Glymphatic Drainage Blocking Aggravates Brain Edema, Neuroinflammation via Modulating TNF-α, IL-10, and AQP4 After Intracerebral Hemorrhage in Rats

Liu, Xichang; Wu, Gang; Tang, Na; Li, Li; Liu, Cuimin; Wang, Feng; Ke, Shaofa

doi:10.3389/fncel.2021.784154

Cited by 25 publications

(21 citation statements)

References 39 publications

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“…However, brain swelling and clinical outcomes are worse in AQP4-/- mice in models of vasogenic (fluid leak) edema, probably due to impaired AQP4-dependent brain water clearance [ 57 ]. AQP4 mediates bidirectional water flux as well as water inflow and outflow during the evolution of edema [ 58 , 59 ]. AQP4 dysfunction in mouse brain tissue leads to impaired water and solute processing and may lead to brain edema or abnormal protein accumulation [ 60 , 61 ].…”

Section: Discussionmentioning

confidence: 99%

Aquaporin 4 Depolarization-Enhanced Transferrin Infiltration Leads to Neuronal Ferroptosis after Subarachnoid Hemorrhage in Mice

Liu

Wang

Cao

et al. 2022

Oxidative Medicine and Cellular Longevity

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The infiltration of blood components into the brain parenchyma through the lymphoid system is an important cause of subarachnoid hemorrhage injury. AQP4, a water channel protein located at the astrocyte foot, has been reported to regulate blood–brain barrier integrity, and its polarization is disrupted after SAH. Neuronal ferroptosis is involved in subarachnoid hemorrhage- (SAH-) induced brain injury, but the inducing factors are not completely clear. Transferrin is one of the inducing factors of ferroptosis. This study is aimed at researching the role and mechanism of AQP4 in brain injury after subarachnoid hemorrhage in mice. An experimental mouse SAH model was established by endovascular perforation. An AAV vector encoding AQP4 with a GFAP-specific promoter was administered to mice to achieve specific overexpression of AQP4 in astrocytes. PI staining, Fer-1 intervention, and transmission electron microscopy were used to detect neuronal ferroptosis, and dextran (40 kD) leakage was used to detect BBB integrity. Western blot analysis of perfused brain tissue protein samples was used to detect transferrin infiltration. First, neuronal ferroptosis 24 h after SAH was observed by PI staining and Fer-1 intervention. Second, a significant increase in transferrin infiltration was found in the brain parenchyma 24 h after SAH modeling, while transferrin content was positively correlated with neuronal ferroptosis. Then, we observed that AQP4 overexpression effectively improved AQP depolarization and BBB injury induced by SAH and significantly reduced transferrin infiltration and neuronal ferroptosis after SAH. Finally, we found that AQP4 overexpression could effectively improve the neurobehavioral ability of SAH mice, and the neurobehavioral ability was negatively correlated with transferrin brain content. Taken together, these data indicate that overexpression of AQP4 in the mouse brain can effectively improve post-SAH neuronal ferroptosis and brain injury, at least partly by inhibiting transferrin infiltration into the brain parenchyma in the glymphatic system.

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Section: Discussionmentioning

confidence: 99%

Aquaporin 4 Depolarization-Enhanced Transferrin Infiltration Leads to Neuronal Ferroptosis after Subarachnoid Hemorrhage in Mice

Liu

Wang

Cao

et al. 2022

Oxidative Medicine and Cellular Longevity

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“…Although almost no studies have explored the relationship between the cerebral drainage venous system and PHE in animals, there have been studies on the influence of the cerebral drainage venous system on PHE in patients with ICH [ 125 – 127 ]. Blocking of brain lymphatic drainage can exacerbate brain edema, neuroinflammation, and neuronal death and cause neurologic deficits in animals with acute ICH [ 128 , 129 ]. Furthermore, the brain lymphatic drainage system is also involved in clearing brain waste from blood after ICH in animals [ 130 ].…”

Section: Factors That May Impact Phementioning

confidence: 99%

“…Regarding ICH, although previous studies have illustrated that abnormalities in the brain lymphatic drainage system can promote the formation of brain edema in animals [ 128 , 129 ], no research has provided information on changes in the brain lymphatic drainage system and its relationship with PHE in patients with ICH [ 161 – 164 ]. Relevant future studies will provide information on the mechanism of post-ICH PHE formation.…”

