Anticonvulsant and Neuroprotective Effects of the Thyroid Hormone Metabolite 3-Iodothyroacetic Acid

BACKGROUND: 3-Iodothyroacetic acid (TA1) is among the thyroid hormone (T3) metabolites that can acutely modify behavior in mice. This study aimed to investigate whether TA1 is also able to reduce neuron hyper-excitability and protect from excitotoxic damage. METHODS: CD1 male mice were treated intraperitoneally with saline solution or TA1 (4, 7, 11, or 33 μg/kg) before receiving 90 mg/kg pentylenetrazole subcutaneously. The following parameters were measured: latency to first seizure onset, number of mice experiencing seizures, hippocampal levels of c-fos, and PI3K/AKT activation levels. Organotypic hippocampal slices were exposed to vehicle or to 5 μM kainic acid (KA) in the absence or presence of 0.01-10 μM TA1. In another set of experiments, slices were exposed to vehicle or 5 μM KA in the absence or presence of 10 μM T3, 3,5,3'-triiodothyroacetic acid (TRIAC), T1AM, thyronamine (T0AM), or thyroacetic acid (TA0). Neuronal cell death was measured fluorimetically. The ability of TA1 and T3, TRIAC, T1AM, T0A, and TA0 to activate the PI3K/AKT cascade was evaluated by Western blot. The effect of TA1 on KA-induced currents in CA3 neurons was evaluated by patch clamp recordings on acute hippocampal slices. RESULTS: TA1 (7 and 11 μg/kg) significantly reduced the number of mice showing convulsions and increased their latency of onset, restored pentylenetrazole-induced reduction of hippocampal c-fos levels, activated the PI3K/AKT, and reduced GSK-3β activity. In rat organotypic hippocampal slices, TA1 reduced KA-induced cell death by activating the PI3K/AKT cascade and increasing GSK-3β phosphorylation levels. Protection against KA toxicity was also exerted by T3 and other T3 metabolites studied. TA1 did not interact at KA receptors. Both the anticonvulsant and neuroprotective effects of TA1 were abolished by pretreating mice or organotypic hippocampal slices with pyrilamine, an histamine type 1 receptor antagonist (10 mg/kg or 1 μM, respectively). CONCLUSIONS: TA1 exerts anticonvulsant activity and is neuroprotective in vivo and in vitro. These findings extend the current knowledge on the pharmacological profile of TA1 and indicate possible novel clinical use for this T3 metabolite.