Thyrotropin-releasing hormone can relieve cancer-related fatigue: hypothesis and preliminary observations.

Fatigue in cancer patients is highly prevalent, predominantly idiopathic, difficult to manage, and has a significant negative impact on quality of life. Thyrotropin-releasing hormone (TRH) exerts normotrophic, state-dependent therapeutic effects in a variety of experimental and clinical situations. To evaluate TRH as a treatment for cancer-related fatigue, an ongoing randomized, placebo-controlled, crossover pilot study of breast cancer patients has been initiated and this report presents preliminary observations conducted with three of these patients over 4 consecutive weeks, thereby involving a total of six TRH treatments and six saline controls. Global assessment using both subjective and objective parameters showed that TRH exerted clear anti-fatigue effects in four of the six TRH treatments. These responses were rapid in onset and persisted through the 24 h observation period. No anti-fatigue responses were seen in five of the six saline controls. No unexpected side-effects were seen with TRH administration. These initial findings support the proposal that TRH can ameliorate cancer-related fatigue.

The thyrotropin-releasing hormone (TRH)-immune system homeostatic hypothesis.

Decades of research have established that the biological functions of thyrotropin-releasing hormone (TRH) extend far beyond its role as a regulator of the hypothalamic-pituitary-thyroid axis. Gary et al. [Gary, K.A., Sevarino, K.A., Yarbrough, G.G., Prange, A.J. Jr., Winokur, A. (2003). The thyrotropin-releasing hormone (TRH) hypothesis of homeostatic regulation: implications for TRH-based therapeutics. J Pharmacol Exp Ther 305(2):410-416.] and Yarbrough et al. [Yarbrough, G.G., Kamath, J., Winokur, A., Prange, A.J. Jr. (2007). Thyrotropin-releasing hormone (TRH) in the neuroaxis: therapeutic effects reflect physiological functions and molecular actions. Med Hypotheses 69(6):1249-1256.] provided a functional framework, predicated on its global homeostatic influences, to conceptualize the numerous interactions of TRH with the central nervous system (CNS) and endocrine system. Herein, we profer a similar analysis to interactions of TRH with the immune system. Autocrine/paracrine cellular signaling motifs of TRH and TRH receptors are expressed in several tissues and organs of the immune system. Consistent with this functional distribution, in vitro and in vivo evidence suggests a critical role for TRH during the developmental stages of the immune system as well as its numerous interactions with the fully developed immune system. Considerable evidence supports a pivotal role for TRH in the pathophysiology of the inflammatory process with specific relevance to the "cytokine-induced sickness behavior" paradigm. These findings, combined with a number of documented clinical actions of TRH strongly support a potential utility of TRH-based therapeutics in select inflammatory disorders. Similar to its global role in behavioral and energy homeostasis a homeostatic role for TRH in its interactions with the immune system is consonant with the large body of available data. Recent advances in the field of immunology provide a significant opportunity for investigation of the TRH-immune system homeostatic hypothesis. Moreover, this hypothesis may provide a foundation for the development of TRH-based therapeutics for certain medical and psychiatric disorders involving immune dysfunction.

Thyrotropin-releasing hormone (TRH) in the neuroaxis: therapeutic effects reflect physiological functions and molecular actions.

