Brain thyrotropin-releasing hormone matures independently of the hypothalamus in the rat

To evaluate the relationship of the extrahypothalamic brain thyrotropin-releasing hormone (TRH) to its hypothalamic counterpart, we studied the maturation of hypothalamic and extrahypothalamic TRH in the rat. The absolute increase of TRH in the whole brain and the extrahypothalamus reached adult levels at 7 days of age, whereas the hypothalamic TRH concentrations did not differ from the adult levels at 23 days. Moreover, the TRH concentrations at 7 days were greater than the adult levels in the striatum, hippocampus, pons-medulla and cerebellum, and similar to the adult levels in the midbrain and cortex. These data indicate the developmental divergency of hypothalamic and extrahypothalamic TRH, implying that the maturation of extrahypothalamic TRH is independent of the hypothalamus. The present study suggests that extrahypothalamic TRH may play a neurophysiological role in the central nervous system at an early infantile age, at which hypothalamic TRH is not ripe for its endocrinological action.     

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.     

Physiological, pathophysiological and pharmacological aspects of exogenous and endogenous opiates

Endogenous opioid peptides have been detected not only in the central nervous system but also in the peripheral autonomic nervous system of the gastrointestinal tract and pancreas and several other organs. In addition opioid active peptides have been found in certain nutrients such as wheat gluten and bovine and human milk. Functional studies have presented evidence for a participation of endogenous opioids in the regulation of certain pituitary and gastrointestinal functions. Apart from being a physiological neuroregulator there is evidence that endogenous opioids might play a role as a pathogenetic factor in various clinical disorders. The evidence for these different aspects of opioid function is reviewed in the present article.     

TRH-like peptides in prostate gland and other tissues

This minireview is aimed to recapitulate the occurrence of TRH-like peptides in the prostate gland and other tissues and to discuss their known functions in the organism. The hypothalamic thyrotropin-releasing hormone (TRH) was the first chemically defined hypophyseotropic hormone with the primary structure pGLU-HIS-PRO.NH2. However, the presence of extrahypothalamic TRH-immunoreactive peptides was reported in peripheral tissues including the gastrointestinal tract, placenta, neural tissues, male reproductive system and certain endocrine tissues. It was supposed that this TRH immunoreactivity can partially originate from TRH-homologous peptides and that these peptides have significant cross-reactions with the antibody specific against authentic TRH. This assumption was confirmed by the identification of prostatic TRH immunoreactivity as pyroGLU-GLU-PRO.NH2 using fast atom bombardment mass spectrometry and gas phase sequence analysis. TRH-like peptides are characterized by substitution of the basic amino acid histidine (related to authentic TRH) for neutral or acidic amino acids, such as glutamic acid, phenylalanine, glutamine or tyrosine. The physiological role of TRH-like peptides in peripheral tissues is not precisely known, but they possess a C-terminal amide group which is characteristic for many biologically active peptides. The occurrence of these peptides in the male reproductive system can influence male fertility. They are also closely related to circulating thyroid and steroid hormones. There might be an important connection of TRH-like peptides to the prostatic local autocrine/paracrine network mediated by extrahypothalamic TRH immunoreactivity corresponding to TRH-like peptides and extrapituitary thyrotropin (TSH) immunoreactivity also found in the prostatic tissue. A similar system of intraepithelial lymphocyte hormonal regulation due to the local paracrine network of TRH/TSH has been described in the gastrointestinal tract. The local network of TRH-like peptides/TSH may be involved in possible regulation of prostatic growth.     

Effect of thyrotropin-releasing hormone on gastro-intestinal secretions in dogs

Thyrotropin-releasing hormone (TRH) immunoreactivity has been shown previously to be distributed throughout the gastrointestinal tract and the pancreas. This study demonstrated that TRH given intravenously suppresses, in a dose-related manner, sham-feeding induced food intake and inhibits gastric secretion provoked by infusion of pentagastrin or instillation of 10% liver extract into the stomach. TRH also reduces pancreatic response to secretin, caerulein, feeding a meat meal or duodenal acidification. The findings that TRH inhibits gastric and pancreatic secretions induced by exogenous and endogenous stimulants, and that the inhibition by TRH of post-prandial secretion is not accompanied by any change in serum gastrin, indicate that TRH probably acts directly on the exocrine stomach and pancreas.     

Gaseous messengers in the nervous system

Nitric oxide is the first gaseous messenger whose functions were comprehensively studied in different systems of organism. Recently, new data on the physiological role of other endogenous gases: carbon monoxide and hydrogen sulfide, appeared. The role of gases in gastrointestinal tract and cardiovascular system have been established; however, data on their function and mechanisms of action in nervous system are insufficient. This article highlights the current information on the role of gaseous messengers in central and peripheral nervous system.     

Antagonism of ethanol narcosis by thyrotropin releasing hormone

Thyrotropin releasing hormone (TRH) reduced the narcosis and hypothermia produced by ethanol in mice. This action of TRH does not appear related to release of thyroid hormone or to the effects of a metabolite of TRH. The ability of TRH to reduce the actions of ethanol after intracisternal injection suggests that the mechanism of the ethanol antagonism is central in origin. The antagonism of ethanol by TRH does not appear to be related to an amphetamine-like stimulant action.     

