Abstract
Thyrotropin releasing hormone (TRH: Glp-His-Pro-NH2) is a peptide mainly produced by brain neurons. In mammals, hypophysiotropic TRH neurons of the paraventricular nucleus of the hypothalamus integrate metabolic information and drive the secretion of thyrotropin from the anterior pituitary, and thus the activity of the thyroid axis. Other hypothalamic or extrahypothalamic TRH neurons have less understood functions although pharmacological studies have shown that TRH has multiple central effects, such as promoting arousal, anorexia and anxiolysis, as well as controlling gastric, cardiac and respiratory autonomic functions. Two G-protein-coupled TRH receptors (TRH-R1 and TRH-R2) transduce TRH effects in some mammals although humans lack TRH-R2. TRH effects are of short duration, in part because the peptide is hydrolyzed in blood and extracellular space by a M1 family metallopeptidase, the TRH-degrading ectoenzyme (TRH-DE), also called pyroglutamyl peptidase II. TRH-DE is enriched in various brain regions but is also expressed in peripheral tissues including the anterior pituitary and the liver, which secretes a soluble form into blood. Among the M1 metallopeptidases, TRH-DE is the only member with a very narrow specificity; its best characterized biological substrate is TRH, making it a target for the specific manipulation of TRH activity. Two other substrates of TRH-DE, Glp-Phe-Pro-NH2 and Glp-Tyr-Pro-NH2, are also present in many tissues. Analogs of TRH resistant to hydrolysis by TRH-DE have prolonged central efficiency. Structure-activity studies allowed the identification of residues critical for activity and specificity. Research with specific inhibitors has confirmed that TRH-DE controls TRH actions. TRH-DE expression by β2-tanycytes of the median eminence of the hypothalamus allows the control of TRH flux into the hypothalamus-pituitary portal vessels and may regulate serum thyrotropin secretion. In this review we describe the critical evidences that suggest that modification of TRH-DE activity in tanycytes, and/or in other brain regions, may generate beneficial consequences in some central and metabolic disorders and identify potential drawbacks and missing information needed to test these hypotheses.
Highlights
Thyrotropin releasing hormone (TRH; Glp-His-Pro-NH2) is a small peptide expressed mainly in the brain, secreted by neurons
The best-known function of TRH is the control of the hypothalamus–pituitary–thyroid (HPT) axis; TRH is synthesized by processing of a protein precursor in neurons of the paraventricular nucleus of the hypothalamus (PVN) that project their terminal boutons into the median eminence
With the available information of the wide distribution of TRH receptors, and the multiple functions TRH displays, the pharmacological use of agonists of the TRH-R1 receptors that resist degradation by TRH-degrading ectoenzyme (TRH-DE) might impact on many functions
Summary
Thyrotropin releasing hormone (TRH; Glp-His-Pro-NH2) is a small peptide expressed mainly in the brain, secreted by neurons. With simultaneous substitution of Glp by pyrazine-2-carboxylic acid (2-Pyz) and central His with C3H7 (2-Pyz-L-His(1-alkyl)-L-Pro-NH2), exhibits high selectivity towards TRH-R2 but poor potency compared to TRH, high stability in rat blood plasma, antagonizes pentobarbital-induced sleeping time with a higher potency than TRH, and is devoid of adverse cardiovascular and CNS effects (Meena et al, 2015) Another class of TRH derivative corresponds to those that have dual pharmacological activity, acting both as inhibitor of TRH-DE and as receptor agonist. The replacement of the hydrophobic L-amino acid residues with their Disomers in C-terminally extended analogs of Glp-Asn-ProNH2 led to Glp-Asn-Pro-D-Tyr-D-Trp-NH2 (named JAK4D), which is effective at producing and potentiating some central actions of TRH without evoking TSH release in vivo This peptide has high plasma stability and combined potent inhibition of TRH-DE (Ki 151 nM) with high affinity binding to central TRH receptors (Ki 6.8 nM). Hippocamposeptal projection, cortex/hippocampus Nucleus of the solitary tract Myenteric plexus of small intestine Subiculum/Cortex Hippocampus CA3 Lateral cortex layer 6: gustatory, barrel field, auditory Superior Coliculus Cortical pyramidal layer 4 Hippocampus interneurons Interneuron-selective interneurons, cortex/ hippocampus Cortical pyramidal layer 6b Cortical pyramidal layer 6 Entorhinal superficial layers Spinal cord, Dorsal cord lamina 2-5 Inhibitory neurons, hindbrain Septal nucleus, Meissnert and diagonal band Cerebral cortex Cortical pyramidal layer 6 Paragigantocellular reticular nucleus Neuroblasts, olfactory bulb Striatum/Amygdala Inhibitory neurons, midbrain Spinal cord, Dorsal cord lamina 2-5 Lateral hypothalamus Piriform cortex Septal nucleus Inhibitory neurons, spinal cord Basket and bistratified cells, cortex/hippocampus Cingulate/retrospenial area, layer 5 Dorsal root ganglion Sleep-active interneurons, cortex/hippocampus Interneuron-selective interneurons, cortex/ hippocampus Cortical pyramidal layer 5 Cortical pyramidal layer 2/3 Piriform cortex, pyramidal neurons Interneuron-selective interneurons, hippocampus Nucleus of the solitary tract Hippocampus CA1 Cingulate/retrospenial area, layer 2 Arcuate nucleus of the hypothalamus Inner horizontal cell, olfactory bulb Superior olivary complex
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