Nearly four decades of research have yielded thousands of publications on the physiology, pharmacology and therapeutic effects of TRH and TRH mimetic analogs. This work addresses both the neuroendocrine and the extrahypothalamic actions and functions of the tripeptide. The many reports of clinical effects of TRH in diverse medical conditions, unrelated to pituitary or thyroid function, can appear bewildering, as can its widespread involvement in a plethora of neuronal and physiological processes. Herein, we hypothesize that a logical and causal interrelationship exists between the fundamental molecular and cellular actions of TRH, its broader physiological functions and the therapeutic effects that attend the administration of exogenous TRH and TRH analogs. When viewed from this perspective, the basic neurobiological actions and functions of TRH provide a rational basis for understanding its diverse therapeutic effects. We posit: that the fundamental excitatory actions of TRH throughout the neuroaxis result from blocking various K+ channels linked to G-protein coupled TRH receptors in neurons and pituitary cells in distinct TRH-innervated anatomical pathways; that the functional consequences of blockade of these K+ channels are to enhance neuronal and secretory outputs in TRH regulatory circuits to modulate behavioral and energy homeostasis, and; that in clinical situations the resultant broad and useful therapeutic effects following administration of TRH reflect the state-dependent normalizing effects of activation of these regulatory circuits. In this light, the spectrum of reported clinical effects of TRH agonism remains unique and impressive but is less enigmatic. With the understanding that the neurobiological actions of TRH underlie and are rationally antecedent to its documented, extensive clinical 'normotrophic' effects, continued empirical efforts to assess the medical uses of TRH and related drugs seem rational and warranted. We predict that the range of disorders whose symptoms are alleviated by TRH therapy will continue to expand and that TRH agonism could conceivably become a near-universal therapeutic adjunct, particularly in the practice of neuropsychiatric medicine.

Molecular approaches to receptors as targets for drug discovery.

The cloning of a great number of receptors and channels has revealed that many of these targets for drug discovery can be grouped into superfamilies based on sequence and structural similarities. This review presents an overview of how molecular biological approaches have revealed a plethora of receptor subtypes, led to new definitions of subtypes and isoforms, and played a role in the development of high selective drugs. Moreover, the diversity of subtypes has molded current views of the structure and function of receptor families. Practical difficulties and limitations inherent in the characterization of the ligand binding and signaling properties of expressed recombinant receptors are discussed. The importance of evaluating drug-receptor interactions that differ with temporally transient and distinct receptor conformational states is emphasized. Structural motifs and signal transduction features are presented for the following major receptor superfamilies: ligand-gated ion channel, voltage-dependent ion channel, G-protein coupled, receptor tyrosine-kinase, receptor protein tyrosine-phosphatase, cytokine and nuclear hormone. In addition, a prototypic receptor is analyzed to illustrate functional properties of a given family. The review concludes with a discussion of future directions in receptor research that will impact drug discovery, with a specific focus on orphan receptors as targets for drug discovery. Methods for classifying orphan receptors based upon homologies with members of existing superfamilies are presented together with molecular approaches to the greater challenge of defining their physiological roles. Besides revealing new orphan receptors, the human genome sequencing project will result in the identification of an abundance of novel receptors that will be molecular targets for the development of highly selective drugs. These findings will spur the discovery and development of an exciting new generation of receptor-subtype specific drugs with enhanced therapeutic specificity.

Cell receptors as drugs. Ligand binding domains of receptors as drugs: a potential new class of therapeutic agents.

Modern technology applied to the study of receptor proteins has revealed that distinct structural domains of these molecules subserve different functions. With many receptors it is known that a soluble, extracellular portion of the molecule is responsible for the recognition and binding of endogenous or exogenous ligands. This binding is the initial event in signal transduction for cell-to-cell communication. Some of these soluble, extracellular ligand binding domains of various receptors have been genetically cloned, expressed and pharmacologically evaluated. The preclinical data available to date suggest that these portions of receptor molecules represent potentially useful new therapeutic agents.

Prospective strategies for cholinergic interventions in Alzheimer's disease.

The cholinergic hypothesis of memory dysfunction has guided most of the recent proposals for treating the primary symptoms of AD. The efficacy of these treatments has been severely limited. This review examines two major lines of evidence which suggest that the cholinergic hypothesis may have to be expanded and revised. The cholinergic hypothesis focuses on pre-synaptic defects. It assumes cholinoceptive neurons would function normally with adequate stimulation. Evidence is not sufficient to support this assumption. In addition, dissociations have been demonstrated between muscarinic receptor number and functional response of cholinoceptive neurons. Various measures are proposed to investigate the functional integrity of muscarinic receptors in AD patients. AD often has been characterized as a disorder produced by generalized cholinergic hypoactivity. Evidence for cortisol hypersecretion, abnormal dexamethasone suppression, and the occurrence of depressive symptoms, motoric dysfunction and sleep abnormalities in AD patients is more consistent with regional cholinergic hyperactivity than generalized hypoactivity. Resolution of these discrepancies could shed new light on the pathophysiology and treatment strategies for AD. Cholinoceptive neurons could be hypersensitive, subsensitive or have unaltered responsivity. These options would have very different treatment implications. New developments in outcome assessment which are capable of discriminating varieties of differential response to treatment can spur treatment development and improve quality of care for patients with complex disorders such as AD.

