X, Uchiyama Y, Truttmann AC, Kroemer G, Puyal J, Blomgren K, Zhu C - Autophagy (2016)

Bottom Line: There is an urgent need to elucidate the neuronal death mechanisms occurring after neonatal hypoxia-ischemia (HI).Neuronal deletion of Atg7 prevented HI-induced autophagy, resulted in 42% decrease of tissue loss compared to wild-type mice after the insult, and reduced cell death in multiple brain regions, including apoptosis, as shown by decreased caspase-dependent and -independent cell death.Moreover, we investigated the lentiform nucleus of human newborns who died after severe perinatal asphyxia and found increased neuronal autophagy after severe hypoxic-ischemic encephalopathy compared to control uninjured brains, as indicated by the numbers of MAP1LC3B/LC3B (microtubule-associated protein 1 light chain 3)-, LAMP1 (lysosomal-associated membrane protein 1)-, and CTSD (cathepsin D)-positive cells.

View Article: PubMed Central - PubMed

Affiliation: a Center for Brain Repair and Rehabilitation, Institute of Neuroscience and Physiology, Sahlgrenska Academy, University of Gothenburg , Gothenburg , Sweden.

ABSTRACT
Perinatal asphyxia induces neuronal cell death and brain injury, and is often associated with irreversible neurological deficits in children. There is an urgent need to elucidate the neuronal death mechanisms occurring after neonatal hypoxia-ischemia (HI). We here investigated the selective neuronal deletion of the Atg7 (autophagy related 7) gene on neuronal cell death and brain injury in a mouse model of severe neonatal hypoxia-ischemia. Neuronal deletion of Atg7 prevented HI-induced autophagy, resulted in 42% decrease of tissue loss compared to wild-type mice after the insult, and reduced cell death in multiple brain regions, including apoptosis, as shown by decreased caspase-dependent and -independent cell death. Moreover, we investigated the lentiform nucleus of human newborns who died after severe perinatal asphyxia and found increased neuronal autophagy after severe hypoxic-ischemic encephalopathy compared to control uninjured brains, as indicated by the numbers of MAP1LC3B/LC3B (microtubule-associated protein 1 light chain 3)-, LAMP1 (lysosomal-associated membrane protein 1)-, and CTSD (cathepsin D)-positive cells. These findings reveal that selective neuronal deletion of Atg7 is strongly protective against neuronal death and overall brain injury occurring after HI and suggest that inhibition of HI-enhanced autophagy should be considered as a potential therapeutic target for the treatment of human newborns developing severe hypoxic-ischemic encephalopathy.

No MeSH data available.


Related in: MedlinePlus

Lentiform nucleus of asphyxiated human term newborns is highly vulnerable. (A) Magnetic resonance (MR) diffusion-weighted images with ADC maps (top panel) of hypoxic-ischemic encephalopathy (HIE) case 1 (left) at 36 h of life and HIE case 7 (right) at 23 h of life showed bilateral restricted diffusion in the basal ganglia (mainly in the putamen, arrowheads) and thalamus (long arrows) as well as in the cortex of case 7 (dashed arrows). MR multivoxel proton spectroscopy of HIE case 7 showing a negative double lactate peak at 1.2 ppm indicating an acute energy failure in this region (white arrow) at 23 h of life (lower panel). (B) Representative hematoxylin-eosin staining of the lentiform nucleus region showed the presence of numerous dying neurons (cell shrinkage and pyknotic nuclei, arrow) in newborns subjected to perinatal asphyxia but not in controls (Ctrl).
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f0008: Lentiform nucleus of asphyxiated human term newborns is highly vulnerable. (A) Magnetic resonance (MR) diffusion-weighted images with ADC maps (top panel) of hypoxic-ischemic encephalopathy (HIE) case 1 (left) at 36 h of life and HIE case 7 (right) at 23 h of life showed bilateral restricted diffusion in the basal ganglia (mainly in the putamen, arrowheads) and thalamus (long arrows) as well as in the cortex of case 7 (dashed arrows). MR multivoxel proton spectroscopy of HIE case 7 showing a negative double lactate peak at 1.2 ppm indicating an acute energy failure in this region (white arrow) at 23 h of life (lower panel). (B) Representative hematoxylin-eosin staining of the lentiform nucleus region showed the presence of numerous dying neurons (cell shrinkage and pyknotic nuclei, arrow) in newborns subjected to perinatal asphyxia but not in controls (Ctrl).

Mentions: We subsequently investigated whether neuronal autophagy was enhanced in brains from asphyxiated human babies with HIE. We focused our investigations on the lentiform nucleus, which includes the putamen and the globus pallidus within the basal ganglia, a region highly sensitive to HI in neonates. Cerebral MRI diffusion-weighted imaging confirmed that perinatal HI led to induced severe and irreversible lesions in the cerebral cortex and basal ganglia (Fig. 8A). Diffusion was severely restricted, confirming the presence of cytotoxic edema. Hematoxylin-eosin staining revealed the presence of pyknotic nuclei and shrunken cells in the lentiform nuclei of all 7 HIE cases, while such signs of cell death were rarely seen in controls. This confirmed the vulnerability of the human neonate basal ganglia to HI (Fig. 8B).Figure 8.


Neuroprotection by selective neuronal deletion of Atg7 in neonatal brain injury.

