Limits...
Decreased progranulin levels in patients and rats with subarachnoid hemorrhage: a potential role in inhibiting inflammation by suppressing neutrophil recruitment.

Zhou C, Xie G, Wang C, Zhang Z, Chen Q, Zhang L, Wu L, Wei Y, Ding H, Hang C, Zhou M, Shi J - J Neuroinflammation (2015)

Bottom Line: The levels of PGRN significantly decreased, and the levels of MPO, IL-1β, and TNF-α were markedly elevated in the CSF from SAH patients.These changes were associated with marked reductions in MPO, MMP-9, and proinflammation cytokine levels, as well as increased levels of Bcl-2 and ZO-1.These results indicate that the levels of PGRN decreased after SAH and that r-PGRN alleviates EBI after SAH possibly via inhibition of neutrophil recruitment, providing a new target for the treatment of SAH.

View Article: PubMed Central - PubMed

Affiliation: Department of Neurosurgery, Jinling Hospital, Medical School of Nanjing University, 210002, No. 305 Zhongshan East Road, Nanjing, Jiangsu Province, China. zhouchenhui1989@126.com.

ABSTRACT

Background: Subarachnoid hemorrhage (SAH) is a devastating neurological injury with high morbidity and mortality that is mainly caused by early brain injury (EBI). Progranulin (PGRN) is known to be involved in various biological functions, such as anti-inflammation and tissue repair. This study aimed to investigate the change of PGRN in the brain after SAH and its role on EBI.

Methods: The levels of PGRN, myeloperoxidase (MPO), interleukin1β (IL-1β), and tumor necrosis factor-α (TNF-α) were detected in the cerebrospinal fluid (CSF) from SAH patients by enzyme-linked immunosorbent assay (ELISA). In addition, PGRN levels were also detected in the cerebral cortex after experimental SAH in rats by western blotting and immunohistochemistry (IHC). Recombinant human PGRN (r-PGRN) or an equal volume of phosphate-buffered saline (PBS) was administrated at 30 min after SAH. All rats were subsequently sacrificed at 24 h after SAH. Neurological score and brain water content were assessed. For mechanistic studies, the changes of MPO, matrix metalloproteinase-9 (MMP-9), zonula occludens 1 (ZO-1), Bcl-2, and cleaved caspase-3 were examined by western blotting and the levels of pro-inflammatory cytokines (IL-1β and TNF-α) were determined by ELISA. In addition, neuronal apoptosis and blood brain barrier (BBB) permeability were examined.

Results: The levels of PGRN significantly decreased, and the levels of MPO, IL-1β, and TNF-α were markedly elevated in the CSF from SAH patients. In rats, PGRN levels in the brain also decreased after SAH. Administration of r-PGRN decreased brain water content and improved neurological scores at 24 h after SAH. These changes were associated with marked reductions in MPO, MMP-9, and proinflammation cytokine levels, as well as increased levels of Bcl-2 and ZO-1. In addition, neuronal apoptosis and BBB permeability were alleviated by r-PGRN.

Conclusions: These results indicate that the levels of PGRN decreased after SAH and that r-PGRN alleviates EBI after SAH possibly via inhibition of neutrophil recruitment, providing a new target for the treatment of SAH.

No MeSH data available.


Related in: MedlinePlus

Effects of PGRN on neurologic scores (a) and brain water content (b) at 24 h after SAH. Neurological function of rats was impaired and brain water content increased significantly at 24 h after SAH compared with rats in the sham group. R-PGRN (3, 10, and 15 ng/rat) dramatically increased neurological scores and alleviated brain edema at 24 h after SAH, but r-PGRN at a dose of 1 ng/rat did not significantly affect neurological scores and brain edema. No difference was detected between the untreated SAH group and the PBS treated SAH group. Data are expressed as the mean ± SEM from six rats. ***p < 0.001 and **p < 0.01 compared with the sham group, nsp > 0.05 compared with the SAH group, ###p < 0.01, ##p < 0.01, and #p < 0.05 compared with the SAH group
© Copyright Policy - OpenAccess
Related In: Results  -  Collection

License 1 - License 2
getmorefigures.php?uid=PMC4630923&req=5

Fig4: Effects of PGRN on neurologic scores (a) and brain water content (b) at 24 h after SAH. Neurological function of rats was impaired and brain water content increased significantly at 24 h after SAH compared with rats in the sham group. R-PGRN (3, 10, and 15 ng/rat) dramatically increased neurological scores and alleviated brain edema at 24 h after SAH, but r-PGRN at a dose of 1 ng/rat did not significantly affect neurological scores and brain edema. No difference was detected between the untreated SAH group and the PBS treated SAH group. Data are expressed as the mean ± SEM from six rats. ***p < 0.001 and **p < 0.01 compared with the sham group, nsp > 0.05 compared with the SAH group, ###p < 0.01, ##p < 0.01, and #p < 0.05 compared with the SAH group

Mentions: To test the neuroprotective effects of r-PGRN on EBI, we evaluated the neurologic function and brain water content at 24 h after SAH. In this study, r-PGRN was given at four different concentrations to SAH rats. As shown in Fig. 4, treatment with r-PGRN at 3, 10, and 15 ng/rat dramatically ameliorated neurologic function (p < 0.01, p < 0.001) and brain edema (p < 0.05, p < 0.01). However, r-PGRN at 1 ng/rat had no significant effect. In addition, r-PGRN at a higher dose of 15 ng/rat did not exhibit a better neuroprotective effect than that at 10 ng/rat. These results suggested that r-PGRN could alleviate EBI and that r-PGRN at 10 ng/rat exhibited the most beneficial effect. Therefore, we selected 10 ng/rat for further experiments.Fig. 4


Decreased progranulin levels in patients and rats with subarachnoid hemorrhage: a potential role in inhibiting inflammation by suppressing neutrophil recruitment.

