Neuroprotective effects of brimonidine against transient ischemia-induced retinal ganglion cell death: a dose response in vivo study.

The purpose of this study was to investigate the dose-response effects of topically administered brimonidine (BMD) on retinal ganglion cell (RGC) survival, short and long periods of time after transient retinal ischemia. In adult Sprague-Dawley rats, RGCs were retrogradely labeled with the fluorescent tracer fluorogold (FG) applied to both superior colliculi. Seven days later, the left ophthalmic vessels were ligated for 90 min. One hr prior to retinal ischemia, two 5 microl drops of saline alone or saline containing 0.0001, 0.001, 0.01 or 0.1% BMD were instilled on the left eye. Rats were processed 7, 14 or 21 days later and densities of surviving RGCs were estimated by counting FG-labeled RGCs in 12 standard regions of each retina. The following have been found. (1) Seven days after 90 min of transient ischemia there is loss of approximately 46% of the RGC population. (2) topical pre-treatment with BMD prevents ischemia-induced RGC death in a dose-dependent manner. Administration of 0.0001% BMD resulted in the loss of approximately 37% of the RGC population and had no significant neuroprotective effects. Administration of higher concentrations of BMD (0.001 or 0.01%) resulted in the survival of 76 or 90%, respectively, of the RGC population, and 0.1% BMD fully prevented RGC death in the first 7 days after ischemia. (3) Between 7 and 21 days after ischemia there was an additional slow cell loss of approximately 25% of the RGC population. Pre-treatment with 0.1% BMD also reduced significantly this slow cell death. These results indicate that the neuroprotective effects of BMD, when administered topically, are dose-dependent and that the 0.1% concentration achieves optimal neuroprotective effects against the early loss of RGCs. Furthermore, this concentration is also effective to diminish the protracted loss of RGCs that occurs with time after transient ischemia.

Retinal ganglion cell death after acute retinal ischemia is an ongoing process whose severity and duration depends on the duration of the insult.

In adult Sprague-Dawley rats we have investigated retinal ganglion cell survival after transient intervals of retinal ischemia of 30, 45, 60, 90 or 120 min duration, induced by ligature of the ophthalmic vessels. Animals were killed 5, 7, 14, 21, 30, 60, 90 or 180 days later and densities of surviving retinal ganglion cells were estimated in retinal whole mounts by counting cells labelled with diAsp. This dye was applied, 3 days prior to death, to the ocular stump of the intraorbitally transected optic nerve. We found that retinal ganglion cell loss after retinal ischemia proceeds for different lengths of time. All the ischemic intervals induced loss of retinal ganglion cells whose severity and duration was related to the length of the ischemic interval. Following 30 or 45 min of ischemia, cell loss lasted 14 days and caused the death of 46 or 50%, respectively, of the population of retinal ganglion cells. Sixty, 90 or 120 min of retinal ischemia were followed by a period of cell loss that lasted up to 90 days and caused the death of 75%, 87% or 99%, respectively, of the population of retinal ganglion cells. We conclude that retinal ganglion cell loss after retinal ischemia is an ongoing process that may last up to 3 months after the injury and that its severity and duration are determined by the ischemic interval.

Brimonidine's neuroprotective effects against transient ischaemia-induced retinal ganglion cell death.

PURPOSE: Brimonidine is a lowering pressure agent currently used in glaucoma. This chronic degenerative condition is characterised by neuronal death, and an agent which offers neuroprotection may slow down or impede the progression of neuronal cell death. METHODS: The effects of brimonidine (BMD) on the short- and long-term survival of retinal ganglion cells (RGCs) after transient retinal ischaemia are reported here using a rat model. The fluorescent tracer Fluorogold (FG) was applied to both superior colliculi to retrogradely label RGCs. A ninety-minute period of ischaemia was induced and densities of surviving RGCs were estimated over time by counting FG-labelled RGCs in 12 standard regions of each retina. RESULTS: Seven days after inducing transient ischaemia, there was loss of approximately half of the RGC population. Topical pre-treatment with 0.1% or 0.5% BMD prevented ischaemia-induced RGC death. CONCLUSIONS: These results indicate that optimal neuroprotective effects against the early loss of RGCs are seen with 0.1% or 0.5% BMD. Ischaemia-induced RGC loss continued between day 7 and day 21 in the vehicle treated groups and amounted to approximately 25% of the RGC population. Topical pre-treatment with 0.1% or 0.5% BMD was also effective in reducing the slow loss of RGCs.

Neuroprotective effects of alpha(2)-selective adrenergic agonists against ischemia-induced retinal ganglion cell death.

