scholarly journals Brain Delivery of Thyrotropin-Releasing Hormone via a Novel Prodrug Approach

Pharmaceutics ◽  
2019 ◽  
Vol 11 (7) ◽  
pp. 349 ◽  
Author(s):  
Katalin Prokai-Tatrai ◽  
Daniel L. De La Cruz ◽  
Vien Nguyen ◽  
Benjamin P. Ross ◽  
Istvan Toth ◽  
...  
Keyword(s):  
Brain Homogenate ◽  
Thyrotropin Releasing Hormone ◽  
Metabolic Stability ◽  
Antidepressant Effect ◽  
Brain Delivery ◽  
Small Peptides ◽  
Releasing Hormone ◽  
Membrane Affinity

Using thyrotropin-releasing hormone (TRH) as a model, we explored whether synergistic combination of lipoamino acid(s) and a linker cleaved by prolyl oligopeptidase (POP) can be used as a promoiety for prodrug design for the preferential brain delivery of the peptide. A representative prodrug based on this design principle was synthesized, and its membrane affinity and in vitro metabolic stability, with or without the presence of a POP inhibitor, were studied. The in vivo formation of TRH from the prodrug construct was probed by utilizing the antidepressant effect of the peptide, as well as its ability to increase acetylcholine (ACh) synthesis and release. We found that the prototype prodrug showed excellent membrane affinity and greatly increased metabolic stability in mouse blood and brain homogenate compared to the parent peptide, yet a POP inhibitor completely prevented prodrug metabolism in brain homogenate. In vivo, administration of the prodrug triggered antidepressant-like effect, and microdialysis sampling showed greatly increased ACh release that was also antagonized upon a POP inhibitor treatment. Altogether, the obtained promising exploratory data warrant further investigations on the utility of the prodrug approach introduced here for brain-enhanced delivery of small peptides with neurotherapeutic potential.

Effects of triiodothyronine, triiodothyroacetic acid, iopanoic acid and iodide on the thyrotropin-releasing hormone-induced thyrotropin release from superfused rat pituitary fragments

1991 ◽  
Vol 125 (4) ◽  
pp. 427-434 ◽  
Author(s):  
I. Szaboles ◽  
H. Schultheiss ◽  
H. Astier ◽  
F. A. Horster
Keyword(s):  
Potassium Iodide ◽  
Inhibitory Effect ◽  
Thyrotropin Releasing Hormone ◽  
Detectable Effect ◽  
Releasing Hormone ◽  
Iopanoic Acid ◽  
Rat Pituitary ◽  
High Concentrations

Abstract. The effects of triiodothyronine, triiodothyroacetic acid, iopanoic acid and potassium iodide were investigated on basal and stimulated thyrotropin release in an in vitro experimental model. Rat pituitary fragments were superfused by Medium-199 with or without T3 (10−7 mol/l), triiodothyroacetic acid (10−8-10−6 mol/l), iopanoic acid (10−7-10−5 mol/l) or potassium iodide (10−7-10−4 mol/l). This was followed by a 6-min pulse of thyrotropin-releasing hormone (10−8 mol/l). TSH was measured in 3-min fractions. The TRH-induced TSH release from the pituitary fragments was inhibited by T3 (10−7 mol/l), by triiodothyroacetic acid (10−7-10−6 mol/l), and by high concentrations of iodide (10−4 or 10−5 mol/l). Iopanoic acid had no significant effect at the concentrations tested. It is assumed that in vitro, and at similar concentrations, the inhibitory effect of triiodothyroacetic acid on the TRH-induced TSH secretion is comparable to that of T3, whereas iopanoic acid may have no direct detectable effect. In contrast, a direct inhibitory effect of inorganic iodide, at least in pharmacological concentrations in vivo, cannot be excluded.

Thyrotropin-releasing hormone (TRH) binding sites and thyrotropin response to TRH are regulated by thyroid hormones in human thyrotropic adenomas

1994 ◽  
Vol 130 (6) ◽  
pp. 559-564 ◽  
Author(s):  
Michèle Le Dafniet ◽  
Anne-Marie Brandi ◽  
Michèle Kujas ◽  
Philippe Chanson ◽  
Françoise Peillon
Keyword(s):  
Membrane Proteins ◽  
Thyroid Hormones ◽  
Binding Sites ◽  
Thyrotropin Releasing Hormone ◽  
Surgical Removal ◽  
Releasing Hormone ◽  
Vitro Effect ◽  
Perifusion System

Le Dafniet M, Brandi A-M, Kujas M, Chanson P, Peillon F. Thyrotropin-releasing hormone (TRH) binding sites and thyrotropin response to TRH are regulated by thyroid hormones in human thyrotropic adenomas. Eur J Endocrinol 1994:130:559–64. ISSN 0804–4643 In order to see whether, in thyrotropic adenomas with thyrotoxicosis, plasma thyroid hormones regulate the thyrotropin-releasing hormone (TRH) binding sites and the thyrotropin (TSH) response to TRH, we investigated: the presence of TRH binding sites in two cases of thyrotropic adenomas associated with hyperthyroidism and in one case of thyrotropic adenoma secondary to thyroid failure; and the in vitro effect, in a perifusion system, of triiodothyronine (T3) on the response of TSH to TRH in three cases of TSH-secreting adenomas associated with hyperthyroidism. The TRH binding sites were absent in the adenomas associated with high levels of circulating thyroid hormones, whereas they were present in the adenoma secondary to primary thyroid failure (K4 =47 nmol/l, Bmax = 40 nmol/ kg membrane proteins). In vitro, the three adenomas spontaneously released TSH in the perifusion medium (1.49 ±0.06 (mean ± sem), 7.25±0.12 and 16.73±0.36 mIU·−1·106 cells−1·2 min−1) and exhibited an ample TSH response to 10−7 mol/l TRH pulses. In two cases, tumoral secretion of fragments was compared with those of fragments maintained since the time of surgical removal in the presence of 10−8 mol/l T3. The TSH responses to TRH were abolished in the presence of T3 in these two cases. We conclude that thyrotropic adenomas associated with hyperthyroidism are still controlled in vivo by T3. In particular, T3 regulates the TSH response to TRH, probably via a down-regulation of the TRH binding sites. Michèle Le Dafniet, Unité INSERM 223, Faculté de Médecine, Pitié-Salpêtrière, 105 Boulevard de l'Hôpital, 75013 Paris, France

A cryptic peptide (160-169) of thyrotropin-releasing hormone prohormone demonstrates biological activity in vivo and in vitro.

Endocrinology ◽  
1992 ◽  
Vol 131 (6) ◽  
pp. 2653-2658 ◽  
Author(s):  
F E Carr ◽  
H G Fein ◽  
C U Fisher ◽  
M W Wessendorf ◽  
R C Smallridge
Keyword(s):  
Biological Activity ◽  
Thyrotropin Releasing Hormone ◽  
Releasing Hormone ◽  
Cryptic Peptide

scholarly journals Thyrotropin Releasing Hormone(TRH)-Induced Release of 7B2 (A Neuroendocrine Polypeptide) In Vivo and In Vitro Using Adenoma Cells of a Patient with Acromegaly.

1991 ◽  
Vol 30 (3) ◽  
pp. 208-212 ◽  
Author(s):  
Shoichi NATORI ◽  
Haruo IGUCHI ◽  
Masao OHASHI ◽  
Tetsuyuki KITAMOTO ◽  
Michel CHRÉTIEN ◽  
...  
Keyword(s):  
Thyrotropin Releasing Hormone ◽  
Releasing Hormone
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