Pharmacology of Thyrotropin-Releasing Hormone

Horita, A.; Carino, M.A.; Lai, Hoang M.

doi:10.1146/annurev.pa.26.040186.001523

Cited by 181 publications

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“…TRH receptors have been found in many areas of the CNS, the highest densities being present in limbic structures such as the amygdala, hippocampus and hypothalmus, and lower densities in the brain stem and cerebellum (Pilotte et al, 1984;Simasko & Horita, 1982). These findings suggest that TRH, in addition to its hormonal activity, plays a role as a neurotransmitter and/or modulator of other neurotransmitter agents (Horita et al, 1986). In particular TRH stimulates the turnover of acetylcholine (ACh) in the parietal cortex of freely moving rats (Malthe-Sorenssen et al, 1978), and in the hippocampus of pentobarbitone-anaesthetized rats (Brunello & Cheney, 1981).…”

Section: Introductionmentioning

confidence: 99%

“…In particular TRH stimulates the turnover of acetylcholine (ACh) in the parietal cortex of freely moving rats (Malthe-Sorenssen et al, 1978), and in the hippocampus of pentobarbitone-anaesthetized rats (Brunello & Cheney, 1981). Since intraseptal injections of TRH antagonize pentobarbitone-induced depression of ACh turnover and the anaesthetic action of this barbiturate (Brunello & Cheney, 1981), it appears that TRH would stimulate the activity of forebrain cholinergic neurones to elicit behavioural arousal (Horita et al, 1986). A role of cholinergic mechanisms in the behavioural effect of TRH is also indicated by the finding that the TRH-induced arousal in pentobarbitone-anaesthetized rats is blocked by atropine (Kalivas & Horita, 1983).…”

Section: Introductionmentioning

confidence: 99%

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Effect of thyrotropin releasing hormone (TRH) on acetylcholine release from different brain areas investigated by microdialysis

Giovannini

Casamenti

Nistri

et al. 1991

British J Pharmacology

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The effect of thyrotropin releasing hormone (TRH) administration upon acetylcholine (ACh) release in freely moving rats was investigated by means of transversal microdialysis coupled to h.p.l.c. TRH administered either s.c. or via local perfusion increased the ACh release from the cortex and hippocampus but not from the striatum. The increase in ACh release was maintained after 7 days of s.c. administration of TRH. 2 After s.c. injection of the neuropeptide, the increase in ACh release was dose-dependent and reached a maximum at 40{min after administration. The maximal percentage increases were 18, 52, 66 and 89% at doses of 1, 2.5, 5 and lOmgkg-' and 35, 48 and 54% at doses of 2.5, 5 and lOmgkg-' in the cortex and hippocampus, respectively. The effect of TRH was dependent on neuronal activity since it was completely inhibited by perfusion with tetrodotoxin (TTX), 5 x 10-7 M.3 Perfusion with TRH, 2.5 pgpul-1, caused 198% and 150% increase in ACh release 60 and 80min after the beginning of the perfusion in the cortex and hippocampus, respectively. After this initial peak, a 100% increase in ACh release persisted throughout the perfusion. 4 Systemic TRH administration was followed by marked hyperactivity and stereotyped behaviour that showed a time course shorter than that of the increase in ACh release. 5 These findings demonstrate that TRH exerts a strong stimulant action on cortical and hippocampal cholinergic pathways.

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Section: Introductionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Effect of thyrotropin releasing hormone (TRH) on acetylcholine release from different brain areas investigated by microdialysis

Giovannini

Casamenti

Nistri

et al. 1991

British J Pharmacology

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“…Various effects of TRH on several neurotransmitter systems have been proposed and its effects on neuronal activity have been described (Yarbrough, 1979;Horita et al, 1986). The mechanisms by which TRH produces cerebral vasodilatation are not fully understood.…”

Section: Introductionmentioning

confidence: 99%

Effects of N^G‐nitro‐l‐arginine methyl ester on the cardiovascular system of the anaesthetized rabbit and on the cardiovascular response to thyrotropin‐releasing hormone

Seligsohn

Bill

1993

British J Pharmacology

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1 The effects of 300 mg kg-' of the nitric oxide (NO) inhibitor NG-nitro-L-arginine methyl ester (L-NAME) on the regional blood flow, on the flow response to 1 mg kg-' of thyrotropin-releasing hormone (TRH) and on cerebral blood flow autoregulation were studied in urethane anaesthetized rabbits subjected to unilateral sectioning of the cervical sympathetic chain. The blood flow measurements were performed by the tracer microspheres method. 2 The cerebral arteriovenous difference in oxygen saturation (CAVOD) was measured before and after the administration of L-NAME and TRH in order to ascertain whether the effects on cerebral blood flow that were observed were secondary to changes in cerebral metabolism. 3 L-NAME caused a significant decrease in blood flow in several cerebral regions; CBF,O, decreased to 72 ± 4% of control (P < 0.001). An increase in blood pressure and a concurrent decrease in heart rate and cardiac output were noted. 4 In the eye, L-NAME caused a reduction in uveal blood flow which was more pronounced on the sympathetically intact side; in the retina the blood flow decreased to 50% of control on both sides. 5 The administration of TRH in animals pretreated with L-NAME caused a significant increase in blood pressure and cerebral blood flow. 6 In L-NAME-treated animals the CBF was not affected when the mean arterial blood pressure was increased by ligation of the abdominal aorta. 7 The CAVOD increased from 56.0 ± 5.2 to 73.6 ± 3.5%, 20 min after the administration of L-NAME.In animals given 1 mg kg-' TRH after L-NAME the CAVOD decreased to 54.6 ± 4.6%, 5 min after the injection of TRH. 8 The results of the present study indicate that endogenous NO is involved in the regulation of regional blood flow and blood pressure in the anaesthetized rabbit. The reduction in cerebral blood flow that was caused by L-NAME was not due to a reduction in cerebral metabolism. An interaction between the NO synthesis/release/effect and the sympathetic nervous system was found in the uvea. There was no evidence for a major involvement of NO in the cardiovascular responses to TRH and autoregulation of cerebral blood flow was not abolished by L-NAME.

