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T. Yanagidaira, Y. Takahashi, T. Murata, T. Hayashi; Protective Function of Chemical Products Against Nmda-Induced Neurotoxity in Normal Tension Glaucoma Model, Nf-Bp50-Deficient Mice. Invest. Ophthalmol. Vis. Sci. 2008;49(13):5508. doi: https://doi.org/.
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© ARVO (1962-2015); The Authors (2016-present)
The transcription factor nuclear factor-kappa B (NF-ΚB)/Rel family, which is activated by various intra-and extra- cellular stimuli, may be involved in neuronal cell death and survival. Although it was reported to prevent neuronal apoptosis, the precise roles of NF-ΚB in neuronal cell death are clearly unknown. Previously, we reported that the NF-ΚBp50 deficient mice (NF-ΚBp50 KO) exhibit many features resembling human normal tension glaucoma-like disease. We investigated the development stage of spontaneous optic neuropathy in NF-ΚBp50 KO mice at various age more in detail. Furthermore we also examined susceptibility of NMDA-induced neurotoxicity, and neuroprotecive effects of NMDA-antagonist and calcium channel blocker against the neurotoxicity in NF-kBp50 KO mice.
To demonstrate the spontaneous optic neuropathy in NF-ΚBp50 KO mice at various ages, histopathological studies were carried out. Adult NF-ΚBp50 KO mice and its parental mice aged 2 months were pre-treated with lomerizine ( T-type and L-type calcium channel blocker) and NMDA receptor antagonists (memantine and MK-801), . and then these mice were subjected to intravitreous injection of 10 nmol NMDA that is a relatively low concentration as for NMDA-induced neurotoxicity to RGCs. Surviving RGCs of 0.35 mm length at 0.3 mm from the edge of the optic disc in the ganglion cell layer were counted under the histological examinations, except for cells infiltrating the ganglion cell layer at 24 hours after NMDA injection.
RGCs loss was observed between 2 and 4 months of aged in NF-ΚBp50 KO mice under total independence of intraocular pressure measurement, but there was no significant change at optic nerve and optic nerve head as recent our report shown. Unexpectedly, the histopathological results show obvious excavation of the optic nerve head in NF-ΚBp50 KO mice at 10 months of age following RGCs loss. Although the morphometric evaluations indicate marked NMDA-induced neurotoxicity to RGCs in NF-ΚBp50 KO mice in contrast with parental mice, specifically pre-treatment with NMDA antagonist dramatically protects RGCs from the neurotoxicity.
Our results, suggesting a new insight into the role of p50 in the pathophysiology of neuropathy and further experiments with NF-kBp50 KO mice show that NMDA receptor antagonists, for instance, memantine, are possible candidates for therapeutic drugs. Our research findings may provide new targets for therapeutic intervention for human glaucoma.
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