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1 From the Department of Ophthalmology and Visual Sciences, Graduate School of Medicine, and the 2 Department of Pharmacology, Graduate School of Pharmaceutical Sciences, Kyoto University; and the 3 Drug Discovery Research Laboratory, Sanwa Kagaku Kenkyusho Co., Ltd., Mie, Japan.
PURPOSE. To identify the localization and expression of bradykinin (BK)-B2 receptors in rat retina and examine the effects of BK on glutamate-induced neurotoxicity using cultured rat retinal neurons.
METHODS. An immunohistochemical study using a specific antibody against BK-B2 receptor was performed with rat retina. Primary cultures were obtained from the retina of fetal rats (gestation day 17–19). Expression of BK-B2 receptor mRNA was determined by reverse transcription–polymerase chain reaction (RT-PCR) using total RNA obtained from cultured retinal neurons. Cultured cells were exposed to glutamate (1 mM) for 10 minutes and followed by incubation in glutamate-free medium for 1 hour. The effects of BK were assessed by simultaneous application of BK with glutamate. The neurotoxic effects on retinal cultures were quantitatively assessed by the trypan blue exclusion method.
RESULTS. Immunohistochemical study demonstrated that BK-B2 receptors were expressed in the ganglion cell, inner nuclear layers, and outer nuclear layers. Furthermore, BK-B2 receptor mRNA expression was observed in cultured retinal neurons. Cell viability was markedly reduced by 10-minute exposure to 1 mM glutamate followed by a 1-hour incubation in glutamate-free medium. Simultaneous application of BK at concentrations of 0.001 to 1 µM with glutamate demonstrated dose-dependent protection against glutamate neurotoxicity. The protective action of BK (1 µM) was inhibited by simultaneous application of BK-B2 receptor antagonist, Hoe140 (1 µM). Furthermore, 1 µM BK had protective effects on neurotoxicity induced by 1 µM ionomycin, a calcium ionophore, and sodium nitroprusside (SNP, 500 µM), a nitric oxide (NO)–generating agent. However, BK did not inhibit neurotoxicity induced by 3-morpholinosydnonimine (SIN-1, 10 µM), an NO and oxygen radical donor.
CONCLUSIONS. These results suggest that BK-B2 receptors were distributed in rat retinas and cultured retinal neurons and that BK had a protective action against glutamate neurotoxicity through BK-B2 receptors in cultured retinal neurons. It is suggested that BK-induced protection against glutamate neurotoxicity took place downstream to NO generation and upstream to oxygen radical generation.
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