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Glutamate carboxypeptidase II gene knockout attenuates oxidative stress and cortical apoptosis after traumatic brain injury.

Cao Y, Gao Y, Xu S, Bao J, Lin Y, Luo X, Wang Y, Luo Q, Jiang J, Neale JH, Zhong C - BMC Neurosci (2016)

Bottom Line: Inhibition of GCPII elevates extracellular levels of the peptide, inhibits glutamate release and is neuroprotective in an animal model of traumatic brain injury.Impact injury reduced glutathione levels and superoxide dismutase and glutathione peroxidase activities and increased malondialdehyde.These data support the hypothesis that the neuroprotective efficacy of GCPII KO in traumatic brain injury is mediated via a reduction in oxidative stress.

View Article: PubMed Central - PubMed

Affiliation: Department of Neurosurgery, Ren Ji Hospital, School of Medicine, Shanghai Jiao Tong University, 160 Pujian Road, Shanghai, 200127, China.

ABSTRACT

Background: Glutamate carboxypeptidase II (GCPII) inactivates the peptide co-transmitter N-acetylaspartylglutamate following synaptic release. Inhibition of GCPII elevates extracellular levels of the peptide, inhibits glutamate release and is neuroprotective in an animal model of traumatic brain injury. GCPII gene knockout mice were used to examine the cellular mechanisms underlying the neuroprotective efficacy of this transmitter system.

Results: Following controlled cortical impact injury, GCPII knockout (KO) mice exhibited reduced TUNEL-positive nuclei in the contusion margin of the cerebral cortex relative to wild type mice. Impact injury reduced glutathione levels and superoxide dismutase and glutathione peroxidase activities and increased malondialdehyde. Each of these effects was moderated in KO mice relative to wild type. Similarly, the injury-induced increases in cleaved caspase-3, cytosolic cytochrome c levels and Bcl-2/Bax ratio observed in wild type mice were attenuated in the knockout mice.

Conclusions: These data support the hypothesis that the neuroprotective efficacy of GCPII KO in traumatic brain injury is mediated via a reduction in oxidative stress.

No MeSH data available.


Related in: MedlinePlus

Effects of GCPII KO on the expression of mitochondrial Bcl-2 and Bax. Representative immunoblots (a) and densitometric analysis (b) revealed a significant reduction in the mitochondrial Bcl-2/Bax ratio following TBI in both wild type and KO mice. The ratio in GCPII KO mice was significantly higher than their WT counterparts. The immunoblot data were scanned and normalized to the density of VDAC. The ratio of the normalized data for the wild type/sham mice was given a value of one. Data from other groups are expressed as values relative to the value for the wild type/sham mice. Data were represented as mean ± SEM (n = 6 per group); *p < 0.05, versus sham control of the same genotype; #p < 0.05, versus injured wild-type mice
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Fig3: Effects of GCPII KO on the expression of mitochondrial Bcl-2 and Bax. Representative immunoblots (a) and densitometric analysis (b) revealed a significant reduction in the mitochondrial Bcl-2/Bax ratio following TBI in both wild type and KO mice. The ratio in GCPII KO mice was significantly higher than their WT counterparts. The immunoblot data were scanned and normalized to the density of VDAC. The ratio of the normalized data for the wild type/sham mice was given a value of one. Data from other groups are expressed as values relative to the value for the wild type/sham mice. Data were represented as mean ± SEM (n = 6 per group); *p < 0.05, versus sham control of the same genotype; #p < 0.05, versus injured wild-type mice

Mentions: A decrease in the ratio of mitochondrial Bcl-2 to Bax is proposed to reflect an increase in the permeability of the mitochondrial membrane and cell susceptibility to an apoptotic stimulus. There was increased Bax levels as well as reduced Bcl-2 levels in the mitochondrial fractions after TBI (Fig. 3a). The mitochondrial Bcl-2/Bax ratio in the WT TBI group was significantly lower than that in the WT sham group (p < 0.05, n = 6, Fig. 3b). GCPII KO significantly increased the ratio of Bcl-2/Bax in the mitochondria compared to their WT counterparts (p < 0.05, n = 6, Fig. 3b). As an apparent result of elevated mitochondrial permeability, the level of cytosolic cytochrome c significantly increased in the TBI groups (both p < 0.05, n = 6, Fig. 4a, c). However, the increase in the cytosolic cytochrome c level in the KO TBI mice was significantly less than that in the WT TBI mice (p < 0.05, n = 6, Fig. 4c).Fig. 3


Glutamate carboxypeptidase II gene knockout attenuates oxidative stress and cortical apoptosis after traumatic brain injury.

