Tonabersat Prevents Inflammatory Damage in the Central Nervous System by Blocking Connexin43 Hemichannels

Kim, Yeri; Griffin, Jarred M.; Nor, Mohd Nasir Mat; Zhang, Jie; Freestone, Peter S.; Danesh‐Meyer, Helen V.; Rupenthal, Ilva D.; Acosta, Mónica L.; Nicholson, Louise; O’Carroll, Simon J.; Green, Colin

doi:10.1007/s13311-017-0536-9

Cited by 59 publications

(80 citation statements)

References 116 publications

(174 reference statements)

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“…A higher concentration of 100µM, tonabersat was not neuroprotective, and likely reflects a long-term effect on reducing gap junction trafficking instead of HC activity, as described previously 43 (Fig. 6a-k).…”

Section: The Cx43 Hc Blocker Tonabersat Provides Dose-dependent Neurosupporting

confidence: 66%

“…Mimetic peptides like Gap19 do not have the capacity to cross the blood brain barrier and therefore their clinical use is limited. Tonabersat (SB-220453) 43 , was selected for its relative specificity as Cx43 HC blocker at low concentrations 43 and also the ability to cross the blood brain barrier 48 . Systemic delivery of tonabersat in low concentrations in a rat retinal damage model (a model for agerelated macular degeneration) improved functional outcomes by electroretinography and also prevented thinning of the retina through its capacity to block Cx43 HC 43 .…”

Section: Discussionmentioning

confidence: 99%

“…Tonabersat (SB-220453) 43 , was selected for its relative specificity as Cx43 HC blocker at low concentrations 43 and also the ability to cross the blood brain barrier 48 . Systemic delivery of tonabersat in low concentrations in a rat retinal damage model (a model for agerelated macular degeneration) improved functional outcomes by electroretinography and also prevented thinning of the retina through its capacity to block Cx43 HC 43 . Tonabersat has been shown to reduce neurogenic inflammation, and to antagonize transient neuronal hyperexcitability associated with cortical spreading depression in animal models of migraine with aura 78,79 , where a role of gap junctions has been proposed 80 .…”

Section: Discussionmentioning

confidence: 99%

“…Our findings from rodent models and from human ALS samples suggest that Cx43 HC may provide an appropriate target for ALS therapeutics. Tonabersat (SB-220453) was selected for its translational potential in human clinical trials and has been shown 43,44 to specifically block Cx43 HC at low concentrations (1-10 µM).…”

Section: The Cx43 Hc Blocker Tonabersat Provides Dose-dependent Neuromentioning

confidence: 99%

“…For pharmacological assays on Cx43 HC, we used GAP19 (Tocris, 53533) at a concentration of 340 µM 31,36 and Tonabersat (SB-220453) at concentrations of 1 µM, 10 µM and 100 µM 43,44 (Millipore Sigma, SML1354).…”

Section: Human Ipsc-astrocyte and Hipsc-motor Neuron Co-culture: Humamentioning

confidence: 99%

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Connexin 43 hemichannels mediate spatial and temporal disease spread in ALS

Almad

Taga

Joseph

et al. 2020

Preprint

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Connexin 43 (Cx43) gap junctions and hemichannels mediate astrocyte intercellular communication in the central nervous system under normal conditions and may contribute to astrocyte-mediated neurotoxicity in amyotrophic lateral sclerosis (ALS). Here we show that astrocyte-specific knockout of Cx43 in a mouse model of ALS slows disease progression both spatially and temporally, provides motor neuron (MN) protection, and improves survival. In human ALS tissues and biofluids, we observe that higher levels of Cx43 correlate with accelerated disease progression. Using human iPSC-derived astrocytes (hiPSC-A) from both familial and sporadic ALS, we show that Cx43 is upregulated and that Cx43-hemichannels are enriched at the astrocyte membrane. We then demonstrate that the pharmacological blockade of Cx43-hemichannels in ALS astrocytes, during a specific temporal window, provides neuroprotection of hiPSC-MN and reduces ALS astrocyte-mediated neuronal hyperexcitability. Our data identify Cx43 hemichannels as novel conduits of astrocyte-mediated disease progression and a pharmacological target for disease-modifying ALS therapies.

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Section: The Cx43 Hc Blocker Tonabersat Provides Dose-dependent Neurosupporting

confidence: 66%

Section: Discussionmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

Section: The Cx43 Hc Blocker Tonabersat Provides Dose-dependent Neuromentioning

confidence: 99%

Section: Human Ipsc-astrocyte and Hipsc-motor Neuron Co-culture: Humamentioning

confidence: 99%

See 3 more Smart Citations

Connexin 43 hemichannels mediate spatial and temporal disease spread in ALS

Almad

Taga

Joseph

et al. 2020

Preprint

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The potential roles of stress‐induced phosphoprotein 1 and connexin 43 in rats with reperfusion arrhythmia

An,

Gao,

Zhong

et al. 2023

Immunity Inflam & Disease

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ObjectiveConnexin 43 (Cx43) is a critical gene for maintaining myocardial homeostasis. Interestingly, Cx43 and stress‐induced phosphoprotein 1 (STIP1) were recorded to be lowly expressed in ischemia/reperfusion (I/R). However, their impacts on reperfusion arrhythmia (RA) remain to be explored. Our study aimed to find out the related underlying mechanisms.MethodsAfter the establishment of an isolated heart model through Langendorff perfusion, the heart rate, conduction activation time, conduction velocity, and conduction direction of the left ventricle were evaluated, along with the apoptotic rate detection in the collected myocardial tissues. After the construction of a hypoxia/reoxygenation (H/R)‐induced cellular model, cell apoptosis, intercellular communication, cell viability, and the content of reactive oxygen species, superoxide dismutase, malondialdehyde, and lactic dehydrogenase were measured. The expression of Cx43 and STIP1 was determined in both rat heart and cell models. The bindings of STIP3 and Cx43 to heat shock protein 90 (HSP90) and heat shock protein 70 (HSP70) were verified.ResultsRelative to the corresponding controls, Cx43 and STIP1 were decreased in myocardial tissues of RA rats and H/R‐stimulated H9C2 cells, where Cx43‐binding HSP70 and HSP90 were respectively increased and decreased, and ubiquitination level of Cx43 was enhanced. STIP1 overexpression promoted protein expression of Cx43, intercellular communication, and cell viability, and reduced cell apoptosis and oxidative stress in H/R‐stimulated H9C2 cells.ConclusionSTIP1 promoted Cx43 expression to improve intercellular communication and reduce oxidative stress in H/R‐stimulated H9C2 cells.

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