GLIA
·
2025
·
IF 5.1
Tingting Yang,Zhenzhou Lin,Mingjia Yu,Yongchuan Li,Jiancong Chen,Yuanchi Liu,Kaibin Huang,Suyue Pan
Status epilepticus (SE) is a severe condition that results in uncontrollable cerebral edema and cognitive dysfunction. Recent studies suggest that the localization of aquaporin-4 (AQP4) in astrocytic endfeet plays a crucial role in regulating blood–brain water transport and cell volume control, particularly along perivascular pathways. However, the signaling mechanisms underlying AQP4 localization remain poorly understood. In this study, we utilized the genetically encoded fluorescent calcium (Ca 2+ ) indicator GCaMp6f to investigate Ca 2+ signals in astrocytic somata, processes, and endfeet during SE induction and observed enhanced Ca 2+ signals in both the somata and perivascular endfeet of astrocytes. We employed genetic knockout of TRPM4 ( Trpm4 −/− ) and glibenclamide treatment to explore the role of sulfonylurea receptor 1 transient receptor potential melastatin-4 (SUR1-TRPM4) channel in these Ca 2+ responses. Both approaches significantly suppressed the Ca 2+ signals in the astrocytic endfeet and reduced perivascular expression of the Ca 2+ -related signaling pathway sensor calmodulin (CaM). Furthermore, we found that AQP4 localization was no longer confined to the domains of astrocytic endfeet following SE. Inhibition of SUR1-TRPM4 through pharmacological blockade or gene deletion restored the subcellular localization of AQP4, reduced cerebral edema, and improved cognitive outcomes post-SE. Our findings suggest that SUR1-TRPM4 plays a pivotal role in regulating astrocytic Ca 2+ signals and mediating the aberrant expression and subcellular localization of astrocytic AQP4 along perivascular pathways. Together, these findings demonstrate a novel molecular mechanism underscoring SUR1-TRPM4 therapy in the treatment of SE characterized by dysregulated Ca 2+ signaling in astrocytic endfeet.
研究领域:
神经生物学
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药理学
·
细胞生物学
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产品关联
DOI
PubMed
高影响因子
ADVANCED FUNCTIONAL MATERIALS
·
2024
·
IF 18.5
Kewei Liu,Yuqin Peng,Mingheng Xu,Kun Yuan,Yongchuan Li,Chuman Lin,Xiaolin Zhao,Juan Zhu,Yuan Chang,Zhenzhou Lin,Suyue Pan,Huanrong Ma,Xiaorui Wang,Kaibin Huang
Brain edema robustly increases mortality and hinders functional recovery after acute ischemic stroke. However, there are currently no effective therapies available for treating or preventing it. The unchecked opening of the transient receptor potential M4 (TRPM4) channel results in an excessive influx of Na + and water, which contributes significantly to the formation of brain edema after ischemic stroke. 9-phenanthrol (9-Phe), a potent TRPM4 inhibitor, has limited clinical applicability due to its potential cytotoxicity and poor solubility. A brain-targeting T7 (HAIYPRH)-modified lipid nanoparticle (LNP) encapsulated 9-Phe (9-Phe@T7-LNP) is designed and synthesized to improve the physicochemical properties and pharmacokinetic properties of 9-Phe for treating brain edema in vivo. These results demonstrated that 9-Phe@T7-LNP can penetrate the intact blood-brain barrier (BBB) in normal mice and target the brain parenchyma. Moreover, 9-Phe@T7-LNP effectively reduced infarct volume and brain edema, prevented neuronal loss and BBB disruption, improved survival, and facilitated neurological function recovery after transient middle cerebral artery occlusion in mice. Additionally, 9-Phe@T7-LNP scavenged oxygen-free radicals and prevented neuronal apoptosis in cultured neurons subjected to oxygen and glucose deprivation/reperfusion. In summary, these findings showed that 9-Phe@T7-LNP holds strong potential as a promising targeted therapy for brain edema after stroke, providing superior pharmacological neuroprotection against brain edema.
