Connexin43 mimetic peptide reduces vascular leak and retinal ganglion cell death following retinal ischaemia

Danesh-Meyer, Helen V.; Kerr, Nathan M.; Zhang, Jie; Eady, Elizabeth K.; O'Carroll, Simon J.; Nicholson, Louise F.B.; Johnson, Cameron S.; Green, Colin R.

doi:10.1093/brain/awr338

Cited by 179Connexins and lens biologyGlaucoma and retinal disordersBarrier Structure and Function Studies

Connexin43 mimetic peptide reduces vascular leak and retinal ganglion cell death following retinal ischaemia

Danesh-Meyer, Helen V., Kerr, Nathan M., Zhang, Jie, Eady, Elizabeth K., O'Carroll, Simon J., Nicholson, Louise F.B., Johnson, Cameron S., Green, Colin R.·2012·Brain

DOI 10.1093/brain/awr338

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Abstract

Connexin43 gap junction protein is expressed in astrocytes and the vascular endothelium in the central nervous system. It is upregulated following central nervous system injury and is recognized as playing an important role in modulating the extent of damage. Studies that have transiently blocked connexin43 in spinal cord injury and central nervous system epileptic models have reported neuronal rescue. The purpose of this study was to investigate neuronal rescue following retinal ischaemia-reperfusion by transiently blocking connexin43 activity using a connexin43 mimetic peptide. A further aim was to evaluate the effect of transiently blocking connexin43 on vascular permeability as this is known to increase following central nervous system ischaemia. Adult male Wistar rats were exposed to 60 min of retinal ischaemia. Treatment groups consisted of no treatment, connexin43 mimetic peptide and scrambled peptide. Retinas were then evaluated at 1-2, 4, 8 and 24 h, and 7 and 21 days post-ischaemia. Evans blue dye leak from retinal blood vessels was used to assess vascular leakage. Blood vessel integrity was examined using isolectin-B4 labelling. Connexin43 levels and astrocyte activation (glial fibrillary acidic protein) were assessed using immunohistochemistry and western blot analysis. Retinal whole mounts and retinal ganglion cell counts were used to quantify neurodegeneration. An in vitro cell culture model of endothelial cell ischaemia was used to assess the effect of connexin43 mimetic peptide on endothelial cell survival and connexin43 hemichannel opening using propidium iodide dye uptake. We found that retinal ischaemia-reperfusion induced significant vascular leakage and disruption at 1-2, 4 and 24 h following injury with a peak at 4 h. Connexin43 immunoreactivity was significantly increased at 1-2, 4, 8 and 24 h post ischaemia-reperfusion injury co-localizing with activated astrocytes, Muller cells and vascular endothelial cells. Connexin43 mimetic peptide significantly reduced dye leak at 4 and 24 h. In vitro studies on endothelial cells demonstrate that endothelial cell death following hypoxia can be mediated directly by opening of connexin43 hemichannels in endothelial cells. Blocking connexin43 mediated vascular leakage using a connexin43 mimetic peptide led to increased retinal ganglion cell survival at 7 and 21 days to levels of uninjured retinas. Treatment with scrambled peptide did not result in retinal ganglion cell rescue. Pharmacological targeting of connexin43 gap junction protein by transiently blocking gap junction hemichannels following injury provides new opportunities for treatment of central nervous system ischaemia.

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Marked fluorescein extravasation was found in ischemic retinas subjected to central retinal artery ligature.
“In contrast, marked fluorescein extravasation was found in ischemic retinas subjected to central retinal artery ligature, a procedure known to compromise the BRB [31] and used as positive control (Fig. S3C).”
From AMPK hyperactivation promotes dendrite retraction, synaptic loss, and neuronal dysfunction in glaucoma (2021) · cites this paper as [31]

