Inducible nitric oxide synthase inhibitors abolished histological protection by late ischemic preconditioning in rat retina

Sakamoto, Kenji; Yonoki, Yuzuru; Kubota, Yuko; Kuwagata, Mayumi; Saito, Maki; Nakahara, Tsutomu; Ishii, Kunio

doi:10.1016/j.exer.2005.08.011

Cited by 38 publications

(21 citation statements)

References 41 publications

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“…Some studies have examined the role of NO as a trigger of the early phase of myocardial ischemia preconditioning [21,22], and the role of NO in the late phase of the protection of preconditioning in the heart, retina etc. [23,7,24]. These reports support our above suggestion.…”

Section: Discussionsupporting

confidence: 92%

The Role of Nitric Oxide in the Neuroprotection of Limb Ischemic Preconditioning in Rats

et al. 2007

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Brief limb ischemia was reported to protect neurons against injury induced by subsequent cerebral ischemia-reperfusion, and this phenomenon is known as limb ischemic preconditioning (LIP). To explore the role of nitric oxide (NO) in neuroprotection of LIP in rats, we observed changes in the content of nitric oxide (NO) and activity of NO synthase (NOS) in the serum and CA1 hippocampus of rats after transient limb ischemic preconditioning (LIP), and the influence of N(G)-nitro-L-arginine methylester (L-NAME), a NOS inhibitor, on the neuroprotection of LIP against cerebral ischemia-reperfusion injury. Results showed that NO content and NOS activity in serum increased significantly after LIP compared with the sham group. The increase showed a double peak pattern, in which the first one appeared at time 0 (immediate time point) and the second one appeared at 48 h after the LIP (P < 0.01). The NO content and NOS activity in the CA1 hippocampus in LIP group showed similar change pattern with the changes in the serum, except for the first peak of up-regulation of NO content and NOS activity appeared at 6 h after LIP. Pretreatment with L-NAME before LIP blocked the neuroprotection of LIP against subsequent cerebral ischemic insult. The blocking effect of L-NAME was abolished with pretreatment of L-Arg. These findings indicated that NO may be associated with the tolerance of pyramidal cells in the CA1 hippocampus to ischemia induced by LIP in rats.

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Section: Discussionsupporting

confidence: 92%

The Role of Nitric Oxide in the Neuroprotection of Limb Ischemic Preconditioning in Rats

et al. 2007

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“…Preconditioning, for example, by brief ischemia, has neuroprotective effects in the retina 57, 58 and typically involves an upregulation of enzymes involved in nitric oxide formation, such as iNOS ( Nos2 ). 59 We found a higher expression level of Nos2 in the retina of P2Y1R-KO mice as compared with Wt retina (Figure 2b), however, we did not study the functional role of iNOS in more detail. Therefore, it remains to be determined in future whether the glial activation in the retina of P2Y1R-KO mice provides preconditioning.…”

Section: Discussionmentioning

confidence: 72%

Differential effects of P2Y1 deletion on glial activation and survival of photoreceptors and amacrine cells in the ischemic mouse retina

