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

Abstract

BackgroundSubarachnoid 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.MethodsThe 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.ResultsThe 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.ConclusionsThese 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.

CSF progranulin increases in the course of Alzheimer's disease and is associated with sTREM 2, neurodegeneration and cognitive decline

“…The mean CSF PGRN level of our MSD‐based assay (1,007 pg/ml) was similar to that published with other assays (Huchtemann et al , ; Zhou et al , ; Berghoff et al , ; Meeter et al , ; Kimura et al , ; Schreiber et al , ), albeit lower than those measured by the more widely used commercial assay from Adipogen (Ghidoni et al , ; De Riz et al , ; Vercellino et al , ; Nicholson et al , ; Morenas‐Rodríguez et al , ; Feneberg et al , ; Molgaard et al , ; Willemse et al , ; Wilke et al , ). We therefore compared our MSD‐based ELISA with that from Adipogen (cat.…”

Non‐Surgical Periodontal Therapy Reduces Saliva Adipokine and Matrix Metalloproteinase Levels in Periodontitis

“…Progranulin has been shown to have anti‐inflammatory properties in some studies 24–26 . In fact, after the proteolytic breakdown of progranulin, small peptide fragments called granulins are released, and they have proinflammatory characteristics 8 .…”

“…Progranulin, also called granulin epithelin precursor, is a 593–amino acid secreted growth factor 23 . Progranulin is an adipokine with various biologic functions, such as cell growth regulation, tissue repair, and inflammation modulation 23 , 24 . It has been shown to have anti‐inflammatory and proinflammatory features 25 .…”

Rapamycin provides anti‑epileptogenic effect in a rat model of post‑traumatic epilepsy via deactivation of mTOR signaling pathway

“…Immunohistochemistry was carried out as previously described ( 21 ). Briefly, rats were anaesthetized with chloral hydrate and perfused transcardially with saline followed by 4% paraformaldehyde in phosphate-buffered saline (PBS; 0.l M, pH 7.4).…”