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Catherine A. Opere, Arnecia Flowers, Namonique Floyd, Edem Kegey, Jamal Jamil, Thierry Durand, Jean-Marie Galano, Alexandre Guy, Ya Fatou Njie-Mbye, Sunny E. Ohia; Role of Prostanoid Receptors in the Excitatory Effect of Neuroprostanes on Potassium Induced [3H]D-Aspartate Release in Isolated Bovine Retina. Invest. Ophthalmol. Vis. Sci. 2012;53(14):5386.
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There is evidence that neuroprostanes (nPs), a series of isoprostane (IsoP)-like compounds that are spontaneously generated via free-radical catalyzed peroxidation of long chain polyunsaturated fatty acids are elevated in neurodegenerative conditions (Musiek et al., Brain Pathol. 15:149,2005). However, their effect on excitatory neurotransmitter release in neuronal tissues has not been fully elucidated. Purpose: In this study, we investigated the regulatory effect of the eicosapentanoic aid (EPA)-derived epimer pair, 5(S)-F3t-IsoP (CO5-667) and 5-epi-5-F3t-IsoP(CO5-668) and the docosahexaenoic acid (DHA)-derived nP, 4(S)-F4t-nP (CO5-738) on K+-induced glutamate release (using [3H]D-aspartate as a marker) in isolated bovine retina. We also examined the mechanism by which CO5-738 regulates this excitatory neurotransmitter release.
Freshly isolated bovine retinae were incubated in oxygenated Krebs solution (pH 7.45; 37 ºC) containing 200nM of [3H] D-aspartate for 60 mins and then prepared for studies of neurotransmitter release using the well established superfusion method. Release of [3H]D-aspartate was evoked by iso-osmotic concentration of K+ (50mM)-stimuli applied at 80-88 mins (S1) and 116-124 mins (S2) after the onset of superfusion. When used, the antagonist was present before and during S1 and S2.
In the concentration range, 1 nM to 1 µM, the nPs enhanced K+-induced [3H]D-aspartate release from bovine retina without affecting basal [3H]D-aspartate efflux. Of the EPA-derived epimer-pair examined, the cis-conformer, C05-668 exhibited a higher potency, achieving a maximal excitatory response of 80% (p<0.01, n=4) at the 10 nM concentration of the nP. At an equimolar concentration of 10 nM, the rank order of activity of the nPs was as follows: CO5-668> CO5-738> CO5-667. Interestingly, the excitatory effect elicited by the DHA-derived nP, CO5-738 (0.1 µM) was completely reversed by the prostanoid TP/DP2-receptor inhibitor, ramatroban (BAY-U3405) (10µM).
In conclusion, the EPA- and DHA-metabolites enhance K+-induced [3H]D-aspartate release in bovine retina. Moreover, prostanoid TP/DP2-receptors mediate the excitatory action exhibited by the DHA-metabolite, CO5-738 on the neurotransmitter release.
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