2. Academic Validation
  3. 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

  • Neurotherapeutics. 2017 Oct;14(4):1148-1165. doi: 10.1007/s13311-017-0536-9.
Yeri Kim 1 2,  Jarred M Griffin 3,  Mohd N Mat Nor 2 4 5,  Jie Zhang 1 2,  Peter S Freestone 6,  Helen V Danesh-Meyer 1 2,  Ilva D Rupenthal 1 2 7,  Monica Acosta 2 4,  Louise F B Nicholson 3,  Simon J O'Carroll 3,  Colin R Green 8 9
Affiliations

Affiliations

  • 1 Department of Ophthalmology, Faculty of Medical and Health Sciences, University of Auckland, Auckland, 1142, New Zealand.
  • 2 New Zealand National Eye Centre, Faculty of Medical and Health Sciences, University of Auckland, Auckland, 1142, New Zealand.
  • 3 Centre for Brain Research, Faculty of Medical and Health Sciences, University of Auckland, Auckland, 1142, New Zealand.
  • 4 School of Optometry and Vision Science, Faculty of Medical and Health Sciences, University of Auckland, Auckland, 1142, New Zealand.
  • 5 Faculty of Medicine, University Sultan Zainal Abidin, Kuala Terengganu, Malaysia.
  • 6 Department of Physiology, Faculty of Medical and Health Sciences, University of Auckland, Auckland, 1142, New Zealand.
  • 7 Buchanan Ocular Therapeutics Unit, Faculty of Medical and Health Sciences, University of Auckland, Auckland, 1142, New Zealand.
  • 8 Department of Ophthalmology, Faculty of Medical and Health Sciences, University of Auckland, Auckland, 1142, New Zealand. c.green@auckland.ac.nz.
  • 9 New Zealand National Eye Centre, Faculty of Medical and Health Sciences, University of Auckland, Auckland, 1142, New Zealand. c.green@auckland.ac.nz.
PMID: 28560708 DOI: 10.1007/s13311-017-0536-9
Abstract

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.

Keywords

CNS disease; Tonabersat; connexin hemichannel; connexin43; gap junction.

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