Critical Role of Connexin 43 in Secondary Expansion of Traumatic Spinal Cord Injury

Huang, Chunlan; Han, Xiaoning; Li, Xi; Lam, Eric; Peng, Weiguo; Lou, Nanhong; Torres, Arnulfo; Yang, Meixiang; Garré, Juan Mauricio; Tian, Guo Feng; Bennett, Michael V. L.; Takano, Takahiro

doi:10.1523/jneurosci.1216-11.2012

Cited by 117 publications

(117 citation statements)

References 33 publications

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“…In the situation of trauma, the astrocytes are the first to sense injury, and the activation of microglia is triggered by astrocytic ATP release. Lack of Cx43 hemichannels causes reduced leakage of ATP and thus inhibits the activation of microglia [25][26][27] . The release of TNF-α and IL-1β from LPS-activated microglia targets astrocytes mainly through Cx43 hemichannels [28,29] .…”

Section: Resultsmentioning

confidence: 99%

Decreased connexin 43 in astrocytes inhibits the neuroinflammatory reaction in an acute mouse model of neonatal sepsis

et al. 2015

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Section: Resultsmentioning

confidence: 99%

Decreased connexin 43 in astrocytes inhibits the neuroinflammatory reaction in an acute mouse model of neonatal sepsis

et al. 2015

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“…41 The significance of this finding is that it provides a specific target for therapeutic intervention. Others have linked connexins, purinergic signaling, and inflammation in a model of spinal cord injury 49 ; however, this is the first demonstration in an implant model.…”

Section: Discussionmentioning

confidence: 88%

“…Connexin hemichannels, and in particular Cx43, are major contributors to the release of purinergic signals that attract inflammatory cells in other injury types. 48,49 Chemical inhibitors of connexins (such as FFA and MFQ, respectively) affect other channel types, including pannexin channels and ion channels. [50][51][52][53] Nonspecific inhibition by these inhibitors may have pleiotropic effects.…”

Section: Resultsmentioning

confidence: 99%

Inhibition of Connexin 43 Hemichannel-Mediated ATP Release Attenuates Early Inflammation During the Foreign Body Response

Calder

Rhett

Bainbridge

et al. 2015

Tissue Engineering Part A

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Background: In the last 50 years, the use of medical implants has increased dramatically. Failure of implanted devices and biomaterials is a significant source of morbidity and increasing healthcare expenditures. An important cause of implant failure is the host inflammatory response. Recent evidence implicates extracellular ATP as an important inflammatory signaling molecule. A major pathway for release of cytoplasmic ATP into the extracellular space is through connexin hemichannels, which are the unpaired constituents of gap junction intercellular channels. Blockade of hemichannels of the connexin 43 (Cx43) isoform has been shown to reduce inflammation and improve healing. We have developed a Cx43 mimetic peptide ( JM2) that targets the microtubule-binding domain of Cx43. The following report investigates the role of the Cx43 microtubule-binding domain in extracellular ATP release by Cx43 hemichannels and how this impacts early inflammatory events of the foreign body reaction. Methods: In vitro Cx43 hemichannel-mediated ATP release by cultured human microvascular endothelial cells subjected to hypocalcemic and normocalcemic conditions was measured after application of JM2 and the known hemichannel blocker, flufenamic acid. A submuscular silicone implant model was used to investigate in vivo ATP signaling during the early foreign body response. Implants were coated with control pluronic vehicle or pluronic carrying JM2, ATP, JM2 + ATP, or known hemichannel blockers and harvested at 24 h for analysis. Results: JM2 significantly inhibited connexin hemichannel-mediated ATP release from cultured endothelial cells. Importantly, the early inflammatory response to submuscular silicone implants was inhibited by JM2. The reduction in inflammation by JM2 was reversed by the addition of exogenous ATP to the pluronic vehicle. Conclusions: These data indicate that ATP released through Cx43 hemichannels into the vasculature is an important signal driving the early inflammatory response to implanted devices. A vital aspect of this work is that it demonstrates that targeted molecular therapeutics, such as JM2, provide the capacity to regulate inflammation in a clinically relevant system.

