SPAK inhibitor ZT‐1a attenuates reactive astrogliosis and oligodendrocyte degeneration in a mouse model of vascular dementia

CNS Neuroscience & Therapeutics, Journal Year: 2024, Volume and Issue: 30(3)

Published: March 1, 2024

Abstract Background Astrogliosis and white matter lesions (WML) are key characteristics of vascular contributions to cognitive impairment dementia (VCID). However, the molecular mechanisms underlying VCID remain poorly understood. Stimulation Na‐K‐Cl cotransport 1 (NKCC1) its upstream kinases WNK (with no lysine) SPAK (the STE20/SPS1‐related proline/alanine‐rich kinase) play a role in astrocytic intracellular Na + overload, hypertrophy, swelling. Therefore, this study, we assessed effect inhibitor ZT‐1a on pathogenesis function mouse model induced by bilateral carotid artery stenosis (BCAS). Methods Following sham or BCAS surgery, mice were randomly assigned receive either vehicle (DMSO) treatment regimen (days 14–35 post‐surgery). Mice then evaluated for functions Morris water maze, WML ex vivo MRI‐DTI analysis, astrogliosis/demyelination immunofluorescence immunoblotting. Results Compared control mice, BCAS‐Veh exhibited chronic cerebral hypoperfusion memory impairments, accompanied significant MRI DTI‐detected oligodendrocyte (OL) death. Increased activation WNK‐SPAK‐NKCC1‐signaling proteins was detected tissues C3d GFAP cytotoxic astrocytes but not S100A10 homeostatic mice. In contrast, ZT‐1a‐treated displayed reduced expression phosphorylation NKCC1, decreased astrogliosis, OL death, WML, along with improved functions. Conclusion BCAS‐induced upregulation WNK‐SPAK‐NKCC1 signaling contributes matter‐reactive impairment. Pharmacological inhibition activity has therapeutic potential alleviating VCID.

Language: Английский

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Ion transporter cascade, reactive astrogliosis and cerebrovascular diseases

Frontiers in Pharmacology, Journal Year: 2024, Volume and Issue: 15

Published: April 9, 2024

Cerebrovascular diseases and their sequalae, such as ischemic stroke, chronic cerebral hypoperfusion, vascular dementia are significant contributors to adult disability cognitive impairment in the modern world. Astrocytes an integral part of neurovascular unit CNS play a pivotal role homeostasis, including ionic p H balance, neurotransmission, blood flow, metabolism. respond insults, inflammation, through unique molecular, morphological, functional changes, collectively known reactive astrogliosis. The function astrocytes has been subject debate. Initially, were thought primarily supportive maintaining structure nervous system. However, recent studies suggest that may have both beneficial detrimental effects. For example, can cause oligodendrocyte death demyelination. In this review, we will summarize (1) roles ion transporter cascade astrogliosis, (2) related dementias, (3) potential therapeutic approaches for dementing disorders targeting astrocytes. Understanding relationship between cascade, cerebrovascular reveal mechanisms targets development therapies brain associated with

Language: Английский

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Edaravone dexborneol alleviates pericyte-mediated fibrosis depositing extracellular matrix through TGF-β1/IL-11 in cerebral small vessel disease

Journal of Translational Medicine, Journal Year: 2025, Volume and Issue: 23(1)

Published: Feb. 5, 2025

Chronic cerebral hypoperfusion (CCH) is a critical pathophysiological mechanism underlying small vessel disease (CSVD). Accumulating evidence have demonstrated that resident pericytes and deposit extracellular matrix (ECM) play key role in mediating fibrosis hypoxic changes. Edaravone dexborneol (EDB) known to target multiple pathways involved fibrosis. We constructed the CCH mouse models were subjected either PBS or EDB at different concentrations. Measures of cognitive function, neuronal damage, white matter lesion (WML), fibrous profiles ECM protein investigated assess effect EDB. RNA sequencing OGD was performed identify signaling pathway. observed both medium high concentrations could ameliorate CCH-induced impairment emotional disorders. Neuronal damage cortical layer hippocampus WML corpus callosum improved by EDB, which consistent with tends proteins these regions. suggested TGF-β1/IL-11 plays an important Subsequently, results confirmed cellular model. Our findings reveal pericyte-mediated depositing pathogenesis CSVD. improve symptoms mice decrease expression proteins, may be regulated TGF-β1/ IL-11. treatment, targeting fibrosis, novel therapeutic strategy for

