Bilirubin Oxidation Products and Cerebral Vasoconstriction

Rapoport, Robert M.

doi:10.3389/fphar.2018.00303

Cited by 12 publications

(9 citation statements)

References 38 publications

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“…On the other hand, previous studies have demonstrated that the mTOR signaling pathway plays a vital role in cerebral vasospasm following SAH ( 243 ). The increased levels of mTOR, P70S6K1, and 4E-BP1 ( 167 ) in basilar arteries were significantly associated with SAH and potentially mediated the activation of cerebral vasospasm. As a member of the PI3K family, mTOR orchestrates the phosphorylation of key downstream proteins P70S6K1 and 4E-BP1, both of which promote the proliferation of key vasculature wall cells ( 168 ).…”

Section: Immune Inflammation Relevant Signaling Pathways In Sahmentioning

confidence: 98%

Inflammation and immune cell abnormalities in intracranial aneurysm subarachnoid hemorrhage (SAH): Relevant signaling pathways and therapeutic strategies

Jin

Duan

et al. 2022

Front. Immunol.

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Intracranial aneurysm subarachnoid hemorrhage (SAH) is a cerebrovascular disorder associated with high overall mortality. Currently, the underlying mechanisms of pathological reaction after aneurysm rupture are still unclear, especially in the immune microenvironment, inflammation, and relevant signaling pathways. SAH-induced immune cell population alteration, immune inflammatory signaling pathway activation, and active substance generation are associated with pro-inflammatory cytokines, immunosuppression, and brain injury. Crosstalk between immune disorders and hyperactivation of inflammatory signals aggravated the devastating consequences of brain injury and cerebral vasospasm and increased the risk of infection. In this review, we discussed the role of inflammation and immune cell responses in the occurrence and development of aneurysm SAH, as well as the most relevant immune inflammatory signaling pathways [PI3K/Akt, extracellular signal-regulated kinase (ERK), hypoxia-inducible factor-1α (HIF-1α), STAT, SIRT, mammalian target of rapamycin (mTOR), NLRP3, TLR4/nuclear factor-κB (NF-κB), and Keap1/nuclear factor (erythroid-derived 2)-like 2 (Nrf2)/ARE cascades] and biomarkers in aneurysm SAH. In addition, we also summarized potential therapeutic drugs targeting the aneurysm SAH immune inflammatory responses, such as nimodipine, dexmedetomidine (DEX), fingolimod, and genomic variation-related aneurysm prophylactic agent sunitinib. The intervention of immune inflammatory responses and immune microenvironment significantly reduces the secondary brain injury, thereby improving the prognosis of patients admitted to SAH. Future studies should focus on exploring potential immune inflammatory mechanisms and developing additional therapeutic strategies for precise aneurysm SAH immune inflammatory regulation and genomic variants associated with aneurysm formation.

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Section: Immune Inflammation Relevant Signaling Pathways In Sahmentioning

confidence: 98%

Inflammation and immune cell abnormalities in intracranial aneurysm subarachnoid hemorrhage (SAH): Relevant signaling pathways and therapeutic strategies

Jin

Duan

et al. 2022

Front. Immunol.

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“…Finally, aSAH patients with DCI have increased levels of bilirubin oxidation products (BOXs) compared to patients without DCI (Pyne-Geithman et al, 2013). This difference is mainly dependent on levels of oxidative products in the CSF (Pyne-Geithman et al, 2013;Rapoport, 2018;Peeyush Kumar et al, 2019). Similar to free Hb, BOXs inhibit endothelial NO synthesis (Peeyush Kumar et al, 2019).…”

Section: Phase Ii: Oxidative Stressmentioning

confidence: 99%

The Role of the Glycocalyx in the Pathophysiology of Subarachnoid Hemorrhage-Induced Delayed Cerebral Ischemia

Schenck

Netti

Teernstra

et al. 2021

Front. Cell Dev. Biol.