Xie C, Ginet V, Sun Y, Koike M, Zhou K, Li T, Li H, Li Q, Wang X, Uchiyama Y, Truttmann AC, Kroemer G, Puyal J, Blomgren K, Zhu C - Autophagy (2016)

Lentiform nucleus of asphyxiated human term newborns is highly vulnerable. (A) Magnetic resonance (MR) diffusion-weighted images with ADC maps (top panel) of hypoxic-ischemic encephalopathy (HIE) case 1 (left) at 36 h of life and HIE case 7 (right) at 23 h of life showed bilateral restricted diffusion in the basal ganglia (mainly in the putamen, arrowheads) and thalamus (long arrows) as well as in the cortex of case 7 (dashed arrows). MR multivoxel proton spectroscopy of HIE case 7 showing a negative double lactate peak at 1.2 ppm indicating an acute energy failure in this region (white arrow) at 23 h of life (lower panel). (B) Representative hematoxylin-eosin staining of the lentiform nucleus region showed the presence of numerous dying neurons (cell shrinkage and pyknotic nuclei, arrow) in newborns subjected to perinatal asphyxia but not in controls (Ctrl).
© Copyright Policy - open-access
Related In: Results  -  Collection

License
Show All Figures
getmorefigures.php?uid=PMC4835980&req=5

f0008: Lentiform nucleus of asphyxiated human term newborns is highly vulnerable. (A) Magnetic resonance (MR) diffusion-weighted images with ADC maps (top panel) of hypoxic-ischemic encephalopathy (HIE) case 1 (left) at 36 h of life and HIE case 7 (right) at 23 h of life showed bilateral restricted diffusion in the basal ganglia (mainly in the putamen, arrowheads) and thalamus (long arrows) as well as in the cortex of case 7 (dashed arrows). MR multivoxel proton spectroscopy of HIE case 7 showing a negative double lactate peak at 1.2 ppm indicating an acute energy failure in this region (white arrow) at 23 h of life (lower panel). (B) Representative hematoxylin-eosin staining of the lentiform nucleus region showed the presence of numerous dying neurons (cell shrinkage and pyknotic nuclei, arrow) in newborns subjected to perinatal asphyxia but not in controls (Ctrl).
Mentions: We subsequently investigated whether neuronal autophagy was enhanced in brains from asphyxiated human babies with HIE. We focused our investigations on the lentiform nucleus, which includes the putamen and the globus pallidus within the basal ganglia, a region highly sensitive to HI in neonates. Cerebral MRI diffusion-weighted imaging confirmed that perinatal HI led to induced severe and irreversible lesions in the cerebral cortex and basal ganglia (Fig. 8A). Diffusion was severely restricted, confirming the presence of cytotoxic edema. Hematoxylin-eosin staining revealed the presence of pyknotic nuclei and shrunken cells in the lentiform nuclei of all 7 HIE cases, while such signs of cell death were rarely seen in controls. This confirmed the vulnerability of the human neonate basal ganglia to HI (Fig. 8B).Figure 8.

Bottom Line: There is an urgent need to elucidate the neuronal death mechanisms occurring after neonatal hypoxia-ischemia (HI).Neuronal deletion of Atg7 prevented HI-induced autophagy, resulted in 42% decrease of tissue loss compared to wild-type mice after the insult, and reduced cell death in multiple brain regions, including apoptosis, as shown by decreased caspase-dependent and -independent cell death.Moreover, we investigated the lentiform nucleus of human newborns who died after severe perinatal asphyxia and found increased neuronal autophagy after severe hypoxic-ischemic encephalopathy compared to control uninjured brains, as indicated by the numbers of MAP1LC3B/LC3B (microtubule-associated protein 1 light chain 3)-, LAMP1 (lysosomal-associated membrane protein 1)-, and CTSD (cathepsin D)-positive cells.

View Article: PubMed Central - PubMed

Affiliation: a Center for Brain Repair and Rehabilitation, Institute of Neuroscience and Physiology, Sahlgrenska Academy, University of Gothenburg , Gothenburg , Sweden.

ABSTRACT
Perinatal asphyxia induces neuronal cell death and brain injury, and is often associated with irreversible neurological deficits in children. There is an urgent need to elucidate the neuronal death mechanisms occurring after neonatal hypoxia-ischemia (HI). We here investigated the selective neuronal deletion of the Atg7 (autophagy related 7) gene on neuronal cell death and brain injury in a mouse model of severe neonatal hypoxia-ischemia. Neuronal deletion of Atg7 prevented HI-induced autophagy, resulted in 42% decrease of tissue loss compared to wild-type mice after the insult, and reduced cell death in multiple brain regions, including apoptosis, as shown by decreased caspase-dependent and -independent cell death. Moreover, we investigated the lentiform nucleus of human newborns who died after severe perinatal asphyxia and found increased neuronal autophagy after severe hypoxic-ischemic encephalopathy compared to control uninjured brains, as indicated by the numbers of MAP1LC3B/LC3B (microtubule-associated protein 1 light chain 3)-, LAMP1 (lysosomal-associated membrane protein 1)-, and CTSD (cathepsin D)-positive cells. These findings reveal that selective neuronal deletion of Atg7 is strongly protective against neuronal death and overall brain injury occurring after HI and suggest that inhibition of HI-enhanced autophagy should be considered as a potential therapeutic target for the treatment of human newborns developing severe hypoxic-ischemic encephalopathy.

No MeSH data available.


Related in: MedlinePlus