Significant visual loss may result from retinal ischemia in retinal arterial or venous occlusion, glaucoma, atherosclerosis, or in systemic disorders such as diabetes mellitus. The pathogenesis involves changes in cellular biochemistry and energy level, blood flow, and gene expression. During the past 11 years of this project, we documented extensive biochemical, functional, structural, and hemo-'dynamic evidence for the complex, but major involvement of the purine nucleoside adenosine in retinal ischemia-reperfusion injury. More recently, we also discovered the closely related and dramatic finding of complete functional and histological protection from ischemic damage in the in vivo retina conferred by a brief period of non damaging ischemia, i.e., ischemic preconditioning (IPC). Other significant accompanying protective mechanisms of IPC include the attenuation of hypoperfusion, protein phosphorylation, and apoptosis. We demonstrated that adeno-'sine is a trigger for IPC, and we began to uncover the roles of downstream signal transduction factors, including mitochondrial KATP channels, PKC, mitogen-activated protein kinase p38, nitric oxide, and reactive oxygen species, in this neuroprotection. These exciting results extend our earlier findings of the remarkable functional and histological protection from ischemic damage afforded by IPC, indicating that IPC has a profound influence upon cell signaling and survival. Examination of the mechanisms responsible for IPC in our established retinal ischemia model provides a unique and innovative window into the retina's endogenous ability to counter ischemic injury.
The first aim will characterize the signaling pathwaysfor IPC involving mitochondrial KATP channels and the associated signal transduction factors.
The second aim will characterize the involvement of NOS and PKC subtypes as essential signaling intermediaries in IPC.
The third aim will examine the mechanisms of the paradoxical effect whereby transient MAPK p38 expression protects the retina, while its blockade prior to ischemia protects against ischemic damage. Our experiments will definitively examine major mechanisms of IPC and should bring us closer to understanding molecular events underlying this robust, intriguing, and clinically relevant neuroprotection.

National Institute of Health (NIH)
National Eye Institute (NEI)
Research Project (R01)
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Biology and Diseases of the Posterior Eye Study Section (BDPE)
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Neuhold, Lisa
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University of Chicago
Schools of Medicine
United States
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Roth, Steven; Dreixler, John C; Mathew, Biji et al. (2016) Hypoxic-Preconditioned Bone Marrow Stem Cell Medium Significantly Improves Outcome After Retinal Ischemia in Rats. Invest Ophthalmol Vis Sci 57:3522-32
Sampat, Ajay; Parakati, Isaac; Kunnavakkam, Rangesh et al. (2015) Corneal abrasion in hysterectomy and prostatectomy: role of laparoscopic and robotic assistance. Anesthesiology 122:994-1001
Roth, Steven (2015) Inhaled Anesthesia, Apoptosis, and the Developing Retina: A Window into the Brain? Anesth Analg 121:1117-8
Dreixler, John C; Poston, Jacqueline N; Balyasnikova, Irina et al. (2014) Delayed administration of bone marrow mesenchymal stem cell conditioned medium significantly improves outcome after retinal ischemia in rats. Invest Ophthalmol Vis Sci 55:3785-96
Dreixler, John C; Poston, Jacqueline N; Shaikh, Afzhal R et al. (2011) Delayed post-ischemic conditioning significantly improves the outcome after retinal ischemia. Exp Eye Res 92:521-7
David, Joel; Melamud, Aleksandr; Kesner, Leo et al. (2011) A novel calpain inhibitor for treatment of transient retinal ischemia in the rat. Neuroreport 22:633-6
Dreixler, John C; Bratton, Anthony; Du, Eugenie et al. (2011) Mitogen-activated protein kinase phosphatase-1 (MKP-1) in retinal ischemic preconditioning. Exp Eye Res 93:340-9
Dreixler, John C; Sampat, Ajay; Shaikh, Afzhal R et al. (2011) Protein kinase B (Akt) and mitogen-activated protein kinase p38α in retinal ischemic post-conditioning. J Mol Neurosci 45:309-20
Dreixler, John C; Shaikh, Afzhal R; Alexander, Michael et al. (2010) Post-ischemic conditioning in the rat retina is dependent upon ischemia duration and is not additive with ischemic pre-conditioning. Exp Eye Res 91:844-52
Dreixler, John C; Hemmert, Jonathan W; Shenoy, Shanti K et al. (2009) The role of Akt/protein kinase B subtypes in retinal ischemic preconditioning. Exp Eye Res 88:512-21

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