Retinal ischemia/reperfusion

D1 (10,17S-docosatriene) from DHA using tandem liquid chromatography-photodiode array-electrospray ionization-tandem mass spectrometry (LC-PDA-ESI-MS-MS)-based lipidomic analysis have been documented in ischemic brain [4] and retinal pigment epithelium [5], This new lipid is called neuroprotectin D1 (1) because of its neuro-protectiveproperties in brain ischemia-reperfusion [4] and in oxidative stress-challenged retinal pigment epithelial cells [5] (2) because of its potent ability to inactivate proapoptotic signaling (see apoptosis, Ch. 35) [5] and (3) because it is the first identified neuroprotective mediator derived from DHA. 

Rieger JM, Shah AR, Gidday JM (2002) Ischemia-reperfusion injury of retinal endothelium by cyclooxygenase- and xanthine oxidase-derived superoxide. Exp. Eye Res. 74 493-501. 

Fig. 1. Representative fluorescent photomicrographs of retinal whole mounts showing the loss of Fluorogold (FG)-labeled RGCs in ischemic retina of rat. RGCs were retrogradely labeled with the fluorescent dye FG injected, under stereotaxic guidance, bilaterally into the superior colliculus of a rat 4 days after 50 min ischemia and sacrificed after additional 4 days. Obvious reduction of FG-labeled RGCs is evident in the retina undergone ischemia/reperfusion (panel B) as compared to the contralateral, nonischemic, retina (panel A). Photomicrographs were obtained from the peripheral area of the superior quadrant of the retina. Scale bar 50 fim.

Fig. 2. Transient retinal ischemia increases intravitreal glutamate in rat. Neurochemical data from microdialysis experiments carried out in anesthetized rats to demonstrate that ischemia/reperfusion insult increases intravitreal glutamate. The extracellular level of glutamate shows a moderate increase during the first 10 min of ischemia, more evident toward the end of the ischemic period, to reach statistical significance at 10 and 150 min of reperfusion. Baseline glutamate concentrations (basal values) are the mean concentrations obtained by averaging six samples collected consecutively at 10 min intervals immediately before the onset of ischemia (n — 6 rats). Glutamate values (pM) are expressed as mean S.E.M. Statistical significance was assessed by ANOVA followed by Dunnett s test for multiple comparisons. P < 0.05 and P < 0.001 versus basal values.

Treatment with the PI3-K inhibitor wortmannin reduces the number of surviving RGCs after retinal ischemia/reperfusion suggesting that, Akt activation is indeed endowed with RGCs neuroprotective properties and represents a prosurvival response of the retina to the ischemic injury (Russo et al., 2008a). 

Russo, R., Cavaliere, F., Berliocchi, L., Nucci, C., Gliozzi, M., Mazzei, C., Tassorelli, C., Corasaniti, M. T., Rotiroti, D., Bagetta, G., and Morrone, L. A. (2008a). Modulation of pro-survival and death-associated pathways under retinal ischemia/reperfusion Effects of NMDA receptor blockade. 

Shibuki, H., Katai, N., Yodoi, J., Uchida, K., and Yoshimura, N. (2000). Lipid peroxidation and peroxynitrite in retinal ischemia-reperfusion injury. Invest. Ophthalmol. Vis. Sci. 41, 3607-3614. 

Presence of mitogen-activated protein kinase in retinal Muller cells and its neuroprotective effect ischemia-reperfusion injury. Neuroreport 13 2103-2107. 

Katai N, Yoshimura N. 1999. Apoptotic retinal neuronal death by ischemia-reperfusion is executed by two distinct caspase family proteases. Invest Ophthalmol Vis Sci 40 2697-2705. 

Yokoyama A, Oshitari T, Negishi H, Dezawa M, Mizota A, Adachi-Usami E. Protection of retinal ganglion cells from ischemia-reperfusion injury by electrically applied Hsp27. Invest Ophthalmol Vis Sci 2001 42 3283-3286. 

Chiang SK, Lam TT. Post-treatment at 12 or 18 hours with 3-aminobenxamide ameliorates retinal ischemia-reperfusion damage. Invest Ophthalmol Vis Sci 2000 41(10) 3210-4. 

Fig. 3. Changes in Akt and GSK-3/3 phosphorylation induced by transient retinal ischemia and effect ofintravitreal application of MK801 in rat. Animals were subjected to retinal ischemia for 50 min in the right eye (R) and reperfusion was allowed for 1, 6, or 24 h. The left eye (L) was used as control. (A) Phosphorylation of Akt on Ser473 is significantly diminished after retinal ischemia and is accompanied by a transient dephosphorylation (activation) of GSK-3/3. During the reperfusion phase, Akt activation is increased within 1 h whereas GSK-3(3 phosphorylation status returns to basal level. (B) Intravitreal treatment with MK801 enhances the phosphorylation of Akt reported after I h reperfusion. Histograms show the results of the densitometric analysis of immunoreactive bands. P < 0.05 versus vehicle.

The Role of Inflammatory Cytokines in Retinal Ischemia It has become increasingly evident in recent years that acute inflammatory responses contribute to ischemic brain injury, especially following reperfusion through a variety of mechanisms (Danton and Dietrich, 2003). These mechanisms are discussed in detail in Section 2.4. 

IL-1 and tumor necrosis factor (TNF) are proinflammatory cytokines. They are produced in response to adverse stimuli. Each cytokine exists as two well-characterized isoforms IL-lot and IL-1P, and TNF-ot and TNF-p, respectively. There is strong evidence for the involvement of IL-1P and TNF ot in the pathogenesis of experimental brain ischemia (Hallenbeck, 2002 Patel et al., 2003). In the retina, transient ischemia causes upregulation of TNF-ot (Fontaine et al., 2002). In the early phase of reperfusion, TNF-ot is primarily upregulated in ganglion cells, amacrine cells, and Muller cells. There is no consensus about the overall efiect of TNF-ot on retinal cell viability. There is an indication that activation of TNF receptor 2 is neuroprotective, whereas activation of TNF receptor 1 augments neuronal death. 

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