N-(3-Ethoxy-phenyl)-4-pyrrolidin-1-yl-3-trifluoromethyl-benzamide (EPPTB) prevents 3-iodothyronamine (T1AM)-induced neuroprotection against kainic acid toxicity

Add time:08/27/2019    Source:sciencedirect.com

Thyroid hormone and thyroid hormone metabolites, including 3-iodothyronamine (T1AM) and 3-iodothyroacetic acid (TA1), activate AKT signaling in hippocampal neurons affording protection from excitotoxic damage. We aim to explore whether the mechanism of T1AM neuroprotection against kainic acid (KA)-induced excitotoxicity included the activation of the trace amine associated receptor isoform 1 (TAAR1), one of T1AM targets.Rat organotypic hippocampal slices were exposed to vehicle (Veh) or to 5 μM kA for 24 h in the absence or presence of 0.1, 1 and 10 μM T1AM or to 0.1, 1 and 10 μM T1AM and 1 μM N-(3-Ethoxy-phenyl)-4-pyrrolidin-1-yl-3-trifluoromethyl-benzamide (EPPTB), the only available TAAR1 antagonist, or to 1 μM T1AM in the absence or in the presence of 10 μM LY294002, an inhibitor of phosphoinositide 3-kinases (PI3Ks). Cell death was evaluated by measuring propidium iodide (PI) levels of fluorescence 24 h after treatment. In parallel, the expression levels of p-AKT and p-PKA were evaluated by Western blot analysis of slice lysates. The activity of mitochondrial monoamine oxidases (MAO) was assayed fluorimetrically.24 h exposure of slices to T1AM resulted in the activation of AKT and PKA. KA exposure induced cell death in the CA3 region and significantly reduced p-AKT and p-PKA levels. The presence of 1 and 10 μM T1AM significantly protected neurons from death and conserved both kinase levels with the essential role of AKT in neuroprotection. Furthermore, EPPTB prevented T1AM-induced neuroprotection, activation of PKA and AKT. Of note, in the presence of EPPTB T1AM degradation by MAO was reduced.Our results indicate that the neuroprotection offered by T1AM depends, as for TA1, on AKT activation but do not allow to conclusively indicate TAAR1 as the target implicated.

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