Inflammasome Activation Mediates Apoptotic and Pyroptotic Death in Astrocytes Under Ischemic Conditions

Wong, Lap Jack; Lee, Bernice Woon Li; Sng, Yi Jing; Poh, Luting; Rajeev, Vismitha; Selvaraji, Sharmelee; Drummond, Grant R.; Sobey, Christopher G.; Arumugam, Thiruma V.; Fann, David Y.

doi:10.1007/s12017-023-08753-2

Cited by 3 publications

(1 citation statement)

References 27 publications

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“…NLRP3 activation facilitates cleavage of pro-caspase-1 into its active form, leading to the subsequent processing of pro-inflammatory cytokines, notably interleukin-1 beta (IL-1β) and IL-18 within microglia and astrocytes, contributing to the pathogenesis of VCID including white matter lesions ( Poh et al, 2021 ; Li L et al, 2022 ; Wang et al, 2023 ). NF-κB signaling activation also induces NLRP3 inflammasome-mediated IL-1β and IL-18 maturation which activate downstream inflammatory cascades including transformation of neurotoxic A1 astrocytes and various cell death pathways including apoptosis, and pyroptosis ( Aachoui et al, 2013 ; Li L et al, 2022 ; Wang et al, 2023 ; Wong et al, 2023 ). In depression-like mice, after 2–6 weeks of chronic mild stress (CMS), the NLRP3 inflammasome activates microglia, leading to the release of an A1 cocktail l (TNF-α, IL-1α, and C1qA) and upregulation of related A1 astrocyte genes ( H2-T23, Serping1, H2-D1, Ugt1a5, Fkbp5, Ligp1, Fbln5, Ggta1, C3, Gbp2, Pmsb8 and Amigo2 ) ( Li S et al, 2022 ).…”

Section: Therapeutic Strategies To Attenuate Reactive Astrogliosis An...mentioning

confidence: 99%

Ion transporter cascade, reactive astrogliosis and cerebrovascular diseases

Rahman,

Islam,

Bhuiyan

2024

Front. Pharmacol.

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

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Section: Therapeutic Strategies To Attenuate Reactive Astrogliosis An...mentioning

confidence: 99%

Ion transporter cascade, reactive astrogliosis and cerebrovascular diseases

Rahman,

Islam,

Bhuiyan

2024

Front. Pharmacol.

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Intranasal Delivery of Lithium Salt Suppresses Inflammatory Pyroptosis in the brain and Ameliorates Memory Loss and Depression-like Behavior in 5XFAD mice

Bhuiyan,

Zhang,

Liang

et al. 2024

Preprint

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This study compares the changes in lithium concentrations in the brain and blood following the administration of intranasal or oral lithium chloride (LiCl) dissolved in either Ryanodex Formulation Vehicle (RFV) or water, as well as the therapeutic effectiveness and side effects of intranasal versus oral lithium chloride (LiCl) in RFV, and their mechanisms for inhibiting inflammation and pyroptosis in 5xFAD Alzheimer’s Disease (AD) mice brains. In comparison to oral LiCl in RFV, intranasal LiCl in RFV decreased lithium blood concentrations but increased brain concentrations and duration, resulting in a significantly higher brain/blood lithium concentration ratio than intranasal LiCl in water or oral LiCl in RFV in young adult mice. Intranasal LiCl in RFV robustly protects both memory loss and depressive behavior in both young and old 5xFAD mice, with no side effects or thyroid/kidney toxicity. In fact, intranasal LiCl in RFV protects against age-dependent kidney function impairment in 5xFAD mice. This lithium mediated neuroprotection was associated with its potent effects on the inhibition of InsP3R-1 Ca2+channel receptor increase, ameliorating pathological inflammation and activation of the pyroptosis pathway, and the associated loss of synapse proteins. Intranasal LiCl in RFV could become an effective and potent inhibitor of pathological inflammation/pyroptosis in the CNS and treat both dementia and depression with no or minimal side effects/organ toxicity, particular in AD

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Dysfunctional K+ Homeostasis as a Driver for Brain Inflammation

Ozsoy,

Dallas

2024

Encyclopedia

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The central nervous system (CNS) relies on precise regulation of potassium ion (K+) concentrations to maintain physiology. This regulation involves complex cellular and molecular mechanisms that work in concert to regulate both intracellular and extracellular K+ levels. Inflammation, a key physiological response, encompasses a series of cell-specific events leading to inflammasome activation. Perturbations in K+-sensitive processes can result in either chronic or uncontrolled inflammation, highlighting the intricate relationship between K+ homeostasis and inflammatory signalling. This review explores molecular targets that influence K+ homeostasis and have been implicated in inflammatory cascades, offering potential therapeutic avenues for managing inflammation. We examine both cell-specific and common molecular targets across different cell types, providing a comprehensive overview of the interplay between K+ regulation and inflammation in the CNS. By elucidating these mechanisms, we identify leads for drug discovery programmes aimed at modulating inflammatory responses. Additionally, we highlight potential consequences of targeting individual molecular entities for therapeutic purposes, emphasizing the need for a nuanced approach in developing anti-inflammatory strategies. This review considers current knowledge on K+-sensitive inflammatory processes within the CNS, offering critical insights into the molecular underpinnings of inflammation and potential therapeutic interventions. Our findings underscore the importance of considering K+ homeostasis in the development of targeted therapies for inflammatory conditions within the CNS.

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Inflammasome Activation Mediates Apoptotic and Pyroptotic Death in Astrocytes Under Ischemic Conditions

Cited by 3 publications

References 27 publications

Ion transporter cascade, reactive astrogliosis and cerebrovascular diseases

Ion transporter cascade, reactive astrogliosis and cerebrovascular diseases

Intranasal Delivery of Lithium Salt Suppresses Inflammatory Pyroptosis in the brain and Ameliorates Memory Loss and Depression-like Behavior in 5XFAD mice

Dysfunctional K+ Homeostasis as a Driver for Brain Inflammation

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