The therapeutic potential of thyrotropin releasing hormone (TRH) in Alzheimer's disease (AD).

In recent years it has been established that patients with AD have a relatively specific loss of cerebral cortical and hippocampal cholinergic nerve terminals. This may be a reflection of degeneration of cholinergic neurons originating in the nucleus basalis of Meynert and septum which project to the cortex and hippocampus, respectively. In view of the long-standing association of cholinergic mechanisms with cognitive processes and the recognition of selective cholinergic deficits in AD, therapeutic attempts to enhance CNS cholinergic function have been undertaken in patients with AD. While only limited success with this strategy has been achieved to date, the use of TRH may offer a novel, yet rational, approach to treating AD. This assumption is predicated on the extensive literature documenting unique, facilitatory interactions of this peptide with cholinergic neurons throughout the neuraxis. Furthermore, the same rationale may account for the recently reported therapeutic benefit of TRH in patients with amyotrophic lateral sclerosis, which like AD, is a disease whose symptoms are manifested through a progressive degeneration of a subpopulation of CNS cholinergic neurons.

A comparative electrophysiological and biochemical assessment of serotonin (5-HT) and a novel 5-HT agonist (MK-212) on central serotonergic receptors.

The inhibitory effects of microiontophoretically-applied serotonin (5-HT) and 6-chloro-2[1-piperazinyl]pyrazine (MK-212) were examined on spontaneously firing somatosensory cerebral cortical neurons and dorsal raphe neurons in rats anesthetized with chloral hydrate. On cortical neurons, MK-212 caused only weak and variable inhibition of extracellularly recorded neuronal activity, compared to the effects of 5-HT. However, on raphe cells, MK-212 exerted potent inhibitory effects, equivalent to those observed with 5-HT. In contrast to the inhibitory actions of D-lysergic acid diethylamide (LSD) and 5-HT at presumed 5-HT autoreceptors, MK-212 did not affect the in vitro release of [3H]5-HT from slices of rat hypothalamus stimulated by methiothepin. These findings, coupled with previously reported behavioral, biochemical and electrophysiological effects of MK-212 may indicate that this novel serotonergic agonist uniquely discriminates between subsets of serotonergic receptors in the CNS.

Pharmacologic profile of a novel potent direct-acting dopamine agonist, (+)-4-propyl-9-hydroxynaphthoxazine [(+)-PHNO].

The (+)-enantiomer of 1,2,3,4a,5,6-hexahydro-9-hydroxy-4-n-propyl-4H-naphth[1,2-b][ 1,4]-oxazine [(+)-PHNO] is demonstrated to be a potent and direct dopamine (DA) agonist in several in vivo and in vitro test procedures. In vitro (+)-PHNO inhibited binding of [3H]apomorphine (IC50 = 23 nM) or [3H]spiperone (IC50 = 55 nM) to rat striatal membranes. Because (+)-PHNO failed to stimulate adenylate cyclase in carp retina, it was classified as a D-2 agonist. ED50 values (shown in parentheses) derived in DA receptor-related in vivo tests were as follows: in mice, (+)-PHNO produced hypothermia (13 micrograms/kg i.p.) and postural asymmetry in the unilaterally caudectomized animal (4 micrograms/kg i.p.). In the rat, (+)-PHNO produced stereotypy (10 micrograms/kg i.p.) and contralateral turning in 6-hydroxydopamine-lesioned animals (5 micrograms/kg i.p.) that lasted 1 to 3 hr. Whereas both of the latter effects were blocked by haloperidol, prior treatment with depletors of endogenous catecholamines, reserpine or alpha-methylparatyrosine failed to reduce (+)-PHNO-induced stereotypy. The naphthoxazine also produced emesis in beagles (0.05 micrograms/kg i.v.) that was blocked by L-646,462, a peripherally selective DA receptor antagonist. (+)-PHNO was well absorbed when given p.o., producing contralateral turning (10 micrograms/kg) with a ratio of p.o. to i.p. ED50 values of 2. This ratio was much lower than those derived for n-propylnorapomorphine (60) and apomorphine (54). At the DA autoreceptor, (+)-PHNO inhibited the accumulation of dOPA in the gamma-butyrolactone-treated rat (11 micrograms/kg i.p.).(ABSTRACT TRUNCATED AT 250 WORDS)