Cao Y, Gao Y, Xu S, Bao J, Lin Y, Luo X, Wang Y, Luo Q, Jiang J, Neale JH, Zhong C - BMC Neurosci (2016)

Effects of GCPII KO on the expression of mitochondrial Bcl-2 and Bax. Representative immunoblots (a) and densitometric analysis (b) revealed a significant reduction in the mitochondrial Bcl-2/Bax ratio following TBI in both wild type and KO mice. The ratio in GCPII KO mice was significantly higher than their WT counterparts. The immunoblot data were scanned and normalized to the density of VDAC. The ratio of the normalized data for the wild type/sham mice was given a value of one. Data from other groups are expressed as values relative to the value for the wild type/sham mice. Data were represented as mean ± SEM (n = 6 per group); *p < 0.05, versus sham control of the same genotype; #p < 0.05, versus injured wild-type mice
© Copyright Policy - OpenAccess
Related In: Results  -  Collection

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Fig3: Effects of GCPII KO on the expression of mitochondrial Bcl-2 and Bax. Representative immunoblots (a) and densitometric analysis (b) revealed a significant reduction in the mitochondrial Bcl-2/Bax ratio following TBI in both wild type and KO mice. The ratio in GCPII KO mice was significantly higher than their WT counterparts. The immunoblot data were scanned and normalized to the density of VDAC. The ratio of the normalized data for the wild type/sham mice was given a value of one. Data from other groups are expressed as values relative to the value for the wild type/sham mice. Data were represented as mean ± SEM (n = 6 per group); *p < 0.05, versus sham control of the same genotype; #p < 0.05, versus injured wild-type mice
Mentions: A decrease in the ratio of mitochondrial Bcl-2 to Bax is proposed to reflect an increase in the permeability of the mitochondrial membrane and cell susceptibility to an apoptotic stimulus. There was increased Bax levels as well as reduced Bcl-2 levels in the mitochondrial fractions after TBI (Fig. 3a). The mitochondrial Bcl-2/Bax ratio in the WT TBI group was significantly lower than that in the WT sham group (p < 0.05, n = 6, Fig. 3b). GCPII KO significantly increased the ratio of Bcl-2/Bax in the mitochondria compared to their WT counterparts (p < 0.05, n = 6, Fig. 3b). As an apparent result of elevated mitochondrial permeability, the level of cytosolic cytochrome c significantly increased in the TBI groups (both p < 0.05, n = 6, Fig. 4a, c). However, the increase in the cytosolic cytochrome c level in the KO TBI mice was significantly less than that in the WT TBI mice (p < 0.05, n = 6, Fig. 4c).Fig. 3

Bottom Line: Inhibition of GCPII elevates extracellular levels of the peptide, inhibits glutamate release and is neuroprotective in an animal model of traumatic brain injury.Impact injury reduced glutathione levels and superoxide dismutase and glutathione peroxidase activities and increased malondialdehyde.These data support the hypothesis that the neuroprotective efficacy of GCPII KO in traumatic brain injury is mediated via a reduction in oxidative stress.

View Article: PubMed Central - PubMed

Affiliation: Department of Neurosurgery, Ren Ji Hospital, School of Medicine, Shanghai Jiao Tong University, 160 Pujian Road, Shanghai, 200127, China.

ABSTRACT

Background: Glutamate carboxypeptidase II (GCPII) inactivates the peptide co-transmitter N-acetylaspartylglutamate following synaptic release. Inhibition of GCPII elevates extracellular levels of the peptide, inhibits glutamate release and is neuroprotective in an animal model of traumatic brain injury. GCPII gene knockout mice were used to examine the cellular mechanisms underlying the neuroprotective efficacy of this transmitter system.

Results: Following controlled cortical impact injury, GCPII knockout (KO) mice exhibited reduced TUNEL-positive nuclei in the contusion margin of the cerebral cortex relative to wild type mice. Impact injury reduced glutathione levels and superoxide dismutase and glutathione peroxidase activities and increased malondialdehyde. Each of these effects was moderated in KO mice relative to wild type. Similarly, the injury-induced increases in cleaved caspase-3, cytosolic cytochrome c levels and Bcl-2/Bax ratio observed in wild type mice were attenuated in the knockout mice.

Conclusions: These data support the hypothesis that the neuroprotective efficacy of GCPII KO in traumatic brain injury is mediated via a reduction in oxidative stress.

No MeSH data available.


Related in: MedlinePlus