Activation of somatostatin receptor (sst 5) protects the rat retina from AMPA-induced neurotoxicity

Abstract

In a recent study, we employed an in vivo model of retinal excitotoxicity to investigate the neuroprotective effect of somatostatinergic agents. Intravitreal administration of somatostatin and sst 2 selective agonists protected the retina from (RS)-α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid hydrobromide (AMPA) induced excitotoxicity. The sst 1 and sst 4 selective ligands had no effect ( Kiagiadaki and Thermos, 2008). The presence of sst 5 receptors in rat retina was only recently reported ( Ke and Zhong, 2007). Synthetic agonists that activate sst 2 receptors also bind with high affinity to the sst 5 subtype. In the present study the putative neuroprotective effects of sst 5 receptor activation were investigated. Adult female and male Sprague–Dawley (250–350 g) rats were employed. Groups of animals received intravitreally PBS (50 mM) or AMPA (42 nmol/eye) alone or in combination with L-817,818 (sst 5, 10 −5, 10 −4 M). To exclude neuroprotective effects via the activation of sst 2 receptors, L-817,818 (10 −4 M) was coinjected with the sst 2 antagonist CYN-154806 (10 −4 M). Immunohistochemistry (IHC) studies using the anti-retinal marker choline acetyltransferase (ChAT) and TUNEL staining were employed to examine retinal cell loss and protection. IHC and Western blot analysis were also employed to assess whether the sst 5 receptors are viable in the AMPA treated tissue as compared to control retina. sst 5 receptors were not affected by AMPA. L-817,818 protected the retina from the AMPA insult in the dose of 10 −4 M, while CYN-154806 (10 −4 M) had no effect on the sst 5 neuroprotection. TUNEL staining confirmed the AMPA-induced retinal toxicity and the L-817,818 neuroprotection. These results demonstrate for the first time that sst 5 receptors are functional in the retina, and that sst 5 analogs administered intravitreally protect the retina from excitotoxicity. Further studies are essential to ascertain the therapeutic relevance of these results.