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Vol. 305, Issue 2, 410-416, May 2003
Department of Psychiatry, University of Connecticut Health Center, Farmington, Connecticut (K.A.G., K.A.S., A.W.); Department of Biology, University of Portland, Portland, Oregon (G.G.Y.); and Department of Psychiatry, School of Medicine, University of North Carolina-Chapel Hill, Chapel Hill, North Carolina (A.J.P.)
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Abstract |
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 Top
 Abstract
 Introduction
Neurobiology of TRH-Mediated...
Future Therapeutic Applications...
References
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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.
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Introduction |
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Abstract
Introduction
Neurobiology of TRH-Mediated...
Future Therapeutic Applications...
References
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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 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:
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.
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Neurobiology of TRH-Mediated Homeostasis |
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Abstract
Introduction
Neurobiology of TRH-Mediated...
Future Therapeutic Applications...
References
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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 hypothalamic-hypophysiotropic 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 activity.
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The TRH Hypothalamic-Hypophysiotropic Neuroendocrine System.
The hypothalamic-hypophysiotropic neuroendocrine axis serves as a key
regulator of metabolism. As part of this function, hypothalamic TRH is
the key positive regulator of thyrotropin (thyroid-stimulating hormone;
TSH) release from the pituitary gland. Thyroid hormones, in turn,
negatively regulate TRH release and hypothalamic prepro-TRH mRNA
content (Scanlon and Toft, 2000). The thyroid axis governs slowly
developing, but long-lasting, increases in metabolic activity; it
appears that TRH has evolved as its CNS activator.
). In virtually all reported studies,
a subset of depressed patients demonstrated a diminished TSH response
to TRH stimulation. The pathophysiological mechanisms that account for
the blunted TSH response have not been elucidated, although
down-regulation of TRH pituitary receptors has been suggested. The TRH
response also is blunted in patients with other psychiatric conditions,
including schizophrenia, bipolar disorder, and alcoholism (Winokur,
1991). Although the majority of studies applying the TRH stimulation
test in depressed patients have employed a morning TRH infusion
paradigm (typically at 8:00 AM), Duval et al. (1990) employed TRH
stimulation tests both in the morning and evening (8:00 AM and 11:00
PM). They subtracted the morning response from the evening response, a
technique that magnifies the response deficit shown by patients as
compared with controls. This finding suggests that thyroid axis
abnormalities in depression may demonstrate a circadian component.
The TRH Brainstem/Midbrain/Spinal Cord System.
Spinal tissue
from several species, including humans, contains substantial
concentrations of TRH and TRH receptors (Winokur et al., 1989). Cell
bodies containing TRH within the raphe nuclei project through the
spinal cord central canal region and terminate in lamina II and lamina
IX. The raphe neurons containing TRH also contain serotonin and,
in some cases, substance P, suggesting physiologically significant
interactions between TRH and these colocalized neuroactive substances.
In both rat and human spinal cord, substantial concentrations of TRH
receptors (consistent with the TRH-R2 receptor subtype) have been
identified in lamina II, which contains the substantia gelatinosa, and
in lamina IX (predominant receptor subtype TRH-R1), in proximity to
anterior horn 
-motoneurons (Heuer et al., 2000). The localization
pattern for TRH projections in spinal cord suggests likely involvement in motor function and modulation of pain transmission.
Electrophysiological studies on spinal cord preparations have reported
excitatory effects of TRH on motoneuron activity and spinal reflexes,
with some data suggesting synergistic effects associated with the
coadministration of TRH and serotonin. In several animal models of
spinal cord injury, TRH administration was associated with improved
motor function (Faden et al., 1989). Additionally, administration of TRH in the Rolling mouse Nagoya model of hereditary ataxia resulted in
improved motor function and decreased ataxic symptoms (Sobue et al.,
1983). As discussed below, these results led to clinical trials of TRH
and a TRH analog in human SCD.
). Thus, in
conjunction with numerous behavioral effects, a coordinated pattern of
autonomic modulation suggests a role for TRH in the adaptive responses
to stress.
The TRH Limbic/Cortical System.