研究领域:
神经科学
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药理学
·
纳米技术
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中风研究
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产品关联
DOI
高影响因子
Theranostics
·
2025
·Vol. 15
·期 14
·6901
·
IF 13.3
Yifan Ren,Qing Cui,Wuming Liu,Hangcheng Liu,Tao Wang,Hongwei Lu,Yi Lv,Rongqian Wu
Background: Mitochondrial dysfunction caused by Ca 2+ overload in pancreatic acinar cells is an important mechanism in the pathogenesis of acute pancreatitis (AP). Transient receptor potential cation channel melastatin 4 (TRPM4), a non-selective cation channel, can be activated by intracellular Ca 2+ , and is involved in mediating damage to neuronal mitochondrial function. However, the role of TRPM4 activation in mitochondrial dysfunction during AP remains unknown. Methods: We employed three mouse models of AP (intraperitoneal administration of L-arginine, cerulein plus lipopolysaccharides (LPS), or cerulein alone) for in vivo studies. For in vitro studies, cerulein+ LPS was used to induce mitochondrial dysfunction and cell death in AR42J cell. Trpm4 gene-defective mice and plasmids were utilized to downregulate the expression of TRPM4 in mice or overexpress TRPM4 in AR42J. 9-Phenanthrol, a specific inhibitor of TRPM4, was used to antagonize TRPM4 activity both in vitro and in vivo . Results: Pancreatic TRPM4 levels were increased in all three AP models. Blocking TRPM4 activity with 9-phenanthrol or knocking down TRPM4 expression alleviated pancreatic damage and reduced mortality in AP mice. The protective effect of TRPM4 defects on AP was associated with improved mitochondrial function in pancreatic acinar cells. Mechanistically, TRPM4 activation induced mitochondrial dysfunction and cell death in AP were dependent on the presence of N-methyl-D-aspartate receptors (NMDARs). Blocking NMDARs mitigates the aggravated mitochondrial damage, ER stress and cell death caused by TRPM4 activation in AP. Conclusions: TRPM4 activation contributes to pancreatic acinar cells damage via an NMDAs-dependent pathway in AP. The TRPM4/NMDARs complex provides a new target for the future treatment of AP.
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产品关联
DOI
PubMed
高影响因子
NEUROPHARMACOLOGY
·
2017
·
IF 5.012
Zhenzhou Lin,Hua Huang,Yong Gu,Kaibin Huang,Yafang Hu,Zhong Ji,Yongming Wu,Shengnan Wang,Tingting Yang,Suyue Pan
Glibenclamide (GBC), a sulfonylurea receptor 1 blocker, emerges recently as a promising neuron protectant in various neurological disorders . This study aimed to determine whether GBC improves survival and neurological outcome of status epilepticus (SE). Male Sprague-Dawley rats successfully undergoing SE for 2.5 h (n = 134) were randomly assigned to GBC or vehicle group. Rats in the GBC group received a loading dose of 10 μg/kg of GBC, followed by 1.2 μg/6 h for 3 days, while same dose of vehicle was used as control. The 28-day survival rate in the GBC group (11/23) was significantly higher than that in the vehicle group (8/36). In addition, the frequency and duration of spontaneous recurrent seizures in SE rats were profoundly reduced by GBC but not by vehicle treatment. Moreover, cognitive impairment was observed in the SE rats at day 28, which was reversed by GBC treatment. Meanwhile, cerebral edema , as well as neuronal loss, was decreased in several brain areas in the GBC group. Additionally, on the molecular basis, the subunits of sulfonylurea receptor 1/transient receptor potential M4 (SUR1-TRPM4) heterodimer were both strongly upregulated after SE but partly suppressed by GBC treatment. Furthermore, gene knockdown of Trpm4 in SE rats reduced BBB disruption and neuronal loss, similar to the inhibitory effects with GBC treatment. Taken together, GBC treatment markedly improved survival and neurologic outcomes after SE. The salutary effects of GBC were correlated to the alleviation of cerebral edema and reduction in neurological injury via down-regulation of SUR1-TRPM4 channel.
