The P2X4 receptor is required for neuroprotection via ischemic preconditioning

Ozaki, Tomohiko; Muramatsu, Rieko; Sasai, Miwa; Yamamoto, Masahiro; Kubota, Yoshiaki; Fujinaka, Toshiyuki; Yoshimine, Toshiki; Yamashita, Toshio

doi:10.1038/srep25893

Cited by 38 publications

(41 citation statements)

References 57 publications

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“…Such a neuroprotective response to mechanoreceptors has previously been suggested in blood‐vessels in mice (Ozaki et al. ) and in the peripheral nervous system of fish (Kolosov & Uzdensky ). Further studies are needed to determine the role of mechanoreceptors in retinal damage.…”

Section: Discussionsupporting

confidence: 55%

Subretinal surgery: functional and histological consequences of entry into the subretinal space

Sørensen

2019

Acta Ophthalmologica

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Background and objectives: Gene-therapy, stem-cell transplantation and surgical robots hold the potential for treatment of currently untreatable retinal degenerative diseases. All of the techniques require entry into the subretinal space, which is a potential space located between the retina and the retinal pigment epithelium (RPE). Knowledge about obstacles and critical steps in relation to subretinal procedures is therefore needed. This thesis explores the functional and histological consequences of separation of the retina from the RPE, extensive RPE damage, a large cut in the retina (retinotomy) and RPE phagocytosis in a porcine model. Methods: Experiments were performed in 106 female domestic pigs of Danish landrace distributed over five studies. Under general anesthesia, different procedures for expansion of the subretinal space were conducted. Outcomes were visual function measured electrophysiologically with multifocal electroretinogram (mfERG) and retinal morphology examined histologically. Study I: The effect of anesthesia on mfERG was examined by repeated recordings for 3 hr in isoflurane or propofol anesthesia. Outcome was mfERG amplitude. Study II: Consequences of a large separation of the photoreceptors from the RPE were examined by injecting a perfluorocarbon-liquid (decalin) into the subretinal space. Two weeks after, in a second surgery, decalin was withdrawn. Outcomes were mfERG and histology 4 weeks after decalin injection. Study III: Extensive RPE damage was examined by expanding the subretinal space with saline and removing large sheets of RPE-cells through a retinotomy. Outcomes were mfERG and histology 2, 4 and 6 weeks after the procedure. Study IV: Consequences of a large retinotomy were examined by similar procedures as in Study III, but in study IV only a few RPE cells were removed. Outcomes were mfERG and histology 2 and 6 weeks after surgery. Study V: Clearance of the subretinal space was examined by injecting fluorescent latex beads of various sizes into the subretinal space. Outcome was histologic location of the beads at different time intervals after the procedure. Results: Study I: MfERG amplitudes decreased linearly as a function of time in propofol or isoflurane anesthesia. Duration of mfERG recording could be decreased without compromising quality, and thereby could time in anesthesia be reduced. Study II: MfERG and histology remained normal after reattachment of a large and 2-week long separation of the photoreceptors and RPE. Repeated entry into the subretinal space was well tolerated. Fluid injection into the subretinal space constitutes a risk of RPE-damage. Study III: Removal of large sheets of retinal pigment epithelial cells triggered a widespread rhegmatogenous-like retinal detachment resulting in visual loss. Study IV: A large retinotomy with limited damage of the RPE was well tolerated, and visual function was preserved. Study V: Subretinal latex beads up to 4 lm were phagocytosed by the RPE and passed into the sub-RPE space. Beads up to 2 lm travelled further through...