Many effects of TRH appear
linked to TRH systems localized in limbic and cortical areas. These
effects often involve interactions with other neurotransmitters. The
first report involved the dihydroxyphenylalanine potentiation test
(Plotnikoff et al., 1972), in which antidepressant-like effects were
noted. Notably, hypophysectomized and/or thyroidectomized animals
demonstrated full behavioral responses. These findings coincided with
clinical studies of TRH efficacy in the treatment of depression as
discussed below. TRH has also been found active in a conflict test
involving punished responding (Vogel et al., 1980), a paradigm used to
screen compounds for likely efficacy in clinical anxiety.
). Initially described on the basis
of TRH's potency to shorten sleep induced by ethanol or barbiturates,
this striking analeptic effect also has been described following
administration of other CNS depressant compounds, including opiates,
phenothiazines, and benzodiazepines. Neuroanatomical substrates of this
analeptic effect were mapped by microinjection studies, with the medial
septal area demonstrating the greatest degree of sensitivity. The
circuitry of this behavioral response to TRH appears to involve the
classical cholinergic septohippocampal projection pathways. Moreover,
it is thought that many other effects of TRH are also mediated by
cholinergic mechanisms (Yarbrough, 1983).
TRH reversal of drug-induced sedation has been extended to reversal of
natural states of sedation in the hibernating ground squirrel (Winokur,
1991). When microinjected into the dorsal hippocampus, TRH produced
physiological and behavioral arousal from hibernation. Furthermore, TRH
similarly administered in the euthermic ground squirrel studied during
slow wave sleep produced physiological and behavioral activating
effects. In contrast, TRH injections in conscious euthermic ground
squirrels produced inhibitory effects. These inhibitory effects were
directly proportional to the extent of behavioral activation at the
time of TRH administration. These findings, taken together, were the
first to suggest that TRH can act as a state-dependent modulator of CNS activity.
Consistent with its cholinergic link in analepsis, TRH along with many
of its analogs enhances performance on several parameters of learning
and memory (Horita, 1998). Thus, TRH or TRH analogs improve maze test
performance in medial septum-lesioned animals and also reverse memory
deficits produced by scopolamine, CO2 exposure,
or lesions of the nucleus basalis of Meynert in some, although not all,
published studies.
Extensive experimental evidence links seizure induction to TRH neuronal
systems (Kubek and Garg, 2002). Induction of generalized seizures
through a variety of experimental procedures, including administration
of pentylenetetrazol, kainic acid, tetanus toxin, amygdala kindling,
and electroconvulsive shock elevate levels of TRH mRNA and reduce TRH
receptor concentrations in limbic regions such as amygdala and
hippocampus. The increases in limbic region TRH following several
alternate day electroconvulsive shock administrations suggests that
activation of TRH neuronal systems underlies the antidepressant effect
of clinical electroconvulsive therapy (Sattin, 1999). Studies of TRH or
TRH analogs in animal seizure models have reported inhibition of
seizure activity in amygdala-kindled seizures, tonic, and absence-like
seizures. Studying the effects of amygdala-kindled seizures, Post and
Weiss (1996) reported activation of hippocampal TRH systems. They
speculated that the activation of TRH neuronal systems by seizures
represents a compensatory mechanism to terminate excessive neuronal
activity (Post and Weiss, 1996), a homeostatic function.
Unpublished studies (K.A.S.) in the field of addictions also illustrate
homeostatic modulation by TRH. TRH is a locomotor activator when
injected into the nucleus accumbens, a key brain reward region
mediating effects of drugs of abuse (Kalivas et al., 1987).
Nevertheless, accumbens injections of TRH block the development of
locomotor sensitization to the psychostimulant cocaine. In this
phenomenon, repeated exposure to cocaine causes progressively greater
locomotor responses. Similarly, systemic TRH blocks development of
conditioned place aversion to opiate withdrawal in rats, whereas TRH by
itself does not produce conditioned place preference.
The TRH Chronobiological System.
We propose that a TRH
chronobiological system represents a fourth functionally integrated
component of the TRH homeostatic system. Numerous findings support
interrelationships between TRH and biological systems that exhibit
rhythmic activity. TRH and TRH receptors are localized in the
hypothalamic suprachiasmatic nuclei (SCN; Manaker et al., 1985), the
primary circadian pacemaker. Although the source of TRH in the SCN
remains unknown, TRH has been localized in two of the three primary
afferent projections to the SCN, the dorsal raphe nuclei (Merchenthaler
et al., 1988) and the ganglion cells of the retina (Lexow, 1996).
