Interference of apoptosis in the pathophysiology of subarachnoid hemorrhage

Palade, C; Ciurea, Alexandru Vlad; Nica, Dan Aurel; Savu, R; Moisa, Horaţiu Alexandru

doi:10.4103/1793-5482.116389

Cited by 13 publications

(4 citation statements)

References 65 publications

(114 reference statements)

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“…A large body of evidence demonstrates that inflammation appears to be the proegumenal cause of brain injury after SAH [ 32 ] and that patients with high levels of cytokines (such as IL-1β and TNF-α) would have unfavorable outcomes and symptoms for clinical deterioration [ 33 ]. Inflammation induces apoptosis [ 34 ] and leads to BBB disruption by increasing endothelial permeability and vessel diameter [ 35 ]. In addition, a number of studies have indicated the critical role of neutrophils in the inflammatory response [ 36 ].…”

Section: Discussionmentioning

confidence: 99%

“…Moreover, PGRN modulates neutrophilic inflammation by inhibiting the activation and recruitment. However, activated neutrophils can secrete neutrophil elastase (NE) to degrade PGRN into individual granulin peptides, which act in the opposite manner, stimulating the production of pro-inflammatory cytokines [ 17 , 34 ]. Therefore, we hypothesized that a decrease in PGRN levels potentiates the inflammation induced by EBI and that high levels of PGRN may inhibit inflammation by suppressing neutrophil activation.…”

Section: Discussionmentioning

confidence: 99%

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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

Xie

Wang

et al. 2015

J Neuroinflammation

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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.

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Section: Discussionmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

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

Zhou

Xie

Wang

et al. 2015

J Neuroinflammation

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“…In the present study, we found that Zileuton significantly upregulated levels of activated (phosphorylated) Akt after SAH while decreasing NF-κB, LTB4, TNF-α, IL-6 and IL-1β. Activated Akt inhibits pro-apoptosis proteins such as Bax and promotes anti-apoptotic proteins such as Bcl-2 [ 31 ]. At the same time, Zileuton could reduced cerebral edema and prevented BBB disruption and attenuated the neurological deficits.…”

Section: Discussionmentioning

confidence: 99%

5-Lipoxygenase inhibition reduces inflammation and neuronal apoptosis via AKT signaling after subarachnoid hemorrhage in rats

Liu

Zhang

et al. 2021

Aging

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Early brain injury (EBI) is a major contributor to the high mortality and morbidity after subarachnoid hemorrhage (SAH). Inflammatory responses and neuronal apoptosis are important causes of EBI. Because 5- lipoxygenase (5-LOX) is known to be involved various central nervous system diseases, we investigated the effects of 5-LOX inhibition during EBI after SAH. Zileuton and LY294002 were used to inhibit expression of 5-LOX and Akt, respectively. We found that 5-LOX expression was significantly increased in the cytoplasm of cortical neurons after SAH and was accompanied by upregulated expression of the inflammatory factors LTB4, TNF-α, IL-1β and IL-6; upregulation of the pro-apoptotic factor Bax; downregulation of the anti-apoptotic factor Bcl-2; and an increased apoptosis rate. Gastric Zileuton administration significantly suppressed all of those effects and improved neurological function. Zileuton also upregulated activated (phosphorylated) AKT levels, and these beneficial effects of Zileuton were abolished by intracerebroventricular infusion of the PI3K inhibitor LY294002. Taken together, these findings indicate that 5-LOX mediates pro-inflammatory and pro-apoptotic effects that contribute to EBI after SAH and that those effects are suppressed by activation of PI3K/Akt signaling. This suggests targeting 5-LOX may be an effective approach to treating EBI after SAH.

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“…There are several molecules within the apoptotic cascade that could be targeted for neuroprotection after SAH, for example, active caspases, p53, the mitochondrial membrane and death receptors [ 69 , 70 ]. We will describe a selection of strategies aimed at reducing apoptosis at various levels of the cascade below.…”

Section: Introductionmentioning

confidence: 99%

The rodent endovascular puncture model of subarachnoid hemorrhage: mechanisms of brain damage and therapeutic strategies

Kooijman

Nijboer

Velthoven

et al. 2014

J Neuroinflammation

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Subarachnoid hemorrhage (SAH) represents a considerable health problem. To date, limited therapeutic options are available. In order to develop effective therapeutic strategies for SAH, the mechanisms involved in SAH brain damage should be fully explored. Here we review the mechanisms of SAH brain damage induced by the experimental endovascular puncture model. We have included a description of similarities and distinctions between experimental SAH in animals and human SAH pathology. Moreover, several novel treatment options to diminish SAH brain damage are discussed.SAH is accompanied by cerebral inflammation as demonstrated by an influx of inflammatory cells into the cerebral parenchyma, upregulation of inflammatory transcriptional pathways and increased expression of cytokines and chemokines. Additionally, various cell death pathways including cerebral apoptosis, necrosis, necroptosis and autophagy are involved in neuronal damage caused by SAH.Treatment strategies aiming at inhibition of inflammatory or cell death pathways demonstrate the importance of these mechanisms for survival after experimental SAH. Moreover, neuroregenerative therapies using stem cells are discussed as a possible strategy to repair the brain after SAH since this therapy may extend the window of treatment considerably. We propose the endovascular puncture model as a suitable animal model which resembles the human pathology of SAH and which could be applied to investigate novel therapeutic therapies to combat this debilitating insult.

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Interference of apoptosis in the pathophysiology of subarachnoid hemorrhage

Cited by 13 publications

References 65 publications

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

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

5-Lipoxygenase inhibition reduces inflammation and neuronal apoptosis via AKT signaling after subarachnoid hemorrhage in rats

The rodent endovascular puncture model of subarachnoid hemorrhage: mechanisms of brain damage and therapeutic strategies

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