研究领域:
神经病学
·
药理学
·
神经科学
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DOI
PubMed
高影响因子
JCI Insight
·
2021
·
IF 8.315
Kewei Liu,Juan Zhu,Yuan Chang,Zhenzhou Lin,Zhu Shi,Xing Li,Xing Chen,Chuman Lin,Suyue Pan,Kaibin Huang
Status epilepticus (SE) is a neurological emergency usually accompanied by acute cerebral edema and long-term cognitive impairment, and is characterized by neurodegeneration and aberrant hyperphosphorylated tau protein (p-tau) aggregation. The glia-lymphatic (glymphatic) system plays a central role in facilitating the clearance of metabolic waste from the brain, but its relationship with cerebral edema and cognitive dysfunction after SE is unclear. We hypothesized that cerebral edema after SE might impair glymphatic system function through compression, thus leading to impaired removal of metabolic waste, and ultimately affecting long-term cognitive function. Our results showed that glymphatic system function was temporarily impaired, as evidenced by 2-photon imaging, MRI enhancement, imaging of brain sections, and astrocytic water channel aquaporin 4 (AQP4) protein polarization. The severity of cerebral edema on MRI correlated well with glymphatic system dysfunction within 8 days following SE. Moreover, when cerebral edema was alleviated by glibenclamide treatment or genetic deletion of Trpm4 , post-SE glymphatic system function recovered earlier, along with fewer p-tau–deposited neurons and neuronal degeneration and better cognitive function. These findings suggest that SE-induced cerebral edema may cause glymphatic system dysfunction and render the post-SE brain vulnerable to p-tau aggregation and neurocognitive impairment.
研究领域:
神经科学
·
神经病学
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药理学
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产品关联
DOI
PubMed
高影响因子
JOURNAL OF NANOBIOTECHNOLOGY
·
2022
·Vol. 20
·期 1
·1-21
·
IF 9.429
Qian ZhiZhi,Wang QianYi,Qiu ZhaoShun,Li DanYang,Zhang ChenCheng,Xiong XiYu,Zheng ZiHui,Ruan QinLi,Guo YiChen,Guo Jun
Acute respiratory distress syndrome (ARDS), caused by noncardiogenic pulmonary edema (PE), contributes significantly to Coronavirus 2019 (COVID-19)-associated morbidity and mortality. We explored the effect of transmembrane osmotic pressure (OP) gradients in PE using a fluorescence resonance energy transfer-based Intermediate filament (IF) tension optical probe. Angiotensin-II- and bradykinin-induced increases in intracellular protein nanoparticle (PN)-OP were associated with inflammasome production and cytoskeletal depolymerization. Intracellular protein nanoparticle production also resulted in cytomembrane hyperpolarization and L-VGCC-induced calcium signals, which differed from diacylglycerol-induced calcium increment via TRPC6 activation. Both pathways involve voltage-dependent cation influx and OP upregulation via SUR1-TRPM4 channels. Meanwhile, intra/extracellular PN-induced OP gradients across membranes upregulated pulmonary endothelial and alveolar barrier permeability. Attenuation of intracellular PN, calcium signals, and cation influx by drug combinations effectively relieved intracellular OP and pulmonary endothelial nonselective permeability, and improved epithelial fluid absorption and PE. Thus, PN-OP is pivotal in pulmonary edema in ARDS and COVID-19, and transmembrane OP recovery could be used to treat pulmonary edema and develop new drug targets in pulmonary injury. Graphical Abstract
研究领域:
肺病学
·
药理学
·
细胞生物学
·
传染病学
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产品关联
DOI
PubMed
高影响因子
危险品化学品经营许可证（带存储）