). A phase response curve was
established by injecting TRH into the SCN at various time points across
the circadian period. Microinjection of TRH during the animals'
subjective day resulted in a pronounced phase advance in the circadian
pattern of wheel running activity.
In this section, we have reviewed both old and new data concerning four
TRH neuronal systems and the physiological and behavioral effects
produced by administration of TRH or TRH analogs. These findings
support our proposal that TRH neuronal systems subserve a broad role as
a CNS homeostatic modulator, a concept depicted in Fig.
2. This figure implies that TRH effects
are dependent on the state of the organism at the time TRH is activated
or administered. This schema provides a way to reconcile much of the
variability in the results reported after TRH administration.
Appreciation of this role provides a rationale for the therapeutic
application of TRH analogs, as described below.
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Therapeutic Implications of TRH-Mediated Homeostasis
Clinical Effects of TRH.
A limited number of clinical studies
have extended preclinical findings to examine the possible therapeutic
value of TRH. Initial reports of a rapid onset of antidepressant
effects following TRH administration to depressed patients were
followed by other studies examining the efficacy of TRH in the
treatment of depression (Winokur, 1991). Inconsistent positive and
negative findings were reported following i.v., oral, and intrathecal
administration of the peptide (Mason et al., 1995). In considering
these results, it is important to recall that the short half-life of
TRH in plasma and the uncertain ability of the peptide to gain access
to the CNS after peripheral administration limit the interpretation of all clinical findings with native TRH. Despite these limitations, however, some additional findings from studies of TRH administration to
depressed patients are noteworthy. First, Itil et al. (1975) reported
not only rapid improvement in symptoms following a single i.v. dose of
TRH but also activation of EEG patterns in a manner that simulated the
effects produced by stimulants and by antidepressant drugs with
activating properties (Itil et al., 1975). Second, Marangell et al.
(1997) administered TRH (500 µg) by intrathecal injection to eight
patients with refractory depression and noted significant reduction of
depression in five, with responses being observed on the day of TRH
administration or a day later (Marangell et al., 1997). Finally, Szuba
et al. (1996) administered TRH (500 µg, i.v.) or placebo to 20 bipolar patients in a depressive episode, with administration occurring
at midnight. Rapid improvement in depressive symptoms was observed in
60% of patients receiving TRH and 10% of patients receiving placebo.
These data support the possibility that circadian factors influence the
response to TRH, findings that complicate the interpretation of
clinical trials but support a chronobiological influence of the peptide.
noted reports of improvement in
cognitive function in various animal paradigms after TRH administration and also recognized the limited CNS penetration of the peptide. Accordingly, they used high doses of i.v. TRH (0.5 mg/kg) in their studies of normal volunteers, with transient cognitive impairment produced by administration of anticholinergic agents and of patients with Alzheimer's disease (Mellow et al., 1989; Molchan et al., 1990).
Modest improvements in some indices of cognitive function were observed
in both groups.
Studies of the therapeutic effects of TRH in ALS were undertaken based
on the demonstration that TRH systems are located in pertinent regions
of spinal cord, on evidence of physiological enhancement of motoneuron
activity following administration of TRH, and on reports of trophic
effects of TRH on spinal cord explants (Engel, 1989). Initial positive
studies indicating that TRH produced acute enhancement of motor
strength and coordination were followed by long-term studies in which
only minimal evidence of therapeutic benefit was observed. A subsequent
study showed that TRH receptor concentrations in postmortem spinal cord
samples from ALS patients are reduced from 60 to 90% in the lamina IX
region (Winokur et al., 1988), however. Thus, the paucity of positive
TRH effects in patients with ALS may be explained by loss of receptor
targets as well as by the limited access of TRH to the CNS.
As noted above, TRH has been studied in several preclinical seizure
models; other studies have tested the use of TRH in the treatment of
seizure disorders in humans. As reviewed by Kubek, limitations of the
clinical studies stem from the facts that TRH was always studied as
"add-on" therapy and that none of the trials were
placebo-controlled (Kubek and Garg, 2002). Additionally, studies have
tended to involve small numbers of subjects. These limitations
notwithstanding, some evidence exists for beneficial effects of TRH in
the management of infantile spasms, Lennox-Gaston syndrome in children,
partial seizures, and myoclonic seizures.
TRH Analogs.