Adrenoceptor and tetrabenazine antagonism activities of some pyridinyltetrahydropyridines.

A series of pyridinyltetrahydropyridine derivatives was synthesized and evaluated as adrenoceptor and tetrabenazine antagonists. 4-(3-Fluoro-2-pyridinyl)-1,2,5,6-tetrahydropyridine proved to be the most potent and selective alpha 2-adrenoceptor antagonist of the series as measured in vitro by displacement of [3H]clonidine and [3H]prazosin from membrane binding sites of calf cerebral cortex and by antagonism of the effects of clonidine and methoxamine in the rat isolated, field-stimulated vas deferens. In addition, this compound, and the corresponding desfluoro derivative, blocked tetrabenazine-induced ptosis in the mouse.

L-646,462, a cyproheptadine-related antagonist of dopamine and serotonin with selectivity for peripheral systems.

The selectivity, peripheral vs. central actions, of the antidopaminergic agent L-646,462 was assessed in two ways. First, elevation of prolactin in serum (peripheral) and homovanillic acid in the striatum were measured in rats. L-646,462 was found to have a central/peripheral activity ratio of 143, whereas comparable values derived for haloperidol, metoclopramide and domperidone were 1.4, 9.4 and 1305, respectively. Second, the ID50 values required to block apomorphine-induced emesis in beagles (peripheral receptor-mediated response) were compared with those required to block apomorphine-induced stereotypy (central receptor-mediated response) in rats. Central/peripheral ID50 ratios of 234, 9.2, 129 and 7040 were obtained, respectively, for L-646,462, haloperidol, metoclopramide and domperidone. The selectivity of L-646,462 for peripheral serotonin (5-HT) receptors in rats was determined by measuring its effectiveness in blocking 5-HT-induced paw edema (peripheral response) and 5-hydroxytryptophan-induced head twitch (central response); a ratio of 114 was obtained. This value agrees nicely with the ratio of 143 derived in the rat ( vide supra) for peripheral selectivity for dopamine receptors. L-646,462 is, therefore, selective in vivo, preferentially blocking dopamine and 5-HT receptors located outside the blood-brain barrier. With regard to dopamine-receptors, L-646,462 was about equipotent and more selective than metoclopramide, while being less potent and less selective than domperidone. Unlike metoclopramide or domperidone, L-646,462 also possessed a reasonably potent 5-HT receptor antagonist effect in vivo.(ABSTRACT TRUNCATED AT 250 WORDS)

Antagonism of xylazine plus chloral hydrate loss of the righting reflex in mice. A simple in vivo procedure for the evaluation of selective alpha 2-adrenoceptor antagonists.

Xylazine causes a dose-related loss of the righting reflex (LRR) in mice when combined with a subanesthetic dose of chloral hydrate. Compounds that preferentially block alpha 2-adrenoceptors antagonize this xylazine plus chloral hydrate LRR at low doses and in a dose-related manner. This action of these compounds appears related to their alpha 2-adrenoceptor blocking properties insofar as their activity in this test correlates reasonably well with their activity in other in vivo and in vitro procedures thought to reflect alpha 2-antagonism. Also, compounds without any appreciable alpha blocking properties or without selectivity for blocking alpha 2-adrenoceptors are not active in this procedure. At higher doses, the alpha 2-blockers antagonize the reversal of the LRR caused by low doses. This action may be indicative of the in vivo alpha 1 blocking properties of these compounds, which may in turn be related to their sedating properties. In any event, antagonism of xylazine plus chloral hydrate LRR in mice appears to be a simple, rapid, and quantitative procedure for the in vivo evaluation and comparison of selective alpha 2-adrenoceptor antagonists.