Zhou C, Xie G, Wang C, Zhang Z, Chen Q, Zhang L, Wu L, Wei Y, Ding H, Hang C, Zhou M, Shi J - J Neuroinflammation (2015)

Effects of PGRN on neurologic scores (a) and brain water content (b) at 24 h after SAH. Neurological function of rats was impaired and brain water content increased significantly at 24 h after SAH compared with rats in the sham group. R-PGRN (3, 10, and 15 ng/rat) dramatically increased neurological scores and alleviated brain edema at 24 h after SAH, but r-PGRN at a dose of 1 ng/rat did not significantly affect neurological scores and brain edema. No difference was detected between the untreated SAH group and the PBS treated SAH group. Data are expressed as the mean ± SEM from six rats. ***p < 0.001 and **p < 0.01 compared with the sham group, nsp > 0.05 compared with the SAH group, ###p < 0.01, ##p < 0.01, and #p < 0.05 compared with the SAH group
© Copyright Policy - OpenAccess
Related In: Results  -  Collection

License 1 - License 2
Show All Figures
getmorefigures.php?uid=PMC4630923&req=5

Fig4: Effects of PGRN on neurologic scores (a) and brain water content (b) at 24 h after SAH. Neurological function of rats was impaired and brain water content increased significantly at 24 h after SAH compared with rats in the sham group. R-PGRN (3, 10, and 15 ng/rat) dramatically increased neurological scores and alleviated brain edema at 24 h after SAH, but r-PGRN at a dose of 1 ng/rat did not significantly affect neurological scores and brain edema. No difference was detected between the untreated SAH group and the PBS treated SAH group. Data are expressed as the mean ± SEM from six rats. ***p < 0.001 and **p < 0.01 compared with the sham group, nsp > 0.05 compared with the SAH group, ###p < 0.01, ##p < 0.01, and #p < 0.05 compared with the SAH group
Mentions: To test the neuroprotective effects of r-PGRN on EBI, we evaluated the neurologic function and brain water content at 24 h after SAH. In this study, r-PGRN was given at four different concentrations to SAH rats. As shown in Fig. 4, treatment with r-PGRN at 3, 10, and 15 ng/rat dramatically ameliorated neurologic function (p < 0.01, p < 0.001) and brain edema (p < 0.05, p < 0.01). However, r-PGRN at 1 ng/rat had no significant effect. In addition, r-PGRN at a higher dose of 15 ng/rat did not exhibit a better neuroprotective effect than that at 10 ng/rat. These results suggested that r-PGRN could alleviate EBI and that r-PGRN at 10 ng/rat exhibited the most beneficial effect. Therefore, we selected 10 ng/rat for further experiments.Fig. 4

Bottom Line: The levels of PGRN significantly decreased, and the levels of MPO, IL-1β, and TNF-α were markedly elevated in the CSF from SAH patients.These changes were associated with marked reductions in MPO, MMP-9, and proinflammation cytokine levels, as well as increased levels of Bcl-2 and ZO-1.These results indicate that the levels of PGRN decreased after SAH and that r-PGRN alleviates EBI after SAH possibly via inhibition of neutrophil recruitment, providing a new target for the treatment of SAH.

View Article: PubMed Central - PubMed

Affiliation: Department of Neurosurgery, Jinling Hospital, Medical School of Nanjing University, 210002, No. 305 Zhongshan East Road, Nanjing, Jiangsu Province, China. zhouchenhui1989@126.com.

ABSTRACT

Background: Subarachnoid hemorrhage (SAH) is a devastating neurological injury with high morbidity and mortality that is mainly caused by early brain injury (EBI). Progranulin (PGRN) is known to be involved in various biological functions, such as anti-inflammation and tissue repair. This study aimed to investigate the change of PGRN in the brain after SAH and its role on EBI.

Methods: The levels of PGRN, myeloperoxidase (MPO), interleukin1β (IL-1β), and tumor necrosis factor-α (TNF-α) were detected in the cerebrospinal fluid (CSF) from SAH patients by enzyme-linked immunosorbent assay (ELISA). In addition, PGRN levels were also detected in the cerebral cortex after experimental SAH in rats by western blotting and immunohistochemistry (IHC). Recombinant human PGRN (r-PGRN) or an equal volume of phosphate-buffered saline (PBS) was administrated at 30 min after SAH. All rats were subsequently sacrificed at 24 h after SAH. Neurological score and brain water content were assessed. For mechanistic studies, the changes of MPO, matrix metalloproteinase-9 (MMP-9), zonula occludens 1 (ZO-1), Bcl-2, and cleaved caspase-3 were examined by western blotting and the levels of pro-inflammatory cytokines (IL-1β and TNF-α) were determined by ELISA. In addition, neuronal apoptosis and blood brain barrier (BBB) permeability were examined.

Results: The levels of PGRN significantly decreased, and the levels of MPO, IL-1β, and TNF-α were markedly elevated in the CSF from SAH patients. In rats, PGRN levels in the brain also decreased after SAH. Administration of r-PGRN decreased brain water content and improved neurological scores at 24 h after SAH. These changes were associated with marked reductions in MPO, MMP-9, and proinflammation cytokine levels, as well as increased levels of Bcl-2 and ZO-1. In addition, neuronal apoptosis and BBB permeability were alleviated by r-PGRN.

Conclusions: These results indicate that the levels of PGRN decreased after SAH and that r-PGRN alleviates EBI after SAH possibly via inhibition of neutrophil recruitment, providing a new target for the treatment of SAH.

No MeSH data available.


Related in: MedlinePlus