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Minocycline prevents retinal inflammation and vascular permeability following ischemia-reperfusion injury
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Connexins and their channels in inflammation
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The inflammasome pathway is amplified and perpetuated in an autocrine manner through connexin43 hemichannel mediated ATP release
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Hyaluronic Acid Coated Albumin Nanoparticles for Targeted Peptide Delivery to the Retina
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Inhibition of connexin43 improves functional recovery after ischemic brain injury in neonatal rats
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Wound healing in the eye: Therapeutic prospects
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Spermidine promotes retinal ganglion cell survival and optic nerve regeneration in adult mice following optic nerve injury
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In-depth transcriptomic analysis of human retina reveals molecular mechanisms underlying diabetic retinopathy
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Gap junctional communication promotes apoptosis in a connexin-type-dependent manner
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Regulation of Connexin43 Gap Junction Protein Triggers Vascular Recovery and Healing in Human Ocular Persistent Epithelial Defect Wounds
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Tonabersat Prevents Inflammatory Damage in the Central Nervous System by Blocking Connexin43 Hemichannels
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Role of Hemichannels in CNS Inflammation and the Inflammasome Pathway
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Connexin Hemichannel Blockade Is Neuroprotective after Asphyxia in Preterm Fetal Sheep
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AMPK hyperactivation promotes dendrite retraction, synaptic loss, and neuronal dysfunction in glaucoma
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“(D), a procedure known to compromise the BRB [31] and used as positive control (Fig.”
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Retinal ischemia induces α-SMA-mediated capillary pericyte contraction coincident with perivascular glycogen depletion
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Connexin 43 Hemichannel Activity Promoted by Pro-Inflammatory Cytokines and High Glucose Alters Endothelial Cell Function
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Molecular Changes and Vision Loss in a Mouse Model of Closed-Globe Blast Trauma
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Gap Junction-Mediated Death of Retinal Neurons Is Connexin and Insult Specific: A Potential Target for Neuroprotection
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Neurological manifestations of oculodentodigital dysplasia: a Cx43 channelopathy of the central nervous system?
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Pannexin channel and connexin hemichannel expression in vascular function and inflammation
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Connexins and Pannexins: Important Players in Tumorigenesis, Metastasis and Potential Therapeutics
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JAK2/STAT3 pathway is involved in the protective effects of epidermal growth factor receptor activation against cerebral ischemia/reperfusion injury in rats
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Connexin43 Mimetic Peptide Improves Retinal Function and Reduces Inflammation in a Light-Damaged Albino Rat Model
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Connexin43 hemichannel block protects against the development of diabetic retinopathy signs in a mouse model of the disease
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Connexin43 hemichannel block protects against retinal pigment epithelial cell barrier breakdown
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Amacrine cells coupled to ganglion cells via gap junctions are highly vulnerable in glaucomatous mouse retinas
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Glutamate Induces Blood–Brain Barrier Permeability through Activation ofN-Methyl-D-Aspartate Receptors
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Characterizing the mode of action of extracellular Connexin43 channel blocking mimetic peptides in an in vitro ischemia injury model
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The Role of Connexins in Wound Healing and Repair: Novel Therapeutic Approaches
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The Connexin Mimetic Peptide Gap27 and Cx43-Knockdown Reveal Differential Roles for Connexin43 in Wound Closure Events in Skin Model Systems
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Targeting inflammasomes and pyroptosis in retinal diseases—molecular mechanisms and future perspectives
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Battle of the hemichannels – Connexins and Pannexins in ischemic brain injury
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Intracellular Cleavage of the Cx43 C‐Terminal Domain by Matrix‐Metalloproteases: A Novel Contributor to Inflammation?
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Function of Connexins in the Interaction between Glial and Vascular Cells in the Central Nervous System and Related Neurological Diseases
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P2X7/P2X4 Receptors Mediate Proliferation and Migration of Retinal Microglia in Experimental Glaucoma in Mice
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Systemic Administration of Connexin43 Mimetic Peptide Improves Functional Recovery after Traumatic Spinal Cord Injury in Adult Rats
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Retinal biomarkers provide “insight” into cortical pharmacology and disease
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Cardiac to cancer: Connecting connexins to clinical opportunity
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Targeting neuronal gap junctions in mouse retina offers neuroprotection in glaucoma
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Targeting gliovascular connexins prevents inflammatory blood-brain barrier leakage and astrogliosis
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Bone-marrow mesenchymal stem-cell administration significantly improves outcome after retinal ischemia in rats
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Ultrasound-mediated nanoparticle delivery across ex vivo bovine retina after intravitreal injection
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Authors: Danesh-Meyer, H. V., Kerr, N. M., Zhang, J., Eady, E. K., O'Carroll, S. J., Nicholson, L. F. B., Johnson, C. S., & Green, C. R.
Affiliations: University of Auckland (NZ)
ORCID: Danesh-Meyer, Helen V.
Kerr, Nathan M.
Nicholson, Louise F.B.
Johnson, Cameron S.
Green, Colin R.
Venue: Brain
Publisher: Oxford University Press (OUP)
Published: 2012-02-01
Volume: 135
Issue: 2
Pages: 506-520
ISSN: 0006-8950 (ISSN-L)
1460-2156
DOI: 10.1093/brain/awr338
OpenAlex: W2120742009
Cited by: 179
References: 65
Citations by year: 2026: 1 · 2025: 5 · 2024: 2 · 2023: 9 · 2022: 8 · 2021: 19 · 2020: 11 · 2019: 14 · 2018: 21 · 2017: 25 · 2016: 16 · 2015: 15 · 2014: 14 · 2013: 15 · 2012: 4
FWCI: 6.17
Type: journal article
Language: en
Open access: closed
Locations: Brain (publishedVersion)
PubMed (publishedVersion)
ResearchSpace (University of Auckland) (submittedVersion)
Funders: Neurological Foundation of New Zealand
Topics: Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Connexins and lens biology
Health Sciences › Medicine › Ophthalmology › Glaucoma and retinal disorders
Life Sciences › Neuroscience › Neurology › Barrier Structure and Function Studies
Keywords: connexin 43, retinal ganglion cell death, vascular leakage, astrocyte activation, Müller cells, endothelial cell death, hypoxia, neuroprotection, gap junctions, retinal vasculature, glial fibrillary acidic protein
MeSH terms: Animals, Ischemia, Male, Oligopeptides, Retina, Retinal Diseases, Retinal Ganglion Cells, Retinal Vessels, Rats, Wistar, Connexin 43, Rats

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Connexin43 mimetic peptide reduces vascular leak and retinal ganglion cell death following retinal ischaemia

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