Electrophysiological, biochemical and behavioral assessment of dopamine autoreceptor activation by a series of dopamine agonists.

The rank order of potency to activate central dopamine autoreceptors of seven compounds known to possess central nervous system dopamine agonist activity were assessed with the following techniques: (1) inhibition of dopaminergic neuronal firing in anesthetized rats, (2) inhibition of dopamine synthesis in rats pretreated with gamma-butyrolactone, and (3) inhibition of mouse locomotor activity. The compounds were also examined for their ability to induce stereotypic behaviors in rats as an index of postsynaptic dopamine receptor activation. The compounds under investigation were apomorphine, N-n-propyl-norapomorphine, lergotrile, bromocriptine, RU 24926 and 6-ethyl-9-oxaergoline (EOE). There was a high degree of correlation between the rank order of potency of the compounds in all three of the presumptive autoreceptor tests and with minor variations the following rank order of potency was found: N-n-propylnorapomorphine greater than or equal to EOE greater than apomorphine greater than lergotrile greater than or equal to RU 24926 greater than bromocriptine. However, in the induction of stereotypies, the rank order of potency was considerably different: N-n-propylnorapomorphine greater than apomorphine greater than EOE greater than RU 24926 greater than lergotrile greater than bromocriptine. There was a poor and statistically significant degree of correlation between the rank order of potency of the test compounds to induce stereotyped behaviors and any of the other three test procedures. Altogether, these data confirm and extend the suspected dopaminergic agonist properties of the compounds under investigation and additionally lend credence to the assumption that the three putative autoreceptor assays employed do in fact reflect dopaminergic autoreceptor activation.

Spontaneously hypertensive rats exhibit an enhanced mydriatic response to clonidine. Evidence for enhanced sensitivity of central alpha 2-adrenoceptors.

Comparisons among spontaneously hypertensive (SHR), Kyoto Wistar (KW), and Wistar (W) rats were made of the functional states of central nervous system (CNS) alpha 2-adrenoceptors (clonidine-induced mydriasis) and nonvascular peripheral presynaptic alpha 2-adrenoceptors (clonidine-induced inhibition of the neurogenic twitch of the isolated vas deferens). While there were no differences among the strains of rats in the concentration of clonidine required to produce a 50% inhibition of the electrically evoked contractile response of the vas deferens, there was a significant reduction in the mean effective concentration (ED50) of clonidine to induce mydriasis in SHR as compared with KW and W rats. These observations indicate that CNS alpha 2-adrenoceptors may be functionally more sensitive in SHR. The data also suggest that the sensitivity of nonvascular presynaptic alpha 2-adrenoceptors, at least in the vas deferens, is not altered in hypertensive animals.

Minireview. Thyrotropin releasing hormone and CNS cholinergic neurons.

The centrally mediated pharmacological effects of thyrotropin releasing hormone (TRH), their mechanistic basis and therapeutic implications, along with the possible physiological significance of extrahypothalamic TRH, have been the subject of numerous investigations for over a decade. Despite this effort a holistic perspective on these issues and considerations does not exist. However, with continued research employing multiple and diverse experimental approaches, many interactions of TRH and related peptides with central cholinergic mechanisms have been revealed. These interactions are documented in this review and it is proposed that they can account for several of the more prominent pharmacological actions of these peptides. Additionally, it is suggested that a function of endogenous YHR, throughout the neuroaxis, may be to regulate the excitability of central cholinergic neurons.

Preparation of some 10-[3-(dimethylamino)-1-propyl]-10H-pyrazino[2,3-b][1,4] benzothiazines as potential neuroleptics.

