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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: 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.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

Experimental SAH model of rats. Schematic diagram of the areas used for assays. (Control) rat brain from the control group; (SAH) rat brain from the SAH group
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Fig1: Experimental SAH model of rats. Schematic diagram of the areas used for assays. (Control) rat brain from the control group; (SAH) rat brain from the SAH group

Mentions: Experimental SAH models were produced as reported previously [25]. In brief, the rats were anesthetized with chloral hydrate (0.4 mg/kg, IP, Jinling Hospital). The head and inguinal region was carefully shaved and disinfected. Rats were then fixed in a stereotaxic apparatus. A midline scalp incision was made and a 1-mm hole was drilled 8.0 mm anterior to Bregma in the midline. To prevent loss of CSF and bleeding from the midline vessels, we used bone wax to plug the burr hole. Rats were placed in the supine position and an insulin syringe (BD Science) was used to draw 300 μL of nonheparinized blood from the femoral artery. The needle was advanced 11 mm into the prechiasmatic cistern through the burr hole, at a 45° angle to the vertical plane, and then 300 μL of blood was injected into the prechiasmatic cistern over 20 s. An equal volume of normal saline was injected into the prechiasmatic cistern of rats in the sham group (Fig. 1). The burr hole was sealed with bone wax, and the incision was surgically sutured. Rats were kept at 30 °C, with their head placed in a downward position for 20 min. After recovery from anesthesia, the rats were returned to their cages and housed at 25 ± 1 °C. Rats that died during surgery or surgical recovery were excluded from the study, and the procedure was repeated until the final group size reached the planned experimental number.Fig. 1


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)

Experimental SAH model of rats. Schematic diagram of the areas used for assays. (Control) rat brain from the control group; (SAH) rat brain from the SAH group
© Copyright Policy - OpenAccess
Related In: Results  -  Collection

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

Fig1: Experimental SAH model of rats. Schematic diagram of the areas used for assays. (Control) rat brain from the control group; (SAH) rat brain from the SAH group
Mentions: Experimental SAH models were produced as reported previously [25]. In brief, the rats were anesthetized with chloral hydrate (0.4 mg/kg, IP, Jinling Hospital). The head and inguinal region was carefully shaved and disinfected. Rats were then fixed in a stereotaxic apparatus. A midline scalp incision was made and a 1-mm hole was drilled 8.0 mm anterior to Bregma in the midline. To prevent loss of CSF and bleeding from the midline vessels, we used bone wax to plug the burr hole. Rats were placed in the supine position and an insulin syringe (BD Science) was used to draw 300 μL of nonheparinized blood from the femoral artery. The needle was advanced 11 mm into the prechiasmatic cistern through the burr hole, at a 45° angle to the vertical plane, and then 300 μL of blood was injected into the prechiasmatic cistern over 20 s. An equal volume of normal saline was injected into the prechiasmatic cistern of rats in the sham group (Fig. 1). The burr hole was sealed with bone wax, and the incision was surgically sutured. Rats were kept at 30 °C, with their head placed in a downward position for 20 min. After recovery from anesthesia, the rats were returned to their cages and housed at 25 ± 1 °C. Rats that died during surgery or surgical recovery were excluded from the study, and the procedure was repeated until the final group size reached the planned experimental number.Fig. 1

Bottom Line: 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.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