Phylogenetic Distribution and Function of the Hypophysiotropic Hormones of the Hypothalamus

SYNOPSIS. Following the isolation, synthesis and subsequentdevelopment of specific and sensitive radioimmunoassays forthe hypothalamic hormones thyrotropin-releasing hormone (TRH),luteinizing hormone-releasing hormone (LH-RH) and growth hormonerelease-inhibiting hormone (somatostatin), it was recognizedthat these peptides were not localized solely in the hypothalamus,but were widely distributed throughout the mammalian nervoussystem. Somatostatin occurs outside the nervous system altogether,being located in the gastrointestinal tract of vertebrates whereit may have a physiologic role in the secretion of gastrointestinalhormones. TRH, also, has been located outside the nervous system,occurring in large quantities in the skin of Rana species whereit may be of physiologic importance in skin function. This tripeptideis found throughout the nervous system of vertebrate and invertebratespecies in situations where it has no pituitary-thyroid function.Thesepeptides are present in brain synaptosomes and enzymatic degradingsystems have been recognized for each in brain tissue. For TRH,specific receptors and synthesizing activity have been detectedoutside the hypothalamic-pituitary system. The anatomic location,phylogenetic distribution, neurophysiologic and behavioral effectsstrongly support a role for these substances in neuronal regulation,apart from control of pituitary secretion. Evolutionary studies,especially of TRH, suggest that their primary function may beas neurotransmitters.     

The hormonal control of food intake

Numerous circulating peptides and steroids produced in the body influence appetite through their actions on the hypothalamus, the brain stem, and the autonomic nervous system. These hormones come from three major sites-fat cells, the gastrointestinal tract, and the pancreas. In this Review we provide a synthesis of recent evidence concerning the actions of these hormones on food intake.     

Histidyl-proline diketopiperazine: its biological role as a regulatory peptide

Summary Histidyl-proline diketopiperazine [cyclo(His-Pro)] is a metabolic of thyrotropin releasing hormone (TRH). This review summarizes the literature concerning cyclo (His-Pro) and, in addition, some studies dealing with TRH and other peptides that are considered of interest. The enzymes concerned with the metabolism of TRH are discussed. Distribution studies of peptides by immunological methods show that, while TRH is concentrated in synaptosomes, cyclo (His-Pro) is not, suggesting that cyclo (His-Pro) is not a classical neurotransmitter. Rat brain contains approximately three times as much cyclo (His-Pro) as TRH, mainly localized in the pituitary and hypothalamus. While the TRH is found in a free form, the cyclo (His-Pro) is bound to a carrier of molecular weight approximately 70 000. While specific membrane receptors for TRH have been detected in pituitary cells, no such receptors for cyclo (His-Pro) have yet been found in brain or pituitary; however, there is a specific binding of cyclo (His-Pro) to adrenal cortex membranes, Both TRH and cyclo (His-Pro) have effects in the central nervous system or pituitary. These include effects on prolactin release, thermoregulation, CNS depression, stereotypic behavior and cyclic nucleotide levels. Possible mechanisms and interrelations of these effects are discussed.     

Evolutionary significance of the phylogenetic distribution of the mammalian hypothalamic releasing hormones

The hypophysiotrophic hormones isolated from the mammalian hypothalamus are distributed throughout the nervous system of vertebrate species. Although their role in regulating pituitary hormone secretion in mammals is clear, a similar function in lower species has not been established. Thyrotropin-releasing hormone is unable to stimulate thyroid function in amphibia and fish, despite being present in the hypothalamus and brain of these species of high concentration. The tripeptide is also found in high concentration in frog skin, a tissue derived from (or programed by) primitive neuroectoderm that is also a rich source of other peptides structurally related to neural peptides located in mammalian brain and gut. Luteinizing hormone-releasing hormone (LHRH) is able to activate gonadotropin secretion in submammalian species but there is evidence that the LHRH material present in avian, reptilian, and piscine brain is not identical to the mammalian decapeptide. An LHRH-like material present in frog sympathetic ganglia appears to function as a neurotransmitter in this location. Somatostatin is present in high concentrations in the hypothalamus, brain, pancreas, and gastrointestinal tract of all vertebrates and chromatographically is identical to the mammalian material, suggesting that this peptide is an "ancient" molecule with an important role in neuronal pancreatic and digestive function. The hypothalamic releasing hormones are part of a family of neural peptides that have a widespread anatomic and phylogenetic distribution and form a diffuse neuroendocrine system. It an material, suggesting that this peptide is an "ancient" molecule with an important role in neuronal pancreatic and digestive function. The hypothalamic releasing hormones are part of a family of neural peptides that have a widespread anatomic and phylogenetic distribution and form a diffuse neuroendocrine system. It an material, suggesting that this peptide is an "ancient" molecule with an important role in neuronal pancreatic and digestive function. The hypothalamic releasing hormones are part of a family of neural peptides that have a widespread anatomic and phylogenetic distribution and form a diffuse neuroendocrine system. It appears likely that the releasing hormones initially arose with a neurocrine or paracrine function, and that only later in evolution did they acquire the role of regulating adenohypophysial secretion.     

Peptidylglycine α-amidating monooxygenase activity and TRH and CRF biosynthesis

Carboxy-terminal amidation of biologically active peptides, an important characteristic of more than half of these substances, occurs during the maturation process of peptide precursors. It is catalyzed by peptidylglycine α-amidating monooