ISO-1, a macrophage migration inhibitory factor antagonist, prevents N-methyl-d-aspartate-induced retinal damage

Naruoka, Taeko; Nakahara, Tsutomu; Tsuda, Yo; Kurauchi, Yuki; Mori, Akira; Sakamoto, Kenji; Nishihira, Jun; Ishii, Kunio

doi:10.1016/j.ejphar.2013.08.041

Cited by 14 publications

(18 citation statements)

References 28 publications

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“…The maintained high potassium conductance of Müller cells in the postischemic P2Y1R-KO retina may stabilize the ion and volume homeostasis, and, thereby, may prevent a cytotoxic hyperexcitation of the already energy-deprived neurons of the inner retina being highly sensitive to hyperexcitation associated with ischemia (Figure 6). 27, 56, 60 …”

Section: Discussionmentioning

confidence: 99%

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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Section: Discussionmentioning

confidence: 99%

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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“…17) Briefly, the eyes were removed after systemic perfusion and were stored in the fixative for 1 h at 4°C. The eyes were rinsed several times with PBS, infiltrated overnight with 30% sucrose in PBS at 4°C, and frozen in an optimal cutting temperature (OCT) compound (Sakura Finetek, Torrance, CA, U.S.A.).…”

Section: Immunohistochemical Staining Of Retinal Crosssectionsmentioning

confidence: 99%

Preventive Effects of Rapamycin on Inflammation and Capillary Degeneration in a Rat Model of NMDA-Induced Retinal Injury

Aoki

Nakahara

Asano

et al. 2015

Biological & Pharmaceutical Bulletin

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Inhibitors of the mammalian target of rapamycin (mTOR) have been shown to protect against neuronal injury, but the mechanisms underlying this effect are not fully understood. The present study aimed to examine the effects of rapamycin, an inhibitor of the mTOR pathway, on inflammation and capillary degeneration in a rat model of N-methyl-D-aspartate (NMDA)-induced retinal neurotoxicity. Inflammation and capillary degeneration were evaluated by counting the numbers of CD45-positive leukocytes and Iba1-positive microglia, and by measuring the length of empty basement membrane sleeves, respectively. Marked increases in the numbers of leukocytes and microglia were observed 1 d after intravitreal injection of NMDA (200 nmol), and significant capillary degeneration was observed after 7 d. These NMDA-induced changes were significantly reduced by the simultaneous injection of rapamycin (20 nmol) with NMDA. These results suggest that rapamycin has preventive effects on inflammation and capillary degeneration during retinal injury.Key words endothelial cell; excitotoxicity; leukocyte; mammalian target of rapamycin; microglia Glutamate is a major excitatory neurotransmitter, and excessive extracellular levels of glutamate cause neuronal cell death. The neurotoxicity induced by elevated glutamate levels is implicated in some ocular diseases, including diabetic retinopathy and glaucoma. 1,2) In many cases, glutamate-induced neurotoxicity has been predominantly attributed to overstimulation of N-methyl-D-aspartate (NMDA) receptors. 3,4) In addition to direct effects on neurons, indirect effects, such as upregulation of pro-inflammatory cytokines and recruitment of leukocytes into the retina, are involved in NMDA-induced retinal neuronal damage. 5,6) Recent studies have shown that rapamycin, an inhibitor of the mammalian target of rapamycin (mTOR), exerts neuroprotective and axon growth-promoting effects during neuronal injury. 7,8) The mTOR is a serine/threonine kinase that regulates a wide array of cellular functions, including cell proliferation and cell-cycle control. 9) There are two distinct functional mTOR complexes, mTOR complex 1 and 2 (mTORC1 and mTORC2). Rapamycin inhibits mTORC1, which prevents phosphorylation of at least 2 well-characterized effectors: the p70S6 kinases (S6K1 and S6K2) and eIF4E-binding proteins (4E-BP1). 10) Inactivation of mTORC1 can cause autophagy, which has an important role in cellular homeostasis. 11) A role for autophagy has been suggested as a neuroprotective mechanism, whereby it enhances the clearance of harmful protein aggregates. 12,13) In addition, rapamycin could prevent inflammatory responses during brain injury, including activation of microglia. 14) Thus, multiple mechanisms might be involved in the neuroprotective effects of rapamycin.In the present study, we examined the effects of rapamycin on inflammation and capillary degeneration in a rat model of retinal neurotoxicity induced by overstimulation of NMDA receptors. MATERIALS AND METHODSAnimals Male Sprague-Dawley rats weighi...

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“…The sections were stained with hematoxylin and eosin. Morphometric analysis was performed as previously reported [14,15,17,23,24]. Briefly, the number of cells in the ganglion cell layer (GCL) was counted at the region found between 1000 and 1250 lm away from the center of the optic nerve head on both sides.…”

Section: Assessment Of Retinal Morphological Changesmentioning

confidence: 99%

Protective effects of PF‐4708671 against N‐methyl‐d‐aspartic acid‐induced retinal damage in rats

Hayashi

Aoki

Ushikubo

et al. 2016

Fundamemntal Clinical Pharma

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We previously demonstrated that rapamycin, an inhibitor of the mammalian target of rapamycin (mTOR), protects against N-methyl-d-aspartic acid (NMDA)-induced retinal damage in rats. Rapamycin inhibits mTOR activity, thereby preventing the phosphorylation of ribosomal protein S6, which is a downstream target of S6 kinase. Therefore, we aimed to determine whether PF-4708671, an inhibitor of S6 kinase, protects against NMDA-induced retinal injury. Intravitreal injection of NMDA (200 nmol/eye) caused cell loss in the ganglion cell layer and neuroinflammatory responses, such as an increase in the number of CD45-positive leukocytes and Iba1-positive microglia. Surprisingly, simultaneous injection of PF-4708671 (50 nmol/eye) with NMDA significantly attenuated these responses without affecting phosphorylated S6 levels. These results suggest that PF-4708671 and rapamycin likely protect against NMDA-induced retinal damage via distinct pathways. The neuroprotective effect of PF-4708671 is unlikely to be associated with inhibition of the S6 kinase, even though PF-4708671 is reported to be a S6 kinase inhibitor.

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ISO-1, a macrophage migration inhibitory factor antagonist, prevents N-methyl-d-aspartate-induced retinal damage

Cited by 14 publications

References 28 publications

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

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

Preventive Effects of Rapamycin on Inflammation and Capillary Degeneration in a Rat Model of NMDA-Induced Retinal Injury

Protective effects of PF‐4708671 against N‐methyl‐d‐aspartic acid‐induced retinal damage in rats

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