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“…Diverse strategies aimed at blocking HC activity using genetic or pharmacological tools have thus been developed [25][26][27][28]. Most of them suppress Cx43 expression and/or function, which are considered the main HC constituent in astrocytes [7] by knocking-out Cx43 gene, for instance, using anti-sense tools, antibodies or mimetic peptides.…”

Section: Commentarymentioning

confidence: 99%

“…Meanwhile, glutamate and ATP can also promote activation of neuronal NMDA and purinergic receptors, further leading to Ca 2+ overload and the activation of intracellular neurotoxic cascades resulting in neurodegeneration [18]. This is summarized in Figure 1.Diverse strategies aimed at blocking HC activity using genetic or pharmacological tools have thus been developed [25][26][27][28]. Most of them suppress Cx43 expression and/or function, which are considered the main HC constituent in astrocytes [7] by knocking-out Cx43 gene, for instance, using anti-sense tools, antibodies or mimetic peptides.…”

mentioning

confidence: 99%

New Insights on Astroglial Connexins as a Therapeutic Target for Alzheimer's Disease

Yi¹,

Koulakoff²,

Giaume³

2017

J Cell Signal

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CommentaryAlzheimer's disease (AD) is the leading cause of dementia in the elderly and characterized by progressive memory loss, behavioral deficits and significant personality alterations [1,2]. The histopathological hallmarks of AD include Aβ plaques, neurofibrillary tangles, neuronal death and synapse loss. One significant feature of Aβ accumulation is the strong reactive gliosis associated with the Aβ plaques themselves [3,4], however, understanding of the properties and functions of astrocytes in AD has only begun to emerge in recent years.In the brain, astrocytes possess the highest levels of connexin (Cx) expression, with Cx43 and Cx30 being the most abundant [5,6]. Cxs are the proteins that form gap junction channels (GJCs) and hemichannels (HCs). Besides Cxs, HCs can be formed by another family of functionally related proteins, pannexins (Panxs), which share the same transmembrane topology as Cxs but have divergent primary sequences [7]. Cxs and Panxs oligomerize into hexameres that isolate a large non-selective pore in the membrane allowing for the diffusion of small molecules (e.g. ions, small signaling molecules and metabolic substrates) between the cell cytoplasm and the extracellular medium. In addition, most Cx HCs dock head-to-head between adjacent cells to form intercellular channels that constitute GJCs, while endogenously expressed Panx HCs do not [8,9]. In the brain, astrocytes provide trophic and metabolic support to neurons throughout the astrocytic network via gap junction communication which comprise of over several hundreds of astrocytes [10]. In brain pathologies, for instance in AD, reactive astrogliosis has been associated with changes in the expression and function of connexins. Increased expression of Cxs has been found in astrocytes that are in contact with amyloid plaques in vivo within the brains of AD patients and also in AD animal models. The most prominent indication of connexin changes in Alzheimer's disease is that increased immunoreactivity of Cx43 has been found at Aβ plaque levels in the post-mortem brains of AD patients, which coincides with the presence of gap junctions between astrocytic processes that are adjacent to dystrophic neuronal processes that are present in plaque areas at the ultrastructural level [11]. This Cx43 puncta enrichment has also been found within cadaveric brain sections from AD patients and is detected intermingled with strongly GFAP-positive astrocytic processes that infiltrate Aβ plaques [12]. These features have also been shown to be present in Cx30, though to a lower extent. This is also the case in AD animal models. In a murine model of familial AD (APPSwe/PS1dE9; or termed APP/PS1), these transgenic mice exhibit a variety of changes, including an increase in Cx43 or Cx30 immunoreactivity at Aβ plaque levels in the hippocampus and cortex of APP/PS1 mice older than 4 months. These connexin immunoreactivities have been found to be concentrated in bright and large puncta at astrocytic processes that infiltrate the plaque core, and are encircled...

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Critical Role of Connexin 43 in Secondary Expansion of Traumatic Spinal Cord Injury

Cited by 117 publications

References 33 publications

Decreased connexin 43 in astrocytes inhibits the neuroinflammatory reaction in an acute mouse model of neonatal sepsis

Decreased connexin 43 in astrocytes inhibits the neuroinflammatory reaction in an acute mouse model of neonatal sepsis

Inhibition of Connexin 43 Hemichannel-Mediated ATP Release Attenuates Early Inflammation During the Foreign Body Response

New Insights on Astroglial Connexins as a Therapeutic Target for Alzheimer's Disease

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