Minocycline: A Novel Stroke Therapy

Møller, Aage R.

doi:10.15406/jnsk.2015.02.00073

Cited by 4 publications

(2 citation statements)

References 68 publications

(109 reference statements)

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“…For example, blocking interleukin-1, a critical mediator driving innate neuroinflammation (30), improved outcome in experimental stroke models (31) and has shown promise in clinical trials (32, 33). Minocycline was promising in clinical trials following ischaemic stroke (34–36). Nonetheless, other anti-inflammatory treatments have been less successful in stroke (37, 38).…”

Section: Introductionmentioning

confidence: 99%

Myeloid Cell and Transcriptome Signatures Associated With Inflammation Resolution in a Model of Self-Limiting Acute Brain Inflammation

2019

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Inflammation contributes to tissue repair and restoration of function after infection or injury. However, some forms of inflammation can cause tissue damage and disease, particularly if inappropriately activated, excessive, or not resolved adequately. The mechanisms that prevent excessive or chronic inflammation are therefore important to understand. This is particularly important in the central nervous system where some effects of inflammation can have particularly harmful consequences, including irreversible damage. An increasing number of neurological disorders, both acute and chronic, and their complications are associated with aberrant neuroinflammatory activity. Here we describe a model of self-limiting acute brain inflammation optimized to study mechanisms underlying inflammation resolution. Inflammation was induced by intracerebral injection of lipopolysaccharide (LPS) and the temporal profile of key cellular and molecular changes were defined during the progression of the inflammatory response. The kinetics of accumulation and loss of neutrophils in the brain enabled well-demarcated phases of inflammation to be operatively defined, including induction and resolution phases. Microglial reactivity and accumulation of monocyte-derived macrophages were maximal at the onset of and during the resolution phase. We profiled the transcriptome-wide gene expression changes at representative induction and resolution timepoints and used gene coexpression network analysis to identify gene clusters. This revealed a distinct cluster of genes associated with inflammation resolution that were induced selectively or maximally during this phase and indicated an active programming of gene expression that may drive resolution as has been described in other tissues. Induction of gene networks involved in lysosomal function, lipid metabolism, and a comparative switch to MHC-II antigen presentation (relative to MHC-I during induction) were prominent during the resolution phase. The restoration and/or further induction of microglial homeostatic signature genes was notable during the resolution phase. We propose the current model as a tractable reductionist system to complement more complex models for further understanding how inflammation resolution in the brain is regulated and as a platform for in vivo testing/screening of candidate resolution-modifying interventions. Our data highlight how resolution involves active cellular and transcriptome reprogramming and identify candidate gene networks associated with resolution-phase adaptations that warrant further study.

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Section: Introductionmentioning

confidence: 99%

Myeloid Cell and Transcriptome Signatures Associated With Inflammation Resolution in a Model of Self-Limiting Acute Brain Inflammation

2019

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“…The impact of controlling the severity of inflammation has been investigated through immunomodulatory interventions. For example, blocking interleukin-1, a critical mediator driving innate neuroinflammation 31 , improved outcome in experimental stroke models 32 and has shown promise in clinical trials 33,34 Minocycline was promising in clinical trials following ischaemic stroke 35–37 . Nonetheless, other anti-inflammatory treatments have been less successful in stroke 38,39 .…”

Section: Introductionmentioning

confidence: 99%

Myeloid cell and transcriptome signatures associated with inflammation resolution in a model of self-limiting acute brain inflammation

Davies

Patir

McColl

2018

Preprint

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Inflammation contributes to tissue repair and restoration of function after infection or injury. However, some forms of inflammation can cause tissue damage and disease, particularly if inappropriately activated, excessive, or not resolved adequately. The mechanisms that prevent excessive or chronic inflammation are therefore important to understand. This is particularly important in the central nervous system where some effects of inflammation can have particularly harmful consequences, including irreversible damage. An increasing number of neurological disorders, both acute and chronic, and their complications are associated with aberrant neuroinflammatory activity.Here we describe a model of self-limiting acute brain inflammation optimised to study mechanisms underlying inflammation resolution. Inflammation was induced by intracerebral injection of lipopolysaccharide (LPS) and the temporal profile of key cellular and molecular changes were defined during the progression of the inflammatory response. The kinetics of accumulation and loss of neutrophils in the brain enabled well demarcated phases of inflammation to be operatively defined, including induction and resolution phases. Microglial reactivity and accumulation of monocyte-derived macrophages were maximal at the onset of and during the resolution phase. We profiled the transcriptome-wide gene expression changes at representative induction and resolution timepoints and used gene coexpression network analysis to identify gene clusters. This revealed a distinct cluster of genes associated with inflammation resolution that were induced selectively or maximally during this phase and indicated an active programming of gene expression that may drive resolution as has been described in other tissues. Induction of gene networks involved in lysosomal function, lipid metabolism and a comparative switch to MHC-II antigen presentation (relative to MHC-I during induction) were prominent during the resolution phase. The restoration and/or further induction of microglial homeostatic signature genes was notable during the resolution phase.We propose the current model as a tractable reductionist system to complement more complex models for further understanding how inflammation resolution in the brain is regulated and as a platform for in vivo testing/screening of candidate resolution-modifying interventions. Our data highlight how resolution involves active cellular and transcriptome reprogramming and identify candidate gene networks associated with resolution-phase adaptations that warrant further study.

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Hypothesized neuroprotective effect of minocycline against COVID-19-induced stroke and neurological dysfunction: possible role of matrix metalloprotease signaling pathway

Shahrivar

Khakpourian²,

Majdi³

et al. 2022

Biologia

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Severe Acute Respiratory Syndrome Coronavirus-2 (COVID-19) is a respiratory disease that causes dysfunction in respiration. Since late 2019, this virus has infected and killed millions of people around the world and imposed many medical and therapeutic problems in the form of a pandemic. According to recent data, COVID-19 disease can increase the risk of stroke, which can be deadly or cause many neurological disorders after the disease. During the last two years, many efforts have been made to introduce new therapies for management of COVID-19-related complications, including stroke. To achieve this goal, several conventional drugs have been investigated for their possible therapeutic roles. Minocycline, a broad-spectrum, long-acting antibiotic with anti-inflammatory and antioxidant properties, is one such conventional drug that should be considered for treating COVID-19-related stroke, as indirect evidence indicates that it exerts neuroprotective effects, can modulate stroke occurrence, and can play an effective and strategic role in management of the molecular signals caused by stroke and its destructive consequences. The matrix metalloprotease (MMP) signaling pathway is one of the main signaling pathways involved in the occurrence and exacerbation of stroke; however, its role in COVID-19-induced stroke and the possible role of minocycline in the management of this signaling pathway in patients with COVID-19 is unclear and requires further investigation. Based on this concept, we hypothesize that minocycline might act via MMP signaling as a neuroprotective agent against COVID-19-induced neurological dysfunction, particularly stroke.

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Minocycline: A Novel Stroke Therapy

Cited by 4 publications

References 68 publications

Myeloid Cell and Transcriptome Signatures Associated With Inflammation Resolution in a Model of Self-Limiting Acute Brain Inflammation

Myeloid Cell and Transcriptome Signatures Associated With Inflammation Resolution in a Model of Self-Limiting Acute Brain Inflammation

Myeloid cell and transcriptome signatures associated with inflammation resolution in a model of self-limiting acute brain inflammation

Hypothesized neuroprotective effect of minocycline against COVID-19-induced stroke and neurological dysfunction: possible role of matrix metalloprotease signaling pathway

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