Effect of intravitreal administration of somatostatin and sst2 analogs on AMPA-induced neurotoxicity in rat retina.
OBJECTIVE
The aim of the present study was to use an in vivo model of retinal excitotoxicity to investigate the neuroprotective effect of somatostatin (SRIF)-ergic agents.


METHODS
Adult Sprague-Dawley rats (weight range, 250-300 g) intravitreally received (RS)-alpha-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid hydrobromide (AMPA; 21, 42, 84 nmol/eye) or PBS (50 mM). Time-dependent responses were examined in animals that received AMPA (42 nmol/eye). Animals received AMPA (42 nmol) alone or in combination with SRIF (10(-5), 10(-4) M) or the sst-selective ligands lanreotide (sst(2),10(-5),10(-4) M), L-779976 (sst(2,)10(-6),10(-5), 10(-4) M), L-797591 (sst(1),10(-4) M), and L-803087 (sst(4),10(-4) M). Immunohistochemistry and TUNEL studies were used to examine retinal cell loss and protection. Immunochemistry, Western blot analysis, and radioimmunoassay assessed the viability of sst(2A) receptors and SRIF levels, respectively, in control and AMPA-treated tissue.


RESULTS
AMPA (42 nmol) treatment resulted in total and major loss of ChAT and bNOS immunoreactivity, respectively, 24 hours after its administration. This loss was sustained up to 30 days for ChAT- and 8 days for bNOS-expressing amacrine cells. SRIF and the sst(2) receptors were not affected by AMPA. SRIF and the sst(2) analogs protected the retina from the AMPA insult in a dose-dependent manner, whereas activation of the sst(1) and sst(4) subtypes had no effect. TUNEL staining confirmed AMPA-induced retinal ischemia and L-779976 neuroprotection.


CONCLUSIONS
These results demonstrate for the first time that SRIF and the sst(2) analogs, administered intravitreally, protect the retina from excitotoxicity. Further studies are essential to ascertain the therapeutic relevance of these results.
Kiagiadaki
Foteini
F
Laboratory of Pharmacology, Department of Basic Sciences, Faculty of Medicine, University of Crete, Heraklion, Crete, Greece.
Thermos
Kyriaki
K
D025042:Amacrine Cells / Q000201:enzymology; D000577:Amides / Q000494:pharmacology; D000818:Animals; D002795:Choline O-Acetyltransferase / Q000037:antagonists & inhibitors; D004305:Dose-Response Relationship, Drug; D005260:Female; D007150:Immunohistochemistry; D007211:Indoles / Q000494:pharmacology; D007511:Ischemia / Q000139:chemically induced; D008297:Male; D018696:Neuroprotective Agents / Q000008:administration & dosage / Q000494:pharmacology*; D009498:Neurotoxins / Q000494:pharmacology*; D052248:Nitric Oxide Synthase Type I / Q000037:antagonists & inhibitors; D051381:Rats; D017207:Rats, Sprague-Dawley; D017481:Receptors, Somatostatin / Q000819:agonists; D012160:Retina / Q000187:drug effects* / Q000201:enzymology; D012171:Retinal Vessels; D013004:Somatostatin / Q000008:administration & dosage / Q000031:analogs & derivatives* / Q000494:pharmacology*; D013997:Time Factors; D014822:Vitreous Body; D018350:alpha-Amino-3-hydroxy-5-methyl-4-isoxazolepropionic Acid / Q000494:pharmacology
D000577:Amides; D007211:Indoles; C121854:L 779976; D018696:Neuroprotective Agents; D009498:Neurotoxins; D017481:Receptors, Somatostatin; D013004:Somatostatin; D018350:alpha-Amino-3-hydroxy-5-methyl-4-isoxazolepropionic Acid; D052248:Nitric Oxide Synthase Type I; D002795:Choline O-Acetyltransferase