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Morphometric Analyses of Retinal Sections
Published on: February 19, 2012
Protective effects of PF-4708671 against N-methyl-d-aspartic acid-induced retinal damage in rats
Ikumi Hayashi1, Yuto Aoki1, Hiroko Ushikubo1
1Department of Molecular Pharmacology, Kitasato University School of Pharmaceutical Sciences, 5-9-1 Shirokane, Minato-ku, Tokyo, 108-8641, Japan.
Abstract:
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.
Insights
PF-4708671, an S6 kinase inhibitor, surprisingly protected against N-methyl-d-aspartic acid (NMDA)-induced retinal damage in rats. This neuroprotection occurred independently of S6 kinase inhibition, suggesting distinct protective pathways from rapamycin.
Area of Science:
- Ophthalmology
- Neuroscience
- Pharmacology
Background:
- The mammalian target of rapamycin (mTOR) pathway plays a role in retinal damage.
- Rapamycin, an mTOR inhibitor, has previously shown neuroprotective effects against N-methyl-d-aspartic acid (NMDA)-induced retinal injury in rats.
- S6 kinase is a downstream target of mTOR, and its phosphorylation is inhibited by rapamycin.
Purpose of the Study:
- To investigate the potential neuroprotective effects of PF-4708671, an S6 kinase inhibitor, against NMDA-induced retinal injury.
- To determine if PF-4708671-mediated protection involves the inhibition of S6 kinase phosphorylation.
Main Methods:
- Intravitreal injection of NMDA (200 nmol/eye) in rats to induce retinal damage.
- Simultaneous intravitreal injection of PF-4708671 (50 nmol/eye) with NMDA.
- Assessment of cell loss in the ganglion cell layer.
- Evaluation of neuroinflammatory responses, including CD45-positive leukocytes and Iba1-positive microglia.
- Measurement of phosphorylated S6 levels.
Main Results:
- NMDA injection caused significant ganglion cell layer loss and increased neuroinflammation.
- Co-injection of PF-4708671 with NMDA significantly attenuated these retinal injuries.
- PF-4708671 treatment did not affect the levels of phosphorylated S6.
- These findings suggest a mechanism of action for PF-4708671 independent of S6 kinase inhibition.
Conclusions:
- PF-4708671 exhibits significant neuroprotective effects against NMDA-induced retinal damage in rats.
- The neuroprotective mechanism of PF-4708671 appears distinct from that of rapamycin and does not rely on S6 kinase inhibition.
- Further research is warranted to elucidate the precise pathways underlying PF-4708671's protective effects in retinal injury.
