Regulation of Endogenous Excitatory Neurotransmitters by Isoprostanes

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Authors
Zhao, Min
Issue Date
2008-07-28
Type
Dissertation
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en_US
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Abstract
We have evidence that isoprostanes (IsoPs) regulate exogenously applied excitatory amino acid neurotransmitter glutamate in bovine retina, in vitro. However, the regulation of retinal endogenous glutamateby IsoPs is unknown. The objective of the present study was to investigate the effect of 8-isoprostaglandin E2 (8-isoPGE2) on endogenous levels of glutamate and its metabolite, glutamine in bovine retina, ex vivo. Freshly isolated bovine eyeballs were injected intravitreally with 8-isoPGE2 and retina and vitreous humor were isolated for measurement of amino acids using high pressure liquid chromatography. 8-isoPGE2 caused a concentration-dependent attenuation of retinal glutamate and glutamine levels. For instance, 8-isoPGE2 (1 μM and 100 μM) significantly (p<0.001) attenuated glutamate levels by 33.9% and 48.0%, respectively. 8-isoPGE2 (100 μM) inhibited (p<0.01) retinal glutamine levels by 37.7%. The IsoP exhibited no effect on glutamine levels in the vitreous humor while glutamate was not detected in the vitreous humor.|To investigate whether prostanoid production is involved in the inhibitory effect of 8-isoPGE2, eyeballs were pretreated with either flurbiprofen, a nonselective COX inhibitor; NS-398, a selective COX-2 inhibitor or furegrelate, a thromboxane (Tx) synthase inhibitor. All the three enzyme inhibitors had no effect (p>0.05) on the inhibitory effects of 8-isoPGE2 (1μM-100μM) on retinal glutamate and glutamine concentrations. To determine the role of prostanoid receptors in the effects of 8-isoPGE2, eyeballs were pretreated with the prostanoid receptor antagonists SC-19220 (EP1), AH-6809 (EP2/3), AH-23848 (EP4) or SQ-29548 (TP). SC-19220 (3 μM-30 μM), AH-6809 (3 μM-30 μM) and AH-23848 (3 μM-30 μM) reversed the inhibitory effects of 8-isoPGE2 on glutamate and glutamine levels in a concentration- dependent manner. As a positive control, the EP receptor agonist, PGE2 (10 μM) inhibited glutamate and glutamine levels by 48.4% (p<0.001) and 45.3% (p<0.001), respectively and its effects were completely reversed by both SC-19220 (30 μM) and AH-6809 (30 μM). Interestingly, the TP antagonist, SQ- 29548 (30 μM) had no significant (P>0.05) effects on 8-isoPGE2-induced inhibition of glutamate and glutamine levels in bovine retina. |In conclusion, 8-isoPGE2 can decrease the levels of endogenous excitatory neurotransmitter, glutamate and its metabolite glutamine in bovine retina, ex vivo by EP-receptor-dependent but not prostanoid synthesis-dependent mechanisms.
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Creighton University
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