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Section: Discussionsupporting

confidence: 55%

Subretinal surgery: functional and histological consequences of entry into the subretinal space

Sørensen

2019

Acta Ophthalmologica

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“…The generation of P2X4R -/mice was described before (75). The generation of P2X4R fl/fl mice was described before (76). pmeLUC transgenic mice were generated by pronuclear injection of a linearized pmeLUC DNA construct (77) into the pronuclei of B6D2F2 zygotes.…”

Section: Methodsmentioning

confidence: 99%

Macrophage P2X4 receptors augment bacterial killing and protect against sepsis

et al. 2018

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The macrophage is a major phagocytic cell type, and its impaired function is a primary cause of immune paralysis, organ injury, and death in sepsis. An incomplete understanding of the endogenous molecules that regulate macrophage bactericidal activity is a major barrier for developing effective therapies for sepsis. Using an in vitro killing assay, we report here that the endogenous purine ATP augments the killing of sepsis-causing bacteria by macrophages through P2X4 receptors (P2X4Rs). Using newly developed transgenic mice expressing a bioluminescent ATP probe on the cell surface, we found that extracellular ATP levels increase during sepsis, indicating that ATP may contribute to bacterial killing in vivo. Studies with P2X4R-deficient mice subjected to sepsis confirm the role of extracellular ATP acting on P2X4Rs in killing bacteria and protecting against organ injury and death. Results with adoptive transfer of macrophages, myeloid-specific P2X4R-deficient mice, and P2rx4 tdTomato reporter mice indicate that macrophages are essential for the antibacterial, antiinflammatory, and organ protective effects of P2X4Rs in sepsis. Pharmacological targeting of P2X4Rs with the allosteric activator ivermectin protects against bacterial dissemination and mortality in sepsis. We propose that P2X4Rs represent a promising target for drug development to control bacterial growth in sepsis and other infections.

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“…P2X4R expressed by microglia are involved in post-ischaemic brain inflammation ( Cheng et al, 2014 ). P2X4R are required for neuroprotection via ischemic preconditioning ( Ozaki et al, 2016 ). Neuronal K ATP channels play a role in hypoxic preconditioning where they decrease neonatal hypoxic-ischaemic brain injury; it has been proposed that openers of K ATP channels may prove to be therapeutically beneficial ( Sun H.S.…”

Section: Disorders Of the Central Nervous System (Cns)mentioning

confidence: 99%

Purinergic Signalling: Therapeutic Developments

2017

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Purinergic signalling, i.e., the role of nucleotides as extracellular signalling molecules, was proposed in 1972. However, this concept was not well accepted until the early 1990’s when receptor subtypes for purines and pyrimidines were cloned and characterised, which includes four subtypes of the P1 (adenosine) receptor, seven subtypes of P2X ion channel receptors and 8 subtypes of the P2Y G protein-coupled receptor. Early studies were largely concerned with the physiology, pharmacology and biochemistry of purinergic signalling. More recently, the focus has been on the pathophysiology and therapeutic potential. There was early recognition of the use of P1 receptor agonists for the treatment of supraventricular tachycardia and A2A receptor antagonists are promising for the treatment of Parkinson’s disease. Clopidogrel, a P2Y12 antagonist, is widely used for the treatment of thrombosis and stroke, blocking P2Y12 receptor-mediated platelet aggregation. Diquafosol, a long acting P2Y2 receptor agonist, is being used for the treatment of dry eye. P2X3 receptor antagonists have been developed that are orally bioavailable and stable in vivo and are currently in clinical trials for the treatment of chronic cough, bladder incontinence, visceral pain and hypertension. Antagonists to P2X7 receptors are being investigated for the treatment of inflammatory disorders, including neurodegenerative diseases. Other investigations are in progress for the use of purinergic agents for the treatment of osteoporosis, myocardial infarction, irritable bowel syndrome, epilepsy, atherosclerosis, depression, autism, diabetes, and cancer.

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The P2X4 receptor is required for neuroprotection via ischemic preconditioning

Cited by 38 publications

References 57 publications

Subretinal surgery: functional and histological consequences of entry into the subretinal space

Subretinal surgery: functional and histological consequences of entry into the subretinal space

Macrophage P2X4 receptors augment bacterial killing and protect against sepsis

Purinergic Signalling: Therapeutic Developments

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