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Inhibition of phosphatase and tensin homolog deleted on chromosome 10 decreases rat cortical neuron injury and blood-brain barrier permeability, and improves neurological functional recovery in traumatic brain injury model.

Ding J, Guo J, Yuan Q, Yuan F, Chen H, Tian H - PLoS ONE (2013)

Bottom Line: Recent evidence has supported the neuroprotective effect of bpV (pic), an inhibitor of phosphatase and tensin homolog deleted on chromosome 10 (PTEN), in models of ischemic stroke.After bpV (pic) treatment, p-Akt was also up-regulated.We found that bpV (pic) significantly decreased BBB permeability and reduced the number of TUNEL-positive cells.

View Article: PubMed Central - PubMed

Affiliation: Department of Neurosurgery, Shanghai 6 th People's Hospital, Shanghai Jiaotong University, Shanghai, China.

ABSTRACT

Background and purpose: Recent evidence has supported the neuroprotective effect of bpV (pic), an inhibitor of phosphatase and tensin homolog deleted on chromosome 10 (PTEN), in models of ischemic stroke. However, whether PTEN inhibitors improve long-term functional recovery after traumatic brain injury (TBI) and whether PTEN affects blood brain barrier (BBB) permeability need further elucidation. The present study was performed to address these issues.

Methods: Adult Sprague-Dawley rats were subjected to fluid percussion injury (FPI) after treatment with a well-established PTEN inhibitor bpV (pic) or saline starting 24 h before FPI. Western blotting, real-time quantitative PCR, or immunostaining was used to measure PTEN, p-Akt, or MMP-9 expression. We determined the presence of neuron apoptosis by TUNEL assay. Evans Blue dye extravasation was measured to evaluate the extent of BBB disruption. Functional recovery was assessed by the neurological severity score (NSS), and Kaplan-Meier analysis was used for survival analysis.

Results: PTEN expression was up-regulated after TBI. After bpV (pic) treatment, p-Akt was also up-regulated. We found that bpV (pic) significantly decreased BBB permeability and reduced the number of TUNEL-positive cells. We further demonstrated that PTEN inhibition improved neurological function recovery in the early stage after TBI.

Conclusion: These data suggest that treatment with the PTEN inhibitor bpV (pic) has a neuroprotective effect in TBI rats.

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Related in: MedlinePlus

Neuronal apoptosis after TBI.(A–E), 2, 6, 24, 48, and 72 h after TBI without bpV (pic) treatment. (F–J), 2, 6, 24, 48, and 72 h after TBI with bpV (pic) treatment. (K) Sham control. (L) shows that neuronal apoptosis was significantly higher in the experimental in the control group after TBI. Cell apoptosis in the bpV (pic) (-) group was significantly higher than that in the bpV (pic) (+) group. [Compared with control, **p<0.01, ***p<0.001; compared with bpV (pic) (+) group, #p<0.05, ##p<0.01, ###p<0.001].
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pone-0080429-g005: Neuronal apoptosis after TBI.(A–E), 2, 6, 24, 48, and 72 h after TBI without bpV (pic) treatment. (F–J), 2, 6, 24, 48, and 72 h after TBI with bpV (pic) treatment. (K) Sham control. (L) shows that neuronal apoptosis was significantly higher in the experimental in the control group after TBI. Cell apoptosis in the bpV (pic) (-) group was significantly higher than that in the bpV (pic) (+) group. [Compared with control, **p<0.01, ***p<0.001; compared with bpV (pic) (+) group, #p<0.05, ##p<0.01, ###p<0.001].

Mentions: Inhibition of PTEN with bpV (pic) increased the expression of p-Akt, which should promote cell survival. We investigated whether apoptosis could be blocked with inhibition of PTEN. Neurons at 2, 6, 24, 48, and 72 h after TBI from both bpV (pic)-treated and non-bpV (pic)-treated rats were used to detect apoptosis using TUNEL assay (n = 5 in each group). We found that the number of TUNEL-positive cells increased hourly after TBI in bpV (pic)-treated compared with sham controls and persisted at a high level even after 72 h. Treatment with bpV (pic) reduced apoptosis at different time points compared with the non-bpV (pic)-treated group (p<0.01) (Figure 5).