et al. 2014

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Gliosis of retinal Müller glial cells may have both beneficial and detrimental effects on neurons. To investigate the role of purinergic signaling in ischemia-induced reactive gliosis, transient retinal ischemia was evoked by elevation of the intraocular pressure in wild-type (Wt) mice and in mice deficient in the glia-specific nucleotide receptor P2Y1 (P2Y1 receptor-deficient (P2Y1R-KO)). While control retinae of P2Y1R-KO mice displayed reduced cell numbers in the ganglion cell and inner nuclear layers, ischemia induced apoptotic death of cells in all retinal layers in both, Wt and P2Y1R-KO mice, but the damage especially on photoreceptors was more pronounced in retinae of P2Y1R-KO mice. In contrast, gene expression profiling and histological data suggest an increased survival of amacrine cells in the postischemic retina of P2Y1R-KO mice. Interestingly, measuring the ischemia-induced downregulation of inwardly rectifying potassium channel (Kir)-mediated K+ currents as an indicator, reactive Müller cell gliosis was found to be weaker in P2Y1R-KO (current amplitude decreased by 18%) than in Wt mice (decrease by 68%). The inner retina harbors those neurons generating action potentials, which strongly rely on an intact ion homeostasis. This may explain why especially these cells appear to benefit from the preserved Kir4.1 expression in Müller cells, which should allow them to keep up their function in the context of spatial buffering of potassium. Especially under ischemic conditions, maintenance of this Müller cell function may dampen cytotoxic neuronal hyperexcitation and subsequent neuronal cell loss. In sum, we found that purinergic signaling modulates the gliotic activation pattern of Müller glia and lack of P2Y1 has janus-faced effects. In the end, the differential effects of a disrupted P2Y1 signaling onto neuronal survival in the ischemic retina call the putative therapeutical use of P2Y1-antagonists into question.

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“…42,43 Repeated injections of high concentrations of VEGF in eyes of nondiabetic monkeys provoke retinal changes that resemble those observed in the early stages of DR, including vascular tortuosity and microaneurysms. 44,45 Clinical trials using anti-VEGF therapies are showing promising results against advanced stages of DR. 46,47 Thus, without excluding the activation of other transduction pathways associated with retinal IPC, such as adenosine, K ATP channels, protein kinase C, 12,48 -49 and NO, 50 among others, and based on the fact that ischemia pulses abrogated the increase in VEGF, it is tempting to speculate that the induction of ischemic conditioning could behave as an anti-VEGF therapy. In fact, it was shown that injection of VEGF into healthy eyes of animals can induce diabetes-associated ocular diseases.…”

Section: Discussionmentioning

confidence: 99%

Induction of Ischemic Tolerance Protects the Retina From Diabetic Retinopathy

Fernandez

Sande

Chianelli

et al. 2011

The American Journal of Pathology

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Diabetic retinopathy is a leading cause of acquired blindness. Available treatments are not very effective. We investigated the effect of a weekly application of retinal ischemia pulses (ischemic conditioning) on retinal damage induced by experimental diabetes. Diabetes was induced by an intraperitoneal injection of streptozotocin. Retinal ischemia was induced by increasing intraocular pressure to 120 mmHg for 5 minutes; this maneuver started 3 days after streptozotocin injection and was weekly repeated in one eye, whereas the contralateral eye was submitted to a sham procedure. Diabetic retinopathy was evaluated in terms of i) retinal function (electroretinogram and oscillatory potentials), ii) integrity of blood-retinal barrier (by albumin-Evans blue complex leakage and astrocyte glial fibrillary acidic protein IHC), iii) optical and electron microscopy histopathologic studies, and iv) vascular endothelial growth factor levels (using Western blot analysis and IHC). Brief ischemia pulses significantly preserved electroretinogram a-and b-wave and oscillatory potentials, avoided albumin-Evans blue leakage, prevented the decrease in astrocyte glial fibrillary acidic protein levels, reduced the appearance of retinal edemas, and prevented the increase in vascular endothelial growth factor levels induced by experimental diabetes. When the application of ischemia pulses started 6 weeks after diabetes onset, retinal function was significantly preserved. These results indicate that induction of ischemic tolerance could constitute a fertile avenue for the development of new therapeutic strategies for diabetic retinopathy treatment.

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Inducible nitric oxide synthase inhibitors abolished histological protection by late ischemic preconditioning in rat retina

Cited by 38 publications

References 41 publications

The Role of Nitric Oxide in the Neuroprotection of Limb Ischemic Preconditioning in Rats

The Role of Nitric Oxide in the Neuroprotection of Limb Ischemic Preconditioning in Rats

Differential effects of P2Y1 deletion on glial activation and survival of photoreceptors and amacrine cells in the ischemic mouse retina

Induction of Ischemic Tolerance Protects the Retina From Diabetic Retinopathy

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