Delineation of the pharmacophoric
domains of TRH led to the development and clinical assessment
of several metabolically stable analogs of TRH. These compounds
can be classified as follows:
| 1. | Modifications of the native C-terminal pyroglutamyl residue of TRH: TA-0910 (Ceredist) (Tanabe Seiyaku Co., Ltd, Osaka, Japan); CG-3703 (montirelin) (Grünenthal GmbH, Aachen, Germany); JTP-2942 [Na-((1S,2R)-2-methyl-4-oxocyclopentylcarbonyl)-L-histidyl-L-prolin amide monohydrate] (Japan Tobacco, Inc., Tokyo, Japan); YM-14637 (azetirelin) (Yamanouchi Pharmaceutical Co., Ltd, Tokyo, Japan). |
| 2. | Modifications of N-terminal prolineamide residue of TRH: RX-77368 (pyroglutamyl-2-histidyl-3,3'-dimethyl-prolineamide) (Ferring Pharmaceuticals, Inc., Copenhagen, Denmark). |
| 3. | Modifications of the C-terminal pyroglutamyl and N-terminal prolineamide TRH residues: MK-771 [1-pyro-2-aminoadipyl-L-histidyl-L-thiazolidine-4-carboxamide] (Merck, Rahway, NJ). |
| 4. | Modifications of the C-terminal pyroglutamyl and histidyl residues of TRH: RGH 2202 (posatirelin) (Gedeon Richter Pharmaceuticals, Budapest, Hungary). |
| 5. | Substitution of a cyclohexane backbone to replace the peptide linkages in native TRH: Ro 24-9975 [1S,3R,5(2S),5S)-5-[(5-oxo-1-phenylmethyl)-2-pyrrolidinyl]-methyl]-5-[(1H-imidazol-5-yl)methyl]cyclohexaneacetamide] (Hoffman-La Roche, Basel, Switzerland). |
Experience with Selected TRH Analogs: TA-0910. Although TA-0910 clearly mimics the biological actions of TRH, it has reduced affinity for brain and pituitary TRH receptors, especially the latter, compared with TRH. The plasma half-life and bioavailability of TA-0910 are substantially enhanced in all species examined, including humans. This enhanced metabolic stability provides greater and longer lasting access to its CNS site(s) of action.
Knowledge of the brainstem TRH system, as noted above, provided a basis for clinical studies of TRH in SCD (Sobue et al., 1986), which yielded
positive results. Moreover, a hereditary animal model reflecting the
pathophysiology of human SCD has been developed (Nishimura, 1975), and
both TRH and TA-0910 were found to be active in this model as well as
in other animal models of motor dysfunction (Kinoshita et al., 1998).
The positive results with TRH and TA-0910 in early clinical trials and
animal models provided an impetus for detailed testing in human SCD
(Kinoshita et al., 1998). Improvements were noted in gait, speech, and
coordination in both phase II and phase III trials. The drug appeared
to slow disease progression in large phase III studies
(n = 400). These findings are consistent with reports
of trophic effects of both TRH and TA-0910 on neurons in the spinal
cord and may indicate therapeutic benefits beyond symptomatic relief.
TA-0910 is the first TRH analog approved for marketing by a major
regulatory agency. It was launched in Japan in 2001 for the treatment
of patients with spinocerebellar degenerative diseases, with reported
sales of about $70,000,000 in its second year (Tanabe, 2002).
CG-3703.
Grünenthal patented CG-3703 in 1984 for the
treatment of ALS. More potent and longer acting than TRH, CG-3703
produced beneficial effects in animal models of concussion-induced
unconsciousness, cerebral ischemia, memory disruption, spontaneous
convulsions in rats, narcolepsy, and spinal trauma (Grünenthal,
1997). Given its efficacy in these models, the potential indications
were broadened to include seizures, nerve trauma, cognitive
dysfunction, and sleep apnea.
). These findings notwithstanding,
it is our understanding that the development of this compound has been suspended.
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Future Therapeutic Applications of TRH Analogs |
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Top
Abstract
Introduction
Neurobiology of TRH-Mediated...
Future Therapeutic Applications...