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“…Although first recognized as a hypothalamic regulatory hormone, TRH is now believed to function as a neurotransmitter and/or neuromodulator within the central nervous system (15,16) where it displays a broad spectrum of stimulatory actions independent of its neuroendocrine functions (15Ϫ17). Based on its central nervous system effects, TRH has been found to have potential use in the treatment of brain and spinal injury (18,19) and several central nervous system disorders, including spinocerebellar degeneration, cognitive deficits, and spinal cord pain transmission (16,17).…”

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confidence: 99%

Kinetic Investigation of the Specificity of Porcine Brain Thyrotropin-releasing Hormone-degrading Ectoenzyme for Thyrotropin-releasing Hormone-like Peptides

Kelly¹,

Slator²,

Tipton³

et al. 2000

Journal of Biological Chemistry

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Evidence indicates that neuronally released thyrotropin-releasing hormone (TRH) is selectively inactivated by TRH-degrading ectoenzyme (TRH-DE) (EC 3.4.19.6). TRH-DE inhibitors may be used to enhance the therapeutic actions of TRH and to investigate the functions of TRH and TRH-DE in the central nervous system.Although TRH-DE appears to exhibit a high degree of specificity toward TRH, systematic specificity studies, which would facilitate inhibitor design, have not been previously conducted for this enzyme. In this paper we present the first description of TRH-DE specificity across a directed peptide library in which the histidyl (P 1 ) residue of TRH was replaced by a series of amino acids. Peptides were synthesized using standard solid phase chemistry. Kinetic parameters were measured either by continuous or discontinuous fluorometric assays or by quantitative high pressure liquid chromatography. The P 1 residue was found to influence significantly both the ability of the peptides to bind to TRH-DE, as measured by their K i values, and the ability of TRH-DE to catalyze their hydrolysis. Moderately bulky, uncharged P 1 residues were found to bind preferentially to TRH-DE. Results from this screen provide valuable information for the development of TRH-DE inhibitors and have led to the identification of two potent, reversible TRH-DE inhibitors, L-pyroglutamyl-L-asparaginyl-L-prolineamide (K i ‫؍‬ 17.5 M) and Glp-AsnPro-7-amido-4-methyl coumarin (K i ‫؍‬ 0.97 M). Thyrotropin-releasinghormone-degrading ectoenzyme (TRH-DE) 1 (EC 3.4.19.6) is a type II cell surface peptidase located on synaptosomal membranes in the central nervous system (1Ϫ4). TRH-DE catalyzes the hydrolysis of the Glp-His bond in thyrotropin-releasing hormone (TRH), a tripeptide with the amino acid sequence L-pyroglutamyl-L-histidyl-L-prolineamide (Glp-His-ProNH 2 ) (5Ϫ10). This enzyme is strategically placed to play a significant role in extracellular inactivation of TRH, and current evidence strongly indicates that TRH-DE is the principal enzyme responsible for terminating the actions of neuronally released TRH (11Ϫ14).Although first recognized as a hypothalamic regulatory hormone, TRH is now believed to function as a neurotransmitter and/or neuromodulator within the central nervous system (15, 16) where it displays a broad spectrum of stimulatory actions independent of its neuroendocrine functions (15Ϫ17). Based on its central nervous system effects, TRH has been found to have potential use in the treatment of brain and spinal injury (18,19) and several central nervous system disorders, including spinocerebellar degeneration, cognitive deficits, and spinal cord pain transmission (16,17). The mechanisms by which TRH improves these conditions are not fully elucidated but appear to involve the potentiation by TRH of other neurotransmitter systems. Despite its promise, the use of TRH as a therapeutic agent is critically undermined by its susceptibility to proteolytic degradation (20).Compounds that potently and selectively inhibit TRH-DE may be use...

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Pharmacology of Thyrotropin-Releasing Hormone

Cited by 181 publications

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Effect of thyrotropin releasing hormone (TRH) on acetylcholine release from different brain areas investigated by microdialysis

Effect of thyrotropin releasing hormone (TRH) on acetylcholine release from different brain areas investigated by microdialysis

Effects of N^G‐nitro‐l‐arginine methyl ester on the cardiovascular system of the anaesthetized rabbit and on the cardiovascular response to thyrotropin‐releasing hormone

Kinetic Investigation of the Specificity of Porcine Brain Thyrotropin-releasing Hormone-degrading Ectoenzyme for Thyrotropin-releasing Hormone-like Peptides

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Pharmacology of Thyrotropin-Releasing Hormone

Cited by 181 publications

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Effect of thyrotropin releasing hormone (TRH) on acetylcholine release from different brain areas investigated by microdialysis

Effect of thyrotropin releasing hormone (TRH) on acetylcholine release from different brain areas investigated by microdialysis

Effects of NG‐nitro‐l‐arginine methyl ester on the cardiovascular system of the anaesthetized rabbit and on the cardiovascular response to thyrotropin‐releasing hormone

Kinetic Investigation of the Specificity of Porcine Brain Thyrotropin-releasing Hormone-degrading Ectoenzyme for Thyrotropin-releasing Hormone-like Peptides

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Effects of N^G‐nitro‐l‐arginine methyl ester on the cardiovascular system of the anaesthetized rabbit and on the cardiovascular response to thyrotropin‐releasing hormone