Impact of Microglial Activation on Astroglial Connexin Expression and Function in Brain Inflammation

Zhang, Jie; O’Carroll, Simon J.; Danesh‐Meyer, Helen V.; Heyde, HC Van der; Becker, DL; Nicholson, Louise; Green, Colin

doi:10.1201/b14166-18

Cited by 6 publications

(4 citation statements)

References 1 publication

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“…Instead, tonabersat appears to be acting primarily and directly on connexin hemichannels to reduce channel opening under injury conditions. Tonabersat may offer an orally available approach for various injuries and chronic inflammatory disease indications, including muscular dystrophy [109], amyotrophic lateral sclerosis [110], CNS trauma [43,44], stroke or ischemia [46,47,111,112], glaucoma, diabetic retinopathy and macular degeneration [37,49,50,54,113], as well as Alzheimer's disease [110,114], chronic pain [115], and infectious disease [116] where connexin hemichannels are implicated in injury spread and the perpetuation of inflammatory processes, especially through the inflammasome pathway [40,84,109].…”

Section: Discussionmentioning

confidence: 99%

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

et al. 2017

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The cis benzopyran compound tonabersat (SB-220453) has previously been reported to inhibit connexin26 expression in the brain by attenuating the p38-mitogen-activated protein kinase pathway. We show here that tonabersat directly inhibits connexin43 hemichannel opening. Connexin43 hemichannels have been called "pathological pores" based upon their role in secondary lesion spread, edema, inflammation, and neuronal loss following central nervous system injuries, as well as in chronic inflammatory disease. Both connexin43 hemichannels and pannexin channels released adenosine triphosphate (ATP) during ischemia in an in vitro ischemia model, but only connexin43 hemichannels contributed to ATP release during reperfusion. Tonabersat inhibited connexin43 hemichannel-mediated ATP release during both ischemia and reperfusion phases, with direct channel block confirmed using electrophysiology. Tonabersat also reduced connexin43 gap junction coupling in vitro, but only at higher concentrations, with junctional plaques internalized and degraded via the lysosomal pathway. Systemic delivery of tonabersat in a rat bright-light retinal damage model (a model for dry age-related macular degeneration) resulted in significantly improved functional outcomes assessed using electroretinography. Tonabersat also prevented thinning of the retina, especially the outer nuclear layer and choroid, assessed using optical coherence tomography. We conclude that tonabersat, already given orally to over 1000 humans in clinical trials (as a potential treatment for, and prophylactic treatment of, migraine because it was thought to inhibit cortical spreading depression), is a connexin hemichannel inhibitor and may have the potential to be a novel treatment of central nervous system injury and chronic neuroinflammatory disease.

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Section: Discussionmentioning

confidence: 99%

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

et al. 2017

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“…Therefore, it is important to distinguish between diabetic retinas and retinas with confirmed DR showing an element of inflammation to develop effective treatments for the different pathologies of non-proliferative DR (NPDR) and proliferative DR (PDR). An increase in connexin43 expression has also been observed in other CNS injuries or diseases associated with inflammation such as astrogliosis and microgliosis [ 14 , 17 , 26 , 27 , 28 , 29 , 30 ]. For instance, connexin43 expression was found to increase in a light damage model of age-related macular degeneration [ 31 ].…”

Section: Introductionmentioning

confidence: 99%

Immunohistochemical Characterization of Connexin43 Expression in a Mouse Model of Diabetic Retinopathy and in Human Donor Retinas

Mugisho

Green

Zhang

et al. 2017

IJMS

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Diabetic retinopathy (DR) develops due to hyperglycemia and inflammation-induced vascular disruptions in the retina with connexin43 expression patterns in the disease still debated. Here, the effects of hyperglycemia and inflammation on connexin43 expression in vitro in a mouse model of DR and in human donor tissues were evaluated. Primary human retinal microvascular endothelial cells (hRMECs) were exposed to high glucose (HG; 25 mM) or pro-inflammatory cytokines IL-1β and TNF-α (10 ng/mL each) or both before assessing connexin43 expression. Additionally, connexin43, glial fibrillary acidic protein (GFAP), and plasmalemma vesicular associated protein (PLVAP) were labeled in wild-type (C57BL/6), Akita (diabetic), and Akimba (DR) mouse retinas. Finally, connexin43 and GFAP expression in donor retinas with confirmed DR was compared to age-matched controls. Co-application of HG and cytokines increased connexin43 expression in hRMECs in line with results seen in mice, with no significant difference in connexin43 or GFAP expression in Akita but higher expression in Akimba compared to wild-type mice. On PLVAP-positive vessels, connexin43 was higher in Akimba but unchanged in Akita compared to wild-type mice. Connexin43 expression appeared higher in donor retinas with confirmed DR compared to age-matched controls, similar to the distribution seen in Akimba mice and correlating with the in vitro results. Although connexin43 expression seems reduced in diabetes, hyperglycemia and inflammation present in the pathology of DR seem to increase connexin43 expression, suggesting a causal role of connexin43 channels in the disease progression.

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“…In a trial experiment, clinical scores showed a significant benefit in using the mimetic peptides ( P = 0.03). Results indicated that treated animals were not succumbing to the infection as rapidly as controls, so providing a window of opportunity for anti‐malarial treatment, potentially extending it by up to 48 h [39].…”

Section: Connexin Roles In Vascular Leakmentioning

confidence: 99%

Connexin hemichannel induced vascular leak suggests a new paradigm for cancer therapy

et al. 2014

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a b s t r a c tIt is 40 years since cancer growth was correlated with neovascularisation. Anti-angiogenic drugs remain at the forefront of cancer investigations but progress has been disappointing and unexpected toxicities are emerging. Gap junction channels are implicated in lesion spread following injury, with channel blockers shown to improve healing; in particular preventing vascular disruption and/or restoring vascular integrity. Here we briefly review connexin roles in vascular leak and endothelial cell death that occurs following acute wounds and during chronic disease, and how connexin channel regulation has been used to ameliorate vascular disruption. We then review chronic inflammatory disorders and trauma in the eye, concluding that vascular disruption under these conditions mimics that seen in tumours, and can be prevented with connexin hemichannel modulation. We apply this knowledge to tumour vessel biology, proposing that contrary to current opinion, these data suggest a need to protect, maintain and/or restore cancer vasculature. This may lead to reduced tumour hypoxia, promote the survival of normal cells, and enable improved therapeutic delivery or more effective radiation therapy.

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Impact of Microglial Activation on Astroglial Connexin Expression and Function in Brain Inflammation

Cited by 6 publications

References 1 publication

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

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

Immunohistochemical Characterization of Connexin43 Expression in a Mouse Model of Diabetic Retinopathy and in Human Donor Retinas

Connexin hemichannel induced vascular leak suggests a new paradigm for cancer therapy

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