References
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We have presented new perspectives on the organization and
functions of TRH and have proposed that an array of anatomical, physiological, and behavioral data support a role for TRH as a CNS
homeostatic modulator. The astonishing array of actions of TRH
proven
in animals and at least suggested in humansrequires a novel
conceptualization. This need can be illustrated by holding in
juxtaposition only two of its properties: it is an analeptic, and it is
an anticonvulsant. TRH is analeptic only when the organism is sedated,
however, and it is an anticonvulsant only when the organism is
threatened by convulsion. TRH will antagonize sedation in one
circumstance and mimic it in another. Thus, TRH is a normalizer, a
homeostatic agent. Many systems contribute to the defense of the
internal milieu. Through activation of one or several of its four
subsystems, TRH contributes to this defense and appears to coordinate
the overall effort toward homeostasis. It may be useful to state our
position as a hypothesis, the TRH hypothesis of homeostatic regulation.
Thus, thyrotropin-releasing hormone is a homeostatic agent that opposes
many, if not all, perturbations in the central nervous system and in
its autonomic outflow, tending to restore its function to normal limits.
To be clinically useful, a TRH analog should exert weak TSH-releasing
effects. As noted, most TRH analogs demonstrate this property while at
the same time producing enhanced "nonendocrine" CNS effects. If
analogs were developed with selective affinity for TRH-R1 and TRH-R2,
they would probably demonstrate more specific profiles of CNS effects.
Moreover, additional TRH receptor subtypes may yet be discovered, as
suggested by the report of Bidaud et al. (2002).
The range of physiological and behavioral effects produced by TRH
provides a basis for considering a variety of therapeutic indications
for TRH analogs, as indicated in Table 1.
A parsimonious and heuristic unifying concept for these diverse
indications relates to the homeostatic modulatory role subserved by
endogenous TRH systems. Although such a broad range of therapeutic
indications might be seen as a liability, we propose that the putative
ability of TRH analogs to exert homeostatic effects represents a
rational, novel, and uniquely promising profile. In some instances a
TRH analog by itself may represent a sufficient therapeutic
intervention to normalize a dysregulated physiologic system. For
example, one might consider what is commonly called jet lag while
contemplating the putative chronobiological properties of TRH. The
ability of a TRH analog to both phase shift circadian rhythms and
enhance alertness and cognitive function may endow it with unique
therapeutic value. In other circumstances, a TRH analog might serve as
an ancillary agent to a primary standard treatment (e.g., a selective serotonin reuptake inhibitor in the treatment of depression) and provide a needed permissive or synergistic effect (e.g., in a patient
with treatment refractory depression). While such speculation requires
empirical validation, we think that the promise of TRH analogs for
therapeutic application in a variety of disorders represents an area of
striking opportunity that has heretofore gone largely unrealized.
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Acknowledgments |
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Sincere thanks to Nedra Lexow for allowing us to modify and update her visual conceptualization of the TRH Network and to S. J. Enna for his encouragement to assimilate and present our thoughts expressed in this commentary.
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Footnotes |
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Accepted for publication February 13, 2003.
Received for publication December 11, 2002.
DOI: 10.1124/jpet.102.044040
Address correspondence to: Dr. Andrew Winokur, Department of Psychiatry, University of Connecticut Health Center, 263 Farmington Ave., Farmington, CT 06030-6415. E-mail:winokur{at}psychiatry.uchc.edu
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Abbreviations |
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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.
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Top
Abstract
Introduction
Neurobiology of TRH-Mediated...
Future Therapeutic Applications...
References
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A CNS Active TRH Analogue pp 1-34,
Grünenthal GmbH, Aachen, Germany.Fourth Generation of Progress (Bloom F andKupfer D eds) pp 493-503,
Raven Press, New York.This article has been cited by other articles:
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  H. Zeng, B. A. Schimpf, A. D. Rohde, M. N. Pavlova, A. Gragerov, and J. E. Bergmann Thyrotropin-Releasing Hormone Receptor 1-Deficient Mice Display Increased Depression and Anxiety-Like Behavior Mol. Endocrinol., November 1, 2007; 21(11): 2795 - 2804. [Abstract] [Full Text] [PDF]
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 L. Chavez-Gutierrez, E. Matta-Camacho, J. Osuna, E. Horjales, P. Joseph-Bravo, B. Maigret, and J.-L. Charli Homology Modeling and Site-directed Mutagenesis of Pyroglutamyl Peptidase II: INSIGHTS INTO OMEGA-VERSUS AMINOPEPTIDASE SPECIFICITY IN THE M1 FAMILY J. Biol. Chem., July 7, 2006; 281(27): 18581 - 18590. [Abstract] [Full Text] [PDF]
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