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The glycocalyx is an important constituent of blood vessels located between the bloodstream and the endothelium. It plays a pivotal role in intercellular interactions in neuroinflammation, reduction of vascular oxidative stress, and provides a barrier regulating vascular permeability. In the brain, the glycocalyx is closely related to functions of the blood-brain barrier and neurovascular unit, both responsible for adequate neurovascular responses to potential threats to cerebral homeostasis. An aneurysmal subarachnoid hemorrhage (aSAH) occurs following rupture of an intracranial aneurysm and leads to immediate brain damage (early brain injury). In some cases, this can result in secondary brain damage, also known as delayed cerebral ischemia (DCI). DCI is a life-threatening condition that affects up to 30% of all aSAH patients. As such, it is associated with substantial societal and healthcare-related costs. Causes of DCI are multifactorial and thought to involve neuroinflammation, oxidative stress, neuroinflammation, thrombosis, and neurovascular uncoupling. To date, prediction of DCI is limited, and preventive and effective treatment strategies of DCI are scarce. There is increasing evidence that the glycocalyx is disrupted following an aSAH, and that glycocalyx disruption could precipitate or aggravate DCI. This review explores the potential role of the glycocalyx in the pathophysiological mechanisms contributing to DCI following aSAH. Understanding the role of the glycocalyx in DCI could advance the development of improved methods to predict DCI or identify patients at risk for DCI. This knowledge may also alter the methods and timing of preventive and treatment strategies of DCI. To this end, we review the potential and limitations of methods currently used to evaluate the glycocalyx, and strategies to restore or prevent glycocalyx shedding.

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“…Red blood cells in the subarachnoid space are hemolyzed, releasing hemoglobin, bilirubin and oxygen free radicals. These toxic molecules induce increased expression of endothelin-1 and reduced levels of nitrous oxide, leading to endothelial cell dysfunction and VSP 6 – 8 . Although angiographic VSP eventually resolves, arterial fibrosis, endothelial thickening and reduced arterial compliance may persist over time and contribute to the poor clinical outcomes observed in patients with DCI 9 .…”

Section: Introductionmentioning

confidence: 99%

Preliminary results in the analysis of the immune response after aneurysmal subarachnoid hemorrhage

Roa

Sarkar

Zanaty

et al. 2020

Sci Rep

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Cerebral vasospasm (VSP) is a common phenomenon after aneurysmal subarachnoid hemorrhage (aSAH) and contributes to neurocognitive decline. The natural history of the pro-inflammatory immune response after aSAH has not been prospectively studied in human cerebrospinal fluid (CSF). In this pilot study, we aimed to identify specific immune mediators of VSP after aSAH. Peripheral blood (PB) and CSF samples from patients with aSAH were prospectively collected at different time-points after hemorrhage: days 0–1 (acute); days 2–4 (pre-VSP); days 5–9 (VSP) and days 10 + (post-VSP peak). Presence and severity of VSP was assessed with computed tomography angiography/perfusion imaging and clinical examination. Cytokine and immune mediators’ levels were quantified using ELISA. Innate and adaptive immune cells were characterized by flow cytometry, and cell counts at different time-points were compared with ANOVA. Confocal immunostaining was used to determine the presence of specific immune cell populations detected in flow cytometry. Thirteen patients/aneurysms were included. Five (38.5%) patients developed VSP after a mean of 6.8 days from hemorrhage. Flow cytometry demonstrated decreased numbers of CD45+ cells during the acute phase in PB of aSAH patients compared with healthy controls. In CSF of VSP patients, NK cells (CD3-CD161 +) were increased during the acute phase and progressively declined, whereas CD8+CD161+ lymphocytes significantly increased at days 5–9. Microglia cells (CD45dimCD11b +) increased over time after SAH. This increase was particularly significant in patients with VSP. Levels of VEGF and MMP-9 were consistently higher in VSP patients, with the highest difference occurring at the acute phase. Confocal immunostaining demonstrated the presence of CD8+CD161+ lymphocytes in the arterial wall of two unruptured intracranial aneurysms. In this preliminary study, human CSF showed active presence of innate and adaptive immune cells after aSAH. CD8+CD161+ lymphocytes may have an important role in the inflammatory response after aneurysmal rupture and were identified in the aneurysmal wall of unruptured brain aneurysms. Microglia activation occurs 6 + days after aSAH.

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Bilirubin Oxidation Products and Cerebral Vasoconstriction

Cited by 12 publications

References 38 publications

Inflammation and immune cell abnormalities in intracranial aneurysm subarachnoid hemorrhage (SAH): Relevant signaling pathways and therapeutic strategies

Inflammation and immune cell abnormalities in intracranial aneurysm subarachnoid hemorrhage (SAH): Relevant signaling pathways and therapeutic strategies

The Role of the Glycocalyx in the Pathophysiology of Subarachnoid Hemorrhage-Induced Delayed Cerebral Ischemia

Preliminary results in the analysis of the immune response after aneurysmal subarachnoid hemorrhage

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