dizocilpine-maleate and Ocular-Hypertension

Apolipoprotein E (ApoE) plays important roles in the body, including a carrier of cholesterols, an anti-oxidant, and a ligand for the low-density lipoprotein receptors. In the nervous system, the presence of ApoE4 isoforms is associated with Alzheimer's disease. ApoE gene polymorphisms are also associated with glaucoma, but the function of ApoE in the retina remains unclear. In this study, we investigated the role of ApoE in axonal damage-induced RGC death. ApoE was detected in the astrocytes and Müller cells in the wild-type (WT) retina. RGC damage was induced in adult ApoE-deficient mice (male, 10-12 weeks old) through ocular hypertension (OH), optic nerve crush (NC), or by administering kainic acid (KA) intravitreally. The WT mice were treated with a glutamate receptor antagonist (MK801 or CNQX) 30 min before performing NC or left untreated. Seven days later, the retinas were flat mounted and Fluorogold-labeled RGCs were counted. We found that the RGCs in the ApoE-deficient mice were resistant to OH-induced RGC death and optic nerve degeneration 4 weeks after induction. In WT mice, NC effectively induced RGC death (control: 4085±331 cells/mm(2), NC: 1728±170 cells/mm(2)). CNQX, an inhibitor of KA receptors, suppressed this RGC death (3031±246 cells/mm(2)), but MK801, an inhibitor of NMDA receptors, did not (1769±212 cells/mm(2)). This indicated the involvement of KA receptor signaling in NC-induced RGC death. We found that NC- or KA-induced RGC death was significantly less in the ApoE-deficient mice than in the WT mice. These data suggest that the ApoE deficiency had a neuroprotective effect against axonal damage-induced RGC death by suppressing the KA receptor signaling.

Topics: 6-Cyano-7-nitroquinoxaline-2,3-dione; Animals; Apolipoproteins E; Cell Death; Disease Models, Animal; Dizocilpine Maleate; Dose-Response Relationship, Drug; Kainic Acid; Male; Mice; Mice, Inbred C57BL; Mice, Knockout; Neuroprotective Agents; Ocular Hypertension; Optic Nerve Injuries; Receptors, Kainic Acid; Retinal Degeneration; Retinal Ganglion Cells; Signal Transduction; Stilbamidines

In this study, we examined the effect of SUN N8075, a radical scavenger with neuroprotective properties, on murine retinal damage induced by intravitreous injection of N-methyl-d-aspartate (NMDA) or high-intraocular pressure (IOP). In both models, systemic administration of SUN N8075 decreased the cell loss in the ganglion cell layer (GCL) after retinal damage occurred. Moreover, SUN N8075 reduced the number of apoptotic cells and the expression of an oxidative stress marker in GCL in the NMDA model. These findings suggest that SUN N8075 has a neuroprotective effect against retinal damage, presumably via the radical scavenging effect.

Topics: 8-Hydroxy-2'-Deoxyguanosine; Aniline Compounds; Animals; Cell Death; Deoxyguanosine; Disease Models, Animal; Dizocilpine Maleate; In Situ Nick-End Labeling; Mice; N-Methylaspartate; Neurons; Neuroprotective Agents; Ocular Hypertension; Piperazines; Retina; Retinal Diseases; Time Factors

To assess the neuroprotective effects of different glutamate modulation strategies, with a nonselective (MK801) and a selective (ifenprodil) NMDA receptor antagonist and a metabotropic glutamate receptor agonist (mGluR Group II, LY354740), in glaucoma-related in vivo rat models of retinal ganglion cell (RGC) apoptosis.. RGC apoptosis was induced in Dark Agouti (DA) rats by staurosporine (SSP) treatment. Single agents MK801, ifenprodil, or LY354740, or MK801 and LY354740 combined, were administrated intravitreally at different doses. Eyes were imaged in vivo using a recently established technique and the results confirmed histologically. The most effective combined therapy regimen of MK801 and LY354740 was then assessed in a chronic ocular hypertension (OHT) rat model with application at 0, 1, and 2 weeks after OHT surgery and the effects assessed as described before.. All strategies of glutamate modulation reduced SSP-induced-RGC apoptosis compared with the control, in a dose-dependent manner: MK801 (R2= 0.8863), ifenprodil (R2= 0.4587), and LY354740 (R2= 0.9094), with EC50s of 0.074, 0.0138, and 19 nanomoles, respectively. The most effective combination dose of MK801 and LY354740 was 0.06 and 20 nanomoles (P < 0.05), respectively, and the optimal timing of the therapy was 0 weeks after OHT surgery (P < 0.05).. This novel SSP model was validated as a useful tool for screening neuroprotective strategies in vivo. Group II mGluR modulation may be a useful treatment for RGC death. Combination therapy optimized to limit neurotoxic effects of MK801 may be an effective neuroprotective approach in retinal degenerative disease. Furthermore, treatments that minimize secondary RGC degeneration may be most useful in glaucoma.

