Potential role of A2A adenosine receptor in traumatic optic neuropathy

Ahmad, Saif; Fatteh, Nadeem; Elsherbiny, Nehal M.; Naime, Mohammad; Ibrahim, Ahmed S.; Elsherbini, Ahmed; Elshafey, Sally; Khan, Sohail; Fulzele, Sadanand; Gonzales, Joyce; Liou, Gregory I.

doi:10.1016/j.jneuroim.2013.09.015

Cited by 48 publications

(38 citation statements)

References 35 publications

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“…It is usually caused by motor vehicle and bicycle accidents, falls, assaults, war, and natural disaster. 1 Directly or indirectly injured optic nerve causes immediate shearing and secondary swelling in a proportion of retinal ganglion cell (RGC) axons, followed by cell death, which results in irreversible visual loss. 2e4 To date, there is no proven effective therapy to treat TON, and mechanisms of RGC death after acute optic nerve injury remain largely unclear.…”

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confidence: 99%

Critical Role of the CXCL10/C-X-C Chemokine Receptor 3 Axis in Promoting Leukocyte Recruitment and Neuronal Injury during Traumatic Optic Neuropathy Induced by Optic Nerve Crush

Liu

Zhu

et al. 2017

The American Journal of Pathology

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Traumatic optic neuropathy (TON) is an acute injury of the optic nerve secondary to trauma. Loss of retinal ganglion cells (RGCs) is a key pathological process in TON, yet mechanisms responsible for RGC death remain unclear. In a mouse model of TON, real-time noninvasive imaging revealed a dramatic increase in leukocyte rolling and adhesion in veins near the optic nerve (ON) head at 9 hours after ON injury. Although RGC dysfunction and loss were not detected at 24 hours after injury, massive leukocyte infiltration was observed in the superficial retina. These cells were identified as T cells, microglia/monocytes, and neutrophils but not B cells. CXCL10 is a chemokine that recruits leukocytes after binding to its receptor C-X-C chemokine receptor (CXCR) 3. The levels of CXCL10 and CXCR3 were markedly elevated in TON, and up-regulation of CXCL10 was mediated by STAT1/3. Deleting CXCR3 in leukocytes significantly reduced leukocyte recruitment, and prevented RGC death at 7 days after ON injury. Treatment with CXCR3 antagonist attenuated TON-induced RGC dysfunction and cell loss. In vitro co-culture of primary RGCs with leukocytes resulted in increased RGC apoptosis, which was exaggerated in the presence of CXCL10. These results indicate that leukocyte recruitment in retinal vessels near the ON head is an early event in TON and the CXCL10/CXCR3 axis has a critical role in recruiting leukocytes and inducing RGC death. (Am J Pathol 2017, 187: 352e365; http://dx

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confidence: 99%

Critical Role of the CXCL10/C-X-C Chemokine Receptor 3 Axis in Promoting Leukocyte Recruitment and Neuronal Injury during Traumatic Optic Neuropathy Induced by Optic Nerve Crush

Liu

Zhu

et al. 2017

The American Journal of Pathology

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“…Activation of the A 2A AR was found to be neuroprotective against traumatic optic neuropathy by attenuating the inflammatory response to optic nerve trauma. 55 Low levels of traumatic optic neuropathy that would otherwise induce only a minimal neuroinflammatory response in wildtype mice induced severe inflammation in A 2A AR -/-mice. In addition, A 2A AR had an anti-inflammatory effect on retinal ganglion cells subjected to elevated pressure.…”

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confidence: 99%

“…60 The neuroprotection was thought to have been mediated by attenuating the microglial-mediated neuroinflammatory response. 55,60 Another caveat is that the effect of A 2A AR agonists on IOP is expected to be unfavorable since the A 2A AR antagonist ZM241385 31 lowered pressure in the mouse, 33 while activation of A 2A ARs transiently increased pressure in rabbit and cynomolgus monkey eyes. 61 In short, A 2A AR agonists and antagonists have multiple effects, and current published evidence that A 2A AR agonists would be helpful in glaucoma is not yet compelling.…”

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confidence: 99%

Ocular Purine Receptors as Drug Targets in the Eye

Civan

2016

Journal of Ocular Pharmacology and Therapeutics

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Agonists and antagonists of various subtypes of G protein coupled adenosine receptors (ARs), P2Y receptors (P2YRs), and ATP-gated P2X receptor ion channels (P2XRs) are under consideration as agents for the treatment of ocular diseases, including glaucoma and dry eye. Numerous nucleoside and nonnucleoside modulators of the receptors are available as research tools and potential therapeutic molecules. Three of the 4 subtypes of ARs have been exploited with clinical candidate molecules for treatment of the eye: A 1 , A 2A , and A 3 . An A 1 AR agonist is in clinical trials for glaucoma, A 2A AR reduces neuroinflammation, A 3 AR protects retinal ganglion cells from apoptosis, and both A 3 AR agonists and antagonists had been reported to lower intraocular pressure (IOP). Extracellular concentrations of endogenous nucleotides, including dinucleoside polyphosphates, are increased in pathological states, activating P2Y and P2XRs throughout the eye. P2YR agonists, including P2Y 2 and P2Y 6 , lower IOP. Antagonists of the P2X7R prevent the ATP-induced neuronal apoptosis in the retina. Thus, modulators of the purinome in the eye might be a source of new therapies for ocular diseases.