Language: Английский

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Target inhibition of SPAK in choroid plexus attenuates T cell infiltration and demyelination in experimental autoimmune encephalomyelitis

Journal of Neuroinflammation, Journal Year: 2025, Volume and Issue: 22(1)

Published: March 13, 2025

Disease-modifying therapies (DMTs) that prevent immune cell infiltration into the brain have demonstrated efficacy in multiple sclerosis (MS) treatment. However, their unpredictable adverse effects necessitate development of safer therapeutic alternatives. The choroid plexus (ChP) functions as a crucial barrier against invasion, and previous studies shown preventing across ChP reduces lesion MS animal models. Understanding regulation is therefore essential for identifying novel targets MS. Here, we explored role Ste20-related proline/alanine-rich kinase (SPAK) experimental autoimmune encephalomyelitis (EAE). We examined expression patterns SPAK signaling using immunofluorescence EAE model. To investigate roles SPAK, matrix metalloproteinase (MMP) 2 MMP9 pathology, performed ChP-specific gene manipulation via intracerebroventricular (ICV) injection recombinant adeno-associated virus 2/5 (rAAV2/5). T central nervous system (CNS) was analyzed CD4 immunostaining flow cytometry. employed immunofluorescence, transwell assays, rescue experiments vitro to study SPAK's on epithelial integrity. also evaluated protective SPAK-Na-K-2Cl cotransporter-1 (NKCC1) inhibitors (ZT-1a bumetanide) invasion demyelination during pharmacological approaches. Following induction, observed progressive increases both total phosphorylated levels epithelium. Notably, knockdown significantly reduced ameliorated while overexpression exacerbated these effects. Bulk RNA sequencing subsequent qPCR validation revealed decreased MMP2 MMP9, MMPs compromise integrity by degrading tight junction proteins. In impaired function through activator protein-1 (AP-1)-MMP2/9-zonula occludens-1 (ZO-1) axis. Furthermore, either or protected pathology. Additionally, identified SPAK-NKCC1 antagonists (bumetanide ZT-1a) promising candidates MS/EAE Our findings demonstrate targeting ChP-SPAK represents strategy

Language: Английский

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Carotid artery vascular stenosis causes the blood-CSF barrier damage and neuroinflammation

Journal of Neuroinflammation, Journal Year: 2024, Volume and Issue: 21(1)

Published: Sept. 10, 2024

The choroid plexus (ChP) helps maintain the homeostasis of brain by forming blood-CSF barrier via tight junctions (TJ) at epithelial cells, and subsequently preventing neuroinflammation restricting immune cells infiltration into central nervous system. However, whether chronic cerebral hypoperfusion causes ChP structural damage impairment remains understudied.

Language: Английский

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The Phenotype Changes of Astrocyte During Different Ischemia Conditions

Brain Sciences, Journal Year: 2024, Volume and Issue: 14(12), P. 1256 - 1256

Published: Dec. 14, 2024

Objectives: Dementia is becoming a major health problem in the world, and chronic brain ischemia an established important risk factor predisposing this disease. Astrocytes, as one part of blood–brain barrier (BBB), are activated during cerebral blood flow hypoperfusion. Reactive astrocytes have been classified into phenotype pro-inflammatory type A1 or neuroprotective A2. However, specific subtype change astrocyte mechanisms still unknown. Methods: In order to depict changes their possible roles process, rat bilateral common carotid artery occlusion model (BCAO) was employed present study. Meanwhile, signaling pathways that possibly regulate these were investigated well. Results: After four-week occlusion, cortex BCAO rats shown be A2 phenotype, identified by significant up-regulation S100a10 accompanied down-regulation Connexin 43 (CX43) protein. Next, we vitro hypoxia models, which set up stimulating primary cultures from with cobalt chloride, low glucose, or/and fibrinogen. Consistent vivo data, cultured also transformed CX43. explore mechanism CX43 protein changes, C6 cells handled both low-glucose stimulus, decreased pERK pJNK expression found. Conclusions: conclusion, our data suggest conditions, gradual ischemic insults could promote transformation instead type, phosphorylation negatively regulated ERK JNK. Also, provide some new evidence how leverage endogenous CNS injury promoting them “protector” not “culprit”.

Language: Английский

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Regulatory mechanism of LncRNA GAS5 in cognitive dysfunction induced by sevoflurane anesthesia in neonatal rats

Brain and Development, Journal Year: 2024, Volume and Issue: 47(1), P. 104295 - 104295

Published: Nov. 16, 2024

Language: Английский

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