Peptidase Inactivation of Hypothalamic Releasing Hormones

Abstract

With the structural characterization of the hypothalamic hormones, luteinizing hormone-releasing hormone (LH-RH), thyrotrophin-releasing hormone (TRH), melanocyt-stimulating hormone release-inhibiting hormone (MIH), and growth hormone release-inhibiting hormone, (GH-RIH or somatostatin), it has been possible to investigate their enzymic inactivation by peptidases which are present at various sites in the body. Enzymes may play an important part in the control of polypeptide hormone levels and the peptidases acting on these four hypothalamic hormones may regulate the amount of TRH, LH-RH, MIH and somatostatin released from the hypothalamus, or their action at the level of the pituitary and their removal from the circulation. By studying the peptidase enzymes, further information may be obtained on the physiological mechanisms controlling the secretion and actions of hypothalamic hormones, as well as on the design of analogues with increased or competitive activity.

Inactivation of Two Hyperactive LH-RH Analogues by Rat Hypothalamic Peptidases

“…Since both LH-RH analogues have proved to be less susceptible to the action of the hypothalamic peptidases, and because they have structural alterations at the proposed sites of enzyme action (Griffiths, 1976), this would strongly suggest that cleavage of the -Gly-Leu-and Pro-Gly NH2 bonds could be tire initial mechanism of LH-RH inactivation. The hypothalamic peptidases acting on LH-RH would appear to be relatively specific for these bonds as both C-and N-terminal ends of the decapeptide are made unavailable for general peptidase action by the amide and pyroGlu-groups (Marks, 1976).…”

“…However, the therapeutic value of this decapeptide hormone is limited by its short half-life, which has been measured as having an initial component of 4 -7 min and a second component of 2 5-50 min (Griffiths, 1976). Several attempts have been made to overcome this problem by the design and synthesis of hyperactive LH-RH analogues: one of the first was produced by replacing the C-terminal glycinamide (position 10) with ethylamide, EA (Rippel et al, 1973), and since then, modifications of position 6 with D-instead of ¿-amino acid residues have proved very successful in increasing the activity of LH-RH (Monahan et al, 1973;Fujino et al, 1974;Coy et al, 1976).…”

“…Hypothalamic peptidases inactivating LH-RH have been demonstrated by several groups (see Griffiths, 1976). It is believed that these peptidases may act on the decapeptide, primarily by cleaving the -Gly-Leu-bond (positions 6 and 7) and the Pro-Gly NH2 bond (positions 9 and 10) {Griffiths et , 1975Koch et al, 1974;Marks and Stern, 1974).…”

Effect of rovatirelin, a novel thyrotropin-releasing hormone analog, on the central noradrenergic system

“…To date, TRH has been clinically investigated for the treatment of spinocerebellar degeneration (SCD), which is a progressive neurodegenerative disorder causing motor dysfunction (Sobue et al, 1983) and has been approved for use in Japan on patients with SCD. However, TRH has certain limitations as a clinical treatment for SCD due to its short biological half-life (4-5 min) in humans, as well as low intestinal and blood-brain barrier permeability (Bassiri and Utiger, 1973;Griffiths, 1976;Kinoshita et al, 1998;Khomane et al, 2011). On the other hand, taltirelin, a metabolically stable TRH analog, has relatively good bioavailability; oral administration of taltirelin is more potent and longer lasting than TRH in stimulating the CNS-mediated actions in normal mice and improving motor dysfunction in SCD model mice (Yamamura et al, 1990;Kinoshita et al, 1995Kinoshita et al, , 1998.…”

Further studies on the inactivation of thyrotrophin releasing hormone (TRH) by enzymes in the rat hypothalamus

“…There have been several reports on hypothala¬ mic enzymes inactivating TRH (see Griffiths 1976;Griffiths & Kelly 1979): -the enzymes involved have proved to be a considerable problem in stu¬ dies of TRH biosynthesis in vitro, since they inter¬ fere with the measurement of TRH formation by degrading the TRH produced in the systems used (Bauer & Lipmann 1976;McKelvy & GrimmJ0rgensen 1977). Attempts have been made to overcome this difficulty by using clonal cell cultures with little inherent enzyme activity or by employing specific enzyme inhibitors (see McKelvy & GrimmJ0rgensen 1977).…”