Chloro- and methyl-substituted 10H-pyrazino[2,3-b][1,4]benzothiazines were prepared and their structures determined by 13C NMR and X-ray crystallographic analysis. Alkylation afforded the 10-[3-(dimethylamino)-1-propyl] derivatives, which were compared to chlorpromazine in receptor-binding assays, in vivo behavioral tests, and electrochemical oxidation studies. In this series, the 2-chloro compound, 4c, proved to be the most effective derivative in displacing [3H]siperone, [3H]apomorphine, and [3H]prazosin radioligands from binding sites, being approximately as potent as chlorpromazine in this respect. However, none of the 10H-pyrazino[2,3-b][1,4]benzothiazines of this study were as active as chlorpromazine in in vivo tests predictive of neuroleptic activity.

Pharmacological characterization of purinergic receptors in the rat vas deferens.

Using the isolated rat vas deferens, we have confirmed the existence of P1 purinergic receptors whose activation results in an inhibition of the neurogenic twitch of the vas deferens. The observed order of potency for agonists (adenosine ethyl carboxamide greater than 2-chloroadenosine greater than adenosine greater than 5'-AMP greater than 5'-ADP greater than ATP) and antagonism of these effects by theophylline supports a P1-mediated response. Metabolically stable analogs of ATP elicited dose-dependent contractile responses which were quantitatively greater than, but qualitatively comparable to, ATP-induced responses. The order of potency for the eliciting contraction was the following: adenylyl-5-imidodiphosphate = beta-gamma-methylene ATP greater than adenosine tetraphosphate much greater than ATP greater than ADP. Interestingly, these compounds also produced an inhibition of the neurogenic twitch with a similar rank order of potency. This response was not due to the activation of P1 receptors insofar as high concentrations of theophylline failed to attenuate either the inhibition of the neurogenic twitch or the contractile response induced by these agonists. Thus, these data demonstrate the presence of both P1 and P2 purinergic receptors in the rat vas deferens. In addition, the data are consistent with the idea that two distinct classes of P2 receptors exist in this tissue. Furthermore, these data suggest that the rat vas deferens provides a useful tissue for studying compounds which interact with both major subtypes of purinergic receptors.

MK-771 antagonizes the enhanced response to apomorphine in rats treated chronically with haloperidol - implications for tardive dyskinesia.

Rats that have been chronically exposed to neuroleptic drugs exhibit an enhanced stereotypic response to dopaminergic agonists, and it has been suggested that this phenomenon is a useful animal model of tardive dyskinesia. Administration of MK-771, a well characterized analog of thyrotropin releasing hormone (TRH), has been found to attenuate the enhanced response to apomorphine in rats chronically treated with haloperidol. This finding is discussed in light of similar observations with choline and physostigmine and the established cholinergic stimulating properties of MK-771 and TRH. It is suggested that peptides of this nature may represent novel and useful agents to ameliorate the symptoms of tardive dyskinesia.

Potent dopamine agonist activity of a novel ergoline, 6-ethyl-9-oxaergoline (EOE).

6-Ethyl-9-oxaergoline (EOE) and its enantiomers were compared with apomorphine in a number of tests designed to measure dopamine (DA) agonist activity within the central nervous system. In rats, the tests were: interaction with DA receptors labeled with 3H-apomorphine or 3H-spiroperidol; the effects on DA synthesis as assessed by the gamma-butyrolactone procedure; turning in 6-OHDA lesioned animals; stereotypy; and, slowing of DA cell firing rates. In the mouse, locomotor activity, hypothermia and postural asymmetry in caudectomized animals were studied. Emesis in the beagle was also examined. The (-)-enantiomer of EOE was more potent than either the (+)-enantiomer or the racemate in all tests. With the exception of inducing stereotypy and the displacement of 3H-apomorphine from rat striatal membranes, (-)-EOE was equi- or more potent than apomorphine in all test procedures. (-)-EOE was effective following oral administration and exhibited a longer duration of action than apomorphine. The results indicate EOE is a potent DA agonist.