Neuroprotection of retinal ganglion cells by brimonidine in rats with laser-induced chronic ocular hypertension.

PURPOSE: To examine the neuroprotective effect of the alpha(2)-adrenergic agonist brimonidine in a chronic ocular hypertension model. METHODS: Intraocular pressure (IOP) was elevated by laser photocoagulation of episcleral and limbal veins. Retinal ganglion cell loss was evaluated in wholemounted retinas. Brimonidine or timolol was administered, either at the time of or 10 days after IOP elevation and continued for 3 weeks. Drug-related immunohistochemical changes in glial fibrillary acidic protein (GFAP) were also determined after 3 weeks. RESULTS: Laser treatment caused a twofold IOP increase over baseline that was maintained for 2 months. A time-dependent loss of ganglion cells occurred with elevated IOP. Systemic administration of brimonidine or timolol caused little decrease in IOP. After 3 weeks of elevated IOP, ganglion cell loss in control rats was 33% +/- 3%. Brimonidine reduced the progressive loss of ganglion cells to 26% +/- 1% and 15% +/- 2% at doses of 0.5 and 1 mg/kg. d, respectively. Timolol had no effect. Ten days of high IOP resulted in 22% +/- 4% ganglion cell loss. Brimonidine administration initiated 10 days after IOP elevation prevented any further loss of ganglion cells. In vehicle- or timolol-treated rats, ganglion cell loss continued to 33%. The increase in immunoreactivity of GFAP in ocular hypertensive retinas was attenuated by brimonidine. CONCLUSIONS: Systemic application of brimonidine or timolol had little effect on IOP. Brimonidine, but not timolol, showed significant protection of retinal ganglion cells when applied at the time of IOP elevation and prevented further cell loss when applied after IOP was elevated. This indicates that brimonidine has a neuroprotective activity unrelated to its effect on ocular hypotension.

Efficacy and safety of memantine, an NMDA-type open-channel blocker, for reduction of retinal injury associated with experimental glaucoma in rat and monkey.

Glutamatergic excitotoxicity has been implicated as a mechanism for injury in a variety of central nervous system pathologies, including glaucoma. Memantine, an NMDA-type glutamatergic open-channel blocker, has pharmacologic properties that make its efficacy greater under excitotoxic conditions, but lesser under normal conditions. Daily oral dosing for approximately 15 months with 4.0 mg/kg memantine in monkeys yielded plasma concentrations similar to those found in patients who received memantine treatment for Parkinson's disease. This same dose of memantine was not associated with any evidence of an effect on the normal function of the retina and central visual pathways, as indicated by measures of the electroretinogram (ERG) and visually-evoked cortical potential (VECP). Amplitude of the VECP response was reduced in eyes with experimentally induced glaucoma. When compared to vehicle-treated control animals, memantine-treated glaucoma eyes suffered significantly less reduction of VECP amplitude. Preliminary results in a rat model for experimental glaucoma also show that, when compared to control animals, systemic treatment with memantine (10 mg/kg/day) was associated with a significant reduction in glaucoma-induced loss of retinal ganglion cells.

Characterization of retinal injury using ERG measures obtained with both conventional and multifocal methods in chronic ocular hypertensive primates.

PURPOSE: To characterize, using both conventional and multifocal electroretinogram (ERG) recordings as well as histologic measures, retinal injury in the chronic ocular hypertensive primate model for experimental glaucoma. METHODS: Ocular hypertension was induced in the right eye of 7 cynomolgous monkeys, Macaca fascicularis, using laser injury to the aqueous outflow tissue at the anterior chamber angle. At 16 months after IOP elevation, ERG recordings were made from both eyes of all animals using both conventional and multifocal methods. After electrophysiological recording, animals were killed and retinal samples were radially sectioned for histologic analysis. RESULTS: Histologic measures showed that ocular hypertensive injury was largely or completely limited to a loss of retinal ganglion cells (RGCs). The degree of RGC loss was similar in central and peripheral retina. Amplitudes of conventional ERG responses were mostly unaffected in eyes having severe loss of RGCs, a finding that is consistent with limited injury to photoreceptors, bipolar cells, and amacrine cells. Peaks in both the first- and second-order multifocal ERG responses were attenuated in ocular hypertensive eyes, and amplitude of these peaks was highly correlated with the density of surviving RGCs. CONCLUSIONS: The results are consistent with a conclusion that both first- and second-order components of the multifocal ERG response from the monkey reflect a significant contribution from activity in RGCs and may provide a useful measure for the clinical diagnosis and management of glaucoma.

Electrophysiological and histological measures of retinal injury in chronic ocular hypertensive monkeys.

PURPOSE: This study was performed to determine whether components of the standard ERG (electroretinogram), multifocal ERG, and flash VECP (visually-evoked cortical potential) response might provide a sensitive measure of retinal ganglion cell injury in a monkey model for chronic ocular hypertension. METHODS: Argon laser treatment of the aqueous outflow tissue was used to induce chronic elevation of intraocular pressure (IOP) in the right eye of 18 young adult cynomolgous monkeys. At 15 months post- IOP elevation, standard methods were used to record ERG and VECP responses. Multifocal ERG responses were also recorded at this time. Loss of retinal ganglion cells due to ocular hypertensive injury was determined by histological analysis of all retinas. RESULTS: Ocular hypertensive retinal injury was associated with a loss of retinal ganglion cells. There was no histological or electrophysiological evidence for injury to any other retinal cell type. Correlation of electrophysiological response amplitudes with histological measures of retinal ganglion cell loss/survival yielded results which suggest that activity in retinal ganglion cells makes a substantial contribution to components of the 30 Hz flicker ERG, the flash VECP, and both first and second order multifocal ERG responses. Of the electrophysiological measures used in this study, multifocal ERG response amplitude had the greatest sensitivity to retinal ganglion cell loss. CONCLUSIONS: Components of the multifocal ERG provide a sensitive measure of ganglion cell injury in a monkey model of chronic ocular hypertension. These same measures may have utility in the clinical diagnosis and management of glaucoma.

Synthesis and carbonic anhydrase inhibitory activity of 4-substituted 2-thiophenesulfonamides.

A series of 4-substituted 2-thiophenesulfonamides was prepared from 3-thiophenecarboxaldehyde using metalation chemistry developed for 3-furaldehyde. Several of these compounds inhibit carbonic anhydrase II in vitro at concentrations of less than 10 nM. In addition, none of these compounds exhibit sensitization potential as determined from in vitro measurement of cysteine reactivity.