An analog of thyrotropin-releasing hormone (TRH) is neuroprotective against glutamate-induced toxicity in fetal rat hippocampal neurons in vitro

Abstract

TRH has been found to be efficacious in treating certain neurodegenerative disorders such as epilepsy, Alzheimer's disease, neurotrauma and depression, however, its mechanism of action is poorly understood. Since Glutamate (Glu) toxicity has been implicated in these disorders, we utilized primary enriched cultures of rat fetal (E 17) hippocampal neurons to test the hypothesis that an analog of TRH, 3-Methyl-Histidine TRH (3Me-H TRH), given concurrently with Glu would protect such neurons against cell damage and cell death. Cell viability was assessed via Trypan Blue exclusion cell counts and neuronal damage was determined by assaying lactic acid dehydrogenase (LDH) released in the conditioned media. Fetal hippocampal neurons were cultured in neurobasal media for 7 days. On day 7, neurons (10 6 /well) were treated with: control media, 10 μM 3Me-H TRH, 500 μM Glu, or 500 μM Glu with either 10, 1, 0.1, 0.01 or 0.001 μM 3Me-H TRH. Both media and neurons were harvested 16 hr after treatment. Prolonged exposure to 10 μM 3Me-H TRH was not toxic to the cells, whereas, neurons exposed to 500 μM Glu resulted in maximal cell death. Notably, 10, 1 and 0.1 μM 3Me-H TRH, when co-treated with 500 μM Glu protected fetal neurons against cell death in a concentration-dependent manner. These results provide support for an important neuroprotective effect of TRH/analogs against glutamate toxicity in primary hippocampal neuronal culture, and implicate a potentially beneficial role of TRH/analogs in neurodegenerative diseases.

Thyroid Toxicogenomics

“…The ancestral role of TRH as a neuroregulator is being increasingly recognized and an analog has been successfully used in vitro as a neuroprotective agent in the glutamateinduced toxicity that is associated with neurodegenerative diseases such as Alzheimer's [101].…”

The role of Thyrotropin Releasing Hormone in aging and neurodegenerative diseases

“…TRH analog ligands can also exert protective effects against Aβ toxicity in neuronal cell culture (Faden et al, 2005), reduce inflammatory cytokines TNF-α and IL-6 and attenuate lipid peroxidation, all of which have been implicated in oxidative stress and the predisposition for AD (Rajput et al, 2011). The TRH analog, 3-methyl-histidine-TRH, has also been shown to functionally antagonize glutamate-mediated neurotoxicity in fetal neurons in a concentration-dependent manner (Veronesi et al, 2007). Administration of L-T 4 in mice injected intrahippocampally with aggregated Aβ was shown to prevent cognitive impairment and improve memory function (Fu et al, 2010).…”

Ghrelin Regulation in Epilepsy

“…Its mechanism of action is poorly understood; however, it seems to be implicated in a protection against neuronal overexcitability. In fact, some authors reported that TRH could inhibit the effects of the glutamate-induced toxicity, in a dose-dependent manner, in cultured fetal rat hippocampal neurons (Pizzi et al, 1999;Veronesi et al, 2007). Furthermore, a paradoxical secretary peak of GH to TRH is more frequent during a status epilepticus.…”