Perspectives in Pharmacology The Thyrotropin-Releasing Hormone (TRH) Hypothesis of Homeostatic Regulation: Implications for TRH-Based Therapeutics

The functions of thyrotropin-releasing hormone (TRH) in the central nervous system (CNS) can be conceptualized as performed by four anatomically distinct components that together comprise a general TRH homeostatic system. These components are 1) the hypothalamic-hypophysiotropic neuroendocrine system, 2) the brainstem/midbrain/spinal cord system, 3) the limbic/cortical system, and 4) the chronobiological system. We propose that the main neurobiological function of TRH is to promote homeostasis, accomplished through neuronal mechanisms resident in these four integrated systems. This hypothesis offers a unifying basis for understanding the myriad actions of TRH and TRH-related drugs already demonstrated in animals and humans. It is consistent with the traditional role of TRH as a regulator of metabolic homeostasis. An appreciation of the global function of TRH to modulate and normalize CNS activity, along with an appreciation of the inherent limitations of TRH itself as a therapeutic agent, leads to rational expectations of therapeutic benefit from metabolically stable TRH-mimetic drugs in a remarkably broad spectrum of clinical situations, both as monotherapy and as an adjunct to other therapeutic agents. The actions of TRH are numerous and varied. This has been viewed in the past as a conceptual and practical impediment to the development of TRH analogs. Herein, we alternatively propose that these manifold actions should be considered as a rational and positive impetus to the development of TRH-based drugs with the potential for unique and widespread applicability in human illness. Thyrotropin-releasing hormone (pGlu-His-Pro-NH2) was the first hypothalamic releasing factor to be identified. Soon after this seminal event, however, it was clear that the biological functions of TRH extend far beyond regulation of the thyroid axis. Greater than two-thirds of immunoreactive TRH in the CNS is detected outside the thyrotropic zone of the hypothalamus (Winokur and Utiger, 1974). Consistent with this widespread distribution, TRH has been implicated in the regulation of arousal, autonomic function, control of circadian rhythmicity, endotoxic and hemorrhagic shock, mood, pain perception, seizure activity, and spinal motor function (Nillni and Sevarino, 1999). As this new information emerged, clinical trials have proceeded to test TRH as a treatment for various disorders including depression, schizophrenia, amyotrophic lateral sclerosis (ALS), and spinocerebellar degeneration (SCD; Griffiths, 1986). Possibly reflecting the consistent use of a metabolically stable TRH analog, trials in SCD have been generally positive. In other conditions, generally employing TRH, early trials showed promise although later trials produced inconsistent results. This variability may reflect the fact that native TRH is poorly suited as a therapeutic agent. It has low bioavailability, and its half-life in plasma is about 5 min. Herein, we first review data concerning the neurobiological mechanisms of TRH systems, and we suggest a new anatomical and functional framework in which to conceptualize these systems. Next, we describe findings related to physiological and behavioral effects of TRH that collectively support Article, publication date, and citation information can be found at http://jpet.aspetjournals.org. DOI: 10.1124/jpet.102.044040. ABBREVIATIONS: TRH, thyrotropin-releasing hormone; CNS, central nervous system; ALS, amyotrophic lateral sclerosis; SCD, spinocerebellar degeneration; TSH, thyrotropin-stimulating hormone; SCN, suprachiasmatic nucleus; ALS, amyotrophic lateral sclerosis. 0022-3565/03/3052-410–416$7.00 THE JOURNAL OF PHARMACOLOGY AND EXPERIMENTAL THERAPEUTICS Vol. 305, No. 2 Copyright © 2003 by The American Society for Pharmacology and Experimental Therapeutics 44040/1062088 JPET 305:410–416, 2003 Printed in U.S.A. 410 at A PE T Jornals on A ril 9, 2017 jpet.asjournals.org D ow nladed from a new perspective on TRH as a CNS homeostatic modulator. After a brief discussion of clinical trials of TRH and the development of various TRH analogs, we propose that this new understanding of the physiological role of TRH systems provides a rationale for new therapeutic applications for TRH-based drugs. Like many other neuroactive peptides, TRH is thought to subserve neurotransmitter or neuromodulatory functions that affect neuronal excitability (Dettmar and Metcalf, 1981). Consistent with this notion are data documenting that: • TRH is enzymatically processed from a larger precursor, prepro-TRH, which contains multiple copies of the TRH progenitor sequence as well as several distinct non-TRH products. • TRH is widely distributed in anatomically distinct pathways throughout the neuroaxis. • TRH is stored as a regulated releasable pool in secretory granules in synaptic terminals and is selectively degraded by specific enzymes. • TRH interacts with at least two known G-protein coupled receptors, TRH-R1 and TRH-R2. Signaling occurs mainly through the phosphoinositide-specific phospholipase C pathway, with subsequent elevations in intracellular calcium, modulation of K -channel conductances, etc. Greater diversity in TRH signaling may occur via a putative third TRH receptor subtype recently described in Xenopus, although affinity data cast doubt as to whether the endogenous ligand(s) for this receptor is TRH (Bidaud et al., 2002). A more precise and conventional understanding of the CNS functions of TRH is impeded by the lack of known selective and potent isosteric TRH receptor antagonists. Much of the above information has been reviewed (Nillni and Sevarino, 1999; Gershengorn and Osman, 2001). In the following paragraphs, we provide a new synthesis of this and other information that supports novel therapeutic possibilities for TRH analogs. Neurobiology of TRH-Mediated Homeostasis In this section, data about the regional anatomical distribution of TRH systems and the diverse physiological and behavioral effects produced by TRH are reviewed. Figure 1 presents a schematic depiction of the proposed TRH homeostatic system. Four distinct yet functionally integrated components of this system are conceptualized: the hypothalamichypophysiotropic neuroendocrine system, the brainstem/ midbrain/spinal cord system, the limbic/cortical system, and the chronobiological system. We hypothesize that these components of the TRH homeostatic system function in a coordinated fashion to normalize the intensity and quality of CNS