Section: Factors That May Impact Phementioning

confidence: 99%

Molecular, Pathological, Clinical, and Therapeutic Aspects of Perihematomal Edema in Different Stages of Intracerebral Hemorrhage

Jiang

Guo

Zhang

et al. 2022

Oxidative Medicine and Cellular Longevity

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Acute intracerebral hemorrhage (ICH) is a devastating type of stroke worldwide. Neuronal destruction involved in the brain damage process caused by ICH includes a primary injury formed by the mass effect of the hematoma and a secondary injury induced by the degradation products of a blood clot. Additionally, factors in the coagulation cascade and complement activation process also contribute to secondary brain injury by promoting the disruption of the blood-brain barrier and neuronal cell degeneration by enhancing the inflammatory response, oxidative stress, etc. Although treatment options for direct damage are limited, various strategies have been proposed to treat secondary injury post-ICH. Perihematomal edema (PHE) is a potential surrogate marker for secondary injury and may contribute to poor outcomes after ICH. Therefore, it is essential to investigate the underlying pathological mechanism, evolution, and potential therapeutic strategies to treat PHE. Here, we review the pathophysiology and imaging characteristics of PHE at different stages after acute ICH. As illustrated in preclinical and clinical studies, we discussed the merits and limitations of varying PHE quantification protocols, including absolute PHE volume, relative PHE volume, and extension distance calculated with images and other techniques. Importantly, this review summarizes the factors that affect PHE by focusing on traditional variables, the cerebral venous drainage system, and the brain lymphatic drainage system. Finally, to facilitate translational research, we analyze why the relationship between PHE and the functional outcome of ICH is currently controversial. We also emphasize promising therapeutic approaches that modulate multiple targets to alleviate PHE and promote neurologic recovery after acute ICH.

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“…A conversion between apoptosis and pyroptosis occurs through a mechanism mediated by caspase-3/GSDME ( 121 ). Many studies have documented caspase-3 activation leading to apoptosis after ICH, and many signaling pathways have been shown to be involved ( 122 – 124 ). However, studies are needed to determine whether caspase-3/GSDME mediates pyroptosis after ICH in the future.…”

Section: Potential Mechanisms Of Pyroptosis After Ichmentioning

confidence: 99%

Perspectives on the mechanism of pyroptosis after intracerebral hemorrhage

et al. 2022

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Intracerebral hemorrhage (ICH) is a highly harmful neurological disorder with high rates of mortality, disability, and recurrence. However, effective therapies are not currently available. Secondary immune injury and cell death are the leading causes of brain injury and a poor prognosis. Pyroptosis is a recently discovered form of programmed cell death that differs from apoptosis and necrosis and is mediated by gasdermin proteins. Pyroptosis is caused by multiple pathways that eventually form pores in the cell membrane, facilitating the release of inflammatory substances and causing the cell to rupture and die. Pyroptosis occurs in neurons, glial cells, and endothelial cells after ICH. Furthermore, pyroptosis causes cell death and releases inflammatory factors such as interleukin (IL)-1β and IL-18, leading to a secondary immune-inflammatory response and further brain damage. The NOD-like receptor protein 3 (NLRP3)/caspase-1/gasdermin D (GSDMD) pathway plays the most critical role in pyroptosis after ICH. Pyroptosis can be inhibited by directly targeting NLRP3 or its upstream molecules, or directly interfering with caspase-1 expression and GSDMD formation, thus significantly improving the prognosis of ICH. The present review discusses key pathological pathways and regulatory mechanisms of pyroptosis after ICH and suggests possible intervention strategies to mitigate pyroptosis and brain dysfunction after ICH.

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Glymphatic Drainage Blocking Aggravates Brain Edema, Neuroinflammation via Modulating TNF-α, IL-10, and AQP4 After Intracerebral Hemorrhage in Rats

Cited by 25 publications

References 39 publications

Aquaporin 4 Depolarization-Enhanced Transferrin Infiltration Leads to Neuronal Ferroptosis after Subarachnoid Hemorrhage in Mice

Aquaporin 4 Depolarization-Enhanced Transferrin Infiltration Leads to Neuronal Ferroptosis after Subarachnoid Hemorrhage in Mice

Molecular, Pathological, Clinical, and Therapeutic Aspects of Perihematomal Edema in Different Stages of Intracerebral Hemorrhage

Perspectives on the mechanism of pyroptosis after intracerebral hemorrhage

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