Topics: Animals; Apoptosis; Bridged Bicyclo Compounds; Disease Models, Animal; Dizocilpine Maleate; Dose-Response Relationship, Drug; Drug Therapy, Combination; Excitatory Amino Acid Agonists; Excitatory Amino Acid Antagonists; Glaucoma; Glutamic Acid; Intraocular Pressure; Male; Neuroprotective Agents; Ocular Hypertension; Piperidines; Rats; Receptors, Metabotropic Glutamate; Receptors, N-Methyl-D-Aspartate; Retinal Ganglion Cells; Staurosporine

To establish a rat model of acute increase in intraocular pressure (IOP) and to investigate the therapeutic window for protection against death of retinal ganglion cells (RGCs) by vaccination with glatiramer acetate (Cop-1) or by treatment with brimonidine or MK-801.. Animal study, laboratory investigation.. IOP was transiently increased in anesthetized Lewis rats by infusing normal saline (0.9%) into the anterior chamber of the eye for one hour. RGC survival was assessed one week and two weeks later by counting the RGCs retrogradely labeled with rhodamine dextran.. RGC survival.. IOP rose to 100 cm H(2)O (76 mm Hg) and returned to baseline after 24 hours. The RGC count decreased by 23% a week after the insult and by a further 7% after the second week. Vaccination with Cop-1 on the day of the insult prevented 50% of the IOP-induced RGC loss. Similar neuroprotection was achieved by daily intraperitoneal injections of brimonidine, but not with MK-801.. A transient increase in IOP to 100 cm H(2)O causes death of RGCs in rats. A single immunization with Cop-1 or daily injections of brimonidine protected up to 50% of potentially doomed RGCs from IOP-induced death, suggesting that not all of the cell death in the untreated model results from the IOP insult directly, but that some of it is caused by insult-induced environmental cytotoxicity, which is unrelated to glutamate toxicity or at least to NMDA receptors. These findings can be applied immediately as a basis for acute glaucoma therapy.

Topics: Acute Disease; Animals; Antihypertensive Agents; Brimonidine Tartrate; Cell Survival; Disease Models, Animal; Dizocilpine Maleate; Glatiramer Acetate; Immunization; Injections; Intraocular Pressure; Male; Neuroprotective Agents; Ocular Hypertension; Optic Nerve Diseases; Peptides; Quinoxalines; Rats; Rats, Inbred Lew; Retinal Ganglion Cells; Vaccination

Excitatory synaptic transmission in the mammalian CNS and retina is mainly mediated through l-glutamate. The effect of MK-801, a non-competitive antagonist of the NMDA subtype of glutamate receptor was studied on rat retinal ganglion cells in hypertensive eyes. MK-801 was administered intraperitoneally to the first group, 1 day before the increase, and in the second group, 2 days after the intraocular pressure (IOP) elevation. Phosphate-buffered saline was administered to the control group. Animals were sacrificed 2 and 4 weeks post-IOP increase. The retinal ganglion cells were counted and compared between control (right) and experimental (left) eyes. The data presented here suggests that MK-801 has neuroprotective properties.

Topics: Animals; Apoptosis; Blotting, Western; Cell Survival; Dizocilpine Maleate; Electrophoresis, Polyacrylamide Gel; Fluorescent Dyes; Intraocular Pressure; Male; Microscopy, Electron; Neuroprotective Agents; Ocular Hypertension; Proto-Oncogene Proteins c-fos; Rats; Rats, Wistar; Retinal Ganglion Cells; Stilbamidines