The identification of thyrotropin releasing hormone (TRH) in hypothalamic and extrahypothalamic loci of the human nervous system

Kubek, Michael J.; Lorincz, Margaret A.; Wilber, John F.

doi:10.1016/0006-8993(77)90230-x

Cited by 99 publications

(29 citation statements)

References 17 publications

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“…Although TRH and TRH receptors are widely distributed throughout the central nervous system [23,24], increased rCBF was not observed in other brain regions. Previous human studies on TRH therapy reported an increased CBF in the cerebrum in cases of viral encephalopathy, but no significant changes in rCBF were observed in healthy controls [25].…”

Section: Discussionmentioning

confidence: 87%

Evaluation of the effect of thyrotropin releasing hormone (TRH) on regional cerebral blood flow in spinocerebellar degeneration using 3DSRT

Kimura

Kumamoto

Masuda

et al. 2009

Journal of the Neurological Sciences

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Section: Discussionmentioning

confidence: 87%

Evaluation of the effect of thyrotropin releasing hormone (TRH) on regional cerebral blood flow in spinocerebellar degeneration using 3DSRT

Kimura

Kumamoto

Masuda

et al. 2009

Journal of the Neurological Sciences

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“…It is released at synaptic terminals and binds, with high affinity, to specific TRH receptors on neurons [50]. TRH and TRH receptors are found in abundance in certain extrahypothalamic brain loci, particularly in the hippocampus, and suggested to have a potential role in neuromodulation [16,37,50]. An increasing body of evidence implicates TRH as an anticonvulsant in regulation of seizure susceptibility [26,27,32,33,36,38,64], and as a neuroprotective agent against Alzheimer's disease [39,40,55], neurotrauma [8,12,13,52] and brain ischemia [63].…”

Section: Introductionmentioning

confidence: 99%

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

et al. 2007

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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.

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“…In addition to its neuroendocrine role in regulating the hypothalamic-pituitary axis, TRH has a noteworthy presence in limbic system areas. [1][2][3] TRH, its metabolic enzymes (PAP I, PAP II), TRH mRNA, posttranslational processing enzymes (PC1, PC2), and TRH receptors (TRH-R1, TRH-R2) are most abundant in olfactory-linked limbic structures, such as the amygdala, septum, hippocampus, and entorhinal cortex. 1,[4][5][6][7] Moreover, both TRH and TRH mRNAs are upregulated substantially over several days, whereas TRH receptors and receptor mRNAs are downregulated in specific seizureprone areas such as the amygdala and hippocampus after electroconvulsive and amygdala-kindled seizures.…”

Section: Introductionmentioning

confidence: 99%

“…[1][2][3] TRH, its metabolic enzymes (PAP I, PAP II), TRH mRNA, posttranslational processing enzymes (PC1, PC2), and TRH receptors (TRH-R1, TRH-R2) are most abundant in olfactory-linked limbic structures, such as the amygdala, septum, hippocampus, and entorhinal cortex. 1,[4][5][6][7] Moreover, both TRH and TRH mRNAs are upregulated substantially over several days, whereas TRH receptors and receptor mRNAs are downregulated in specific seizureprone areas such as the amygdala and hippocampus after electroconvulsive and amygdala-kindled seizures. [8][9][10][11][12][13][14] Recent reports have documented an anticonvulsant role of TRH, from animal studies [15][16][17][18][19][20] to clinical trials in intractable epilepsies such as West syndrome and Lennox-Gastaut syndrome, with none of the reported morbidity or mortality seen with current therapy.…”

Section: Introductionmentioning

confidence: 99%

Attenuation of Kindled Seizures by Intranasal Delivery of Neuropeptide-Loaded Nanoparticles

2009

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Summary: Thyrotropin-releasing hormone (TRH; Protirelin), an endogenous neuropeptide, is known to have anticonvulsant effects in animal seizure models and certain intractable epileptic patients. Its duration of action, however, is limited by rapid tissue metabolism and the blood-brain barrier. Direct nose-tobrain delivery of neuropeptides in sustained-release biodegradable nanoparticles (NPs) is a promising mode of therapy for enhancing CNS neuropeptide bioavailability. To provide proof of principle for this delivery approach, we used the kindling model of temporal lobe epilepsy to show that 1) TRH-loaded copolymer microdisks implanted in a seizure focus can attenuate kindling development in terms of behavioral stage, afterdischarge duration (ADD), and clonus duration; 2) intranasal administration of an unprotected TRH analog can acutely suppress fully kindled seizures in a concentration-dependent manner in terms of ADD and seizure stage; and 3) intranasal administration of polylactide nanoparticles (PLA-NPs) containing TRH (TRH-NPs) can impede kindling development in terms of behavioral stage, ADD, and clonus duration. Additionally, we used intranasal delivery of fluorescent dye-loaded PLA-NPs in rats and application of dye-loaded or dye-attached NPs to cortical neurons in culture to demonstrate NP uptake and distribution over time in vivo and in vitro respectively. Also, a nanoparticle immunostaining method was developed as a procedure for directly visualizing the tissue level and distribution of neuropeptide-loaded nanoparticles. Collectively, the data provide proof of concept for intranasal delivery of TRH-NPs as a viable means to 1) suppress seizures and perhaps epileptogenesis and 2) become the lead compound for intranasal anticonvulsant nanoparticle therapeutics.

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The identification of thyrotropin releasing hormone (TRH) in hypothalamic and extrahypothalamic loci of the human nervous system

Cited by 99 publications

References 17 publications

Evaluation of the effect of thyrotropin releasing hormone (TRH) on regional cerebral blood flow in spinocerebellar degeneration using 3DSRT

Evaluation of the effect of thyrotropin releasing hormone (TRH) on regional cerebral blood flow in spinocerebellar degeneration using 3DSRT

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

Attenuation of Kindled Seizures by Intranasal Delivery of Neuropeptide-Loaded Nanoparticles

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