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“…The above tasks have been performed, hypotheses 1 and 2 have been tested and the results have been published [10]. The article including Abstract, Introduction, Experimental Design, Results, Discussion and References are attached as an Appendix.…”

Section: Hypothesismentioning

confidence: 99%

“…Indeed, transgenic mice overexpressing AK are highly susceptible to stroke-induced brain injury [9]. We have studied the role of A 2A AR in diabetic retinopathy [5] and in TON [10]. We have also evaluated AK in regulating adenosine signaling in diabetic retinopathy [11], and aim to evaluate the role of AK in TON.…”

mentioning

confidence: 99%

Role of Adenosine Receptor A2A in Traumatic Optic Neuropathies

Liou¹,

Ahmad²,

Elsherbini³

2013

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Public reporting burden for this collection of information is estimated to average 1 hour per response, including the time for reviewing instructions, searching existing data sources, gathering and maintaining the data needed, and completing and reviewing this collection of information. Send comments regarding this burden estimate or any other aspect of this collection of information, including suggestions for reducing this burden to Department of Defense, Washington Headquarters Services, Directorate for Information , 1215 Jefferson Davis Highway, Suite 1204, Arlington, VA 22202-4302. Respondents should be aware that notwithstanding any other provision of law, no person shall be subject to any penalty for failing to comply with a collection of information if it does not display a currently valid OMB control number. PLEASE DO NOT RETURN YOUR FORM TO THE ABOVE ADDRESS. REPORT DATE PERFORMING ORGANIZATION NAME(S) AND ADDRESS(ES) AND ADDRESS(ES) PERFORMING ORGANIZATION REPORT NUMBER GEORGIA HEALTH SCIENCES UNIVERSITY RESEARCH INSTITUTE, INC.Augusta, GA 30912-4810 SPONSORING / MONITORING AGENCY NAME(S) AND ADDRESS(ES) 10. SPONSOR/MONITOR'S ACRONYM(S) U.S. Army Medical Research and Materiel Command Fort Detrick, Maryland 21702-5012 SPONSOR/MONITOR'S REPORT NUMBER(S) DISTRIBUTION / AVAILABILITY STATEMENTApproved for Public Release; Distribution Unlimited SUPPLEMENTARY NOTES14. ABSTRACT Traumatic optic neuropathy (TON) is a type of injury commonly seen in the war. There are currently no proven treatments that reverse the damage in TON. The proposed mechanism of TON involves optic nerve injury-induced activation of retinal microglial cells and their release of pro-inflammatory cytokines, and retinal ganglion cell (RGC) death. As a self-defense system, activated microglial cells also release adenosine, which attenuates inflammation via adenosine receptors (AR)s, including A2AAR. Although AR agonists attenuate inflammation, the way to minimize nonspecific effects associated with systemic administration of these agonists remains unclear. Released adenosine levels in the injured brain are mainly regulated by adenosine kinase (AK). Inhibition of AK potentiates local extracellular adenosine levels at cell and tissue sites which are undergoing accelerated adenosine release. Thus, AK inhibition represents a mechanism to selectively enhance the endogenous protective actions of adenosine during cellular stress. Our studies have shown that microglial activation, retinal inflammation, and RGC death occur in the mouse model of TON, and that A2AAR signaling provides protection from TON. Further, our preliminary data suggest that AK inhibitor (AKI)-enhanced A2AAR signaling provides protection from TON in mice. Therefore, inhibition of AK potentially amplifies the therapeutic effects of site-and event-specific accumulation of extracellular adenosine, which is of highly translational impact. SUBJECT TERMSTraumatic optic neuropathy, adenosine receptor A2A, adenosine kinase, INTRODUCTIONTraumatic optic nerve injury is commonly seen in ...

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Potential role of A2A adenosine receptor in traumatic optic neuropathy

Cited by 48 publications

References 35 publications

Critical Role of the CXCL10/C-X-C Chemokine Receptor 3 Axis in Promoting Leukocyte Recruitment and Neuronal Injury during Traumatic Optic Neuropathy Induced by Optic Nerve Crush

Critical Role of the CXCL10/C-X-C Chemokine Receptor 3 Axis in Promoting Leukocyte Recruitment and Neuronal Injury during Traumatic Optic Neuropathy Induced by Optic Nerve Crush

Ocular Purine Receptors as Drug Targets in the Eye

Role of Adenosine Receptor A2A in Traumatic Optic Neuropathies

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