PURPOSE: To investigate in adult rats the effects of two alpha(2)-selective adrenergic agonists (alpha(2)-SAs; AGN 191103 and AGN 190342) on retinal ganglion cell (RGC) survival after transient retinal ischemia. METHODS: RGCs were labeled with a Fluorogold (FG) tracer applied to both superior colliculi. Seven days later, the left ophthalmic vessels were ligated for 60 or 90 minutes. In one group, a single dose of saline or one alpha(2)-SA was administered intraperitoneally (IP) or topically 1 hour before ischemia. In another group, a single dose of AGN 190342 was administered IP, 1, 2, 4, 24, or 72 hours after ischemia. Rats were processed 7, 14, or 21 days later. Densities of surviving RGCs were estimated by counting FG-labeled cells in 12 standard retinal areas. RESULTS: Seven days after 60 or 90 minutes of retinal ischemia, death had occurred in 36% or 47%, respectively, of the RGC population, and by 21 days the loss of RGCs amounted to 42% or 62%, respectively. Systemic pretreatment with an alpha(2)-SA resulted in enhanced survival of ischemic-injured RGCs. Topical pretreatment with an alpha(2)-SA prevented up to 100% of the ischemia-induced RGC loss. Pretreatment with an alpha(2)-SA abolished the secondary slow RGC loss that occurred between days 7 and 21 after ischemia. When administered shortly after ischemia (up to 2 hours) AGN 190342 rescued substantial proportions of RGCs destined to die and diminished slow RGC death. CONCLUSIONS: Pretreatment and early posttreatment with an alpha(2)-SA induces marked long-lasting neuroprotective in vivo protection against ischemia-induced cell death in RGCs.

Retinal ganglion cell death induced by retinal ischemia. neuroprotective effects of two alpha-2 agonists.

We have investigated in adult Sprague-Dawley rats the neuroprotective effects of two alpha-2-selective agonists [AGN 191,103 (AGN) and brimonidine tartrate (BMD)] on retinal ganglion cell (RGC) survival after transient retinal ischemia. RGCs were labelled with Fluorogold (FG) applied to both superior colliculi. Seven days later, 90 min of retinal ischemia were induced in the left eyes by ligature of the ophthalmic vessels (LOV). In one group of animals, vehicle or AGN (0.01 mg/kg) were administered systemically 1 hr before ischemia. In another group of animals, two 5 microl drops of vehicle, AGN (0.05%) or BMD (0.1%) were administered topically in the left eye 1 hr before ischemia. The animals were processed 7 or 21 days later. RGC survival was estimated by counting FG-labelled cells in 12 standard areas of each retina. In control retinas of systemically pretreated animals, mean densities of labelled RGCs were 2372 +/- 49 cells/mm(2) (mean +/- SEM; n = 6). In experimental retinas of systemically pretreated animals, mean RGC densities had decreased 7 days after ischemia to 53% (n = 6) or 81% (n = 6) of control in the groups treated with vehicle or AGN, respectively. Twenty-one days after ischemia, mean RGC densities had decreased to 38% (n = 6) or 79% (n = 6) of control in the groups treated with vehicle or AGN, respectively. In control retinas of topically pretreated animals, mean densities of labelled RGCs were 2208 +/- 29 cells/mm(2) (n = 6). In experimental retinas of topically pretreated animals, mean RGC densities had decreased 7 days after ischemia to 54% (n = 6), 95% (n = 6) or 96% (n = 6) of control in the groups treated with vehicle, AGN or BMD, respectively. These results indicate that pretreatment with a single systemic or topical dose of AGN or BMD can prevent completely the early rapid phase of RGC loss and abolish the delayed RGC loss observed after 90 min of retinal ischemia induced by ligature of the ophthalmic vessels.

[An analysis of the level of accuracy of the official diagnosis of temporary work incapacity]. / Análisis del nivel de exactitud del diagnóstico oficial de la incapacidad laboral transitoria.

OBJECTIVE: To assess the precision of the Sickness Certificate (SC) issued for Temporary Unfitness for Work (TUW). To measure the percentage of TUW where the diagnoses in the medical records and in the TUW Sickness Certificate do not coincide. To seek objective criteria to determine TUW. DESIGN: A descriptive, prospective and observational study. SETTING: Health Centre in an urban area in Vitoria. PATIENTS AND OTHERS PARTICIPANTS: All the sickness occasioning time off work between May and July, 1991, recorded at the above Health Centre: a sample of 224 TUW. MEASUREMENTS AND MAIN RESULTS: In 11.6% of the TUW the diagnoses did not coincide. The main reasons for the lack of correspondence were: initial ignorance of the diagnosis (34.6%); confidentiality before a third party (25.9%); pretense (14.8%). There was a notable difference between the psychological diagnoses (12) and those found in the official certificate 3 for TUW (p = 0.032). The most common diagnostic group was the locomotive one (29%). CONCLUSIONS: There is considerable inexactness in the diagnoses on the official TUW certificate. A lot of time off for psychological reasons is covered up by organic complaints. The locomotive group of complaints is the most commonly found one. We propose that the CIAP classification should be adopted to standardise diagnoses in this area.