Inhibition of phosphatase and tensin homolog deleted on chromosome 10 decreases rat cortical neuron injury and blood-brain barrier permeability, and improves neurological functional recovery in traumatic brain injury model.

Ding J, Guo J, Yuan Q, Yuan F, Chen H, Tian H - PLoS ONE (2013)

Neuronal apoptosis after TBI.(A–E), 2, 6, 24, 48, and 72 h after TBI without bpV (pic) treatment. (F–J), 2, 6, 24, 48, and 72 h after TBI with bpV (pic) treatment. (K) Sham control. (L) shows that neuronal apoptosis was significantly higher in the experimental in the control group after TBI. Cell apoptosis in the bpV (pic) (-) group was significantly higher than that in the bpV (pic) (+) group. [Compared with control, **p<0.01, ***p<0.001; compared with bpV (pic) (+) group, #p<0.05, ##p<0.01, ###p<0.001].
© Copyright Policy
Related In: Results  -  Collection

License
Show All Figures
getmorefigures.php?uid=PMC3842922&req=5

pone-0080429-g005: Neuronal apoptosis after TBI.(A–E), 2, 6, 24, 48, and 72 h after TBI without bpV (pic) treatment. (F–J), 2, 6, 24, 48, and 72 h after TBI with bpV (pic) treatment. (K) Sham control. (L) shows that neuronal apoptosis was significantly higher in the experimental in the control group after TBI. Cell apoptosis in the bpV (pic) (-) group was significantly higher than that in the bpV (pic) (+) group. [Compared with control, **p<0.01, ***p<0.001; compared with bpV (pic) (+) group, #p<0.05, ##p<0.01, ###p<0.001].
Mentions: Inhibition of PTEN with bpV (pic) increased the expression of p-Akt, which should promote cell survival. We investigated whether apoptosis could be blocked with inhibition of PTEN. Neurons at 2, 6, 24, 48, and 72 h after TBI from both bpV (pic)-treated and non-bpV (pic)-treated rats were used to detect apoptosis using TUNEL assay (n = 5 in each group). We found that the number of TUNEL-positive cells increased hourly after TBI in bpV (pic)-treated compared with sham controls and persisted at a high level even after 72 h. Treatment with bpV (pic) reduced apoptosis at different time points compared with the non-bpV (pic)-treated group (p<0.01) (Figure 5).

Bottom Line: Recent evidence has supported the neuroprotective effect of bpV (pic), an inhibitor of phosphatase and tensin homolog deleted on chromosome 10 (PTEN), in models of ischemic stroke.After bpV (pic) treatment, p-Akt was also up-regulated.We found that bpV (pic) significantly decreased BBB permeability and reduced the number of TUNEL-positive cells.

View Article: PubMed Central - PubMed

Affiliation: Department of Neurosurgery, Shanghai 6 th People's Hospital, Shanghai Jiaotong University, Shanghai, China.

ABSTRACT

Background and purpose: Recent evidence has supported the neuroprotective effect of bpV (pic), an inhibitor of phosphatase and tensin homolog deleted on chromosome 10 (PTEN), in models of ischemic stroke. However, whether PTEN inhibitors improve long-term functional recovery after traumatic brain injury (TBI) and whether PTEN affects blood brain barrier (BBB) permeability need further elucidation. The present study was performed to address these issues.

Methods: Adult Sprague-Dawley rats were subjected to fluid percussion injury (FPI) after treatment with a well-established PTEN inhibitor bpV (pic) or saline starting 24 h before FPI. Western blotting, real-time quantitative PCR, or immunostaining was used to measure PTEN, p-Akt, or MMP-9 expression. We determined the presence of neuron apoptosis by TUNEL assay. Evans Blue dye extravasation was measured to evaluate the extent of BBB disruption. Functional recovery was assessed by the neurological severity score (NSS), and Kaplan-Meier analysis was used for survival analysis.

Results: PTEN expression was up-regulated after TBI. After bpV (pic) treatment, p-Akt was also up-regulated. We found that bpV (pic) significantly decreased BBB permeability and reduced the number of TUNEL-positive cells. We further demonstrated that PTEN inhibition improved neurological function recovery in the early stage after TBI.

Conclusion: These data suggest that treatment with the PTEN inhibitor bpV (pic) has a neuroprotective effect in TBI rats.

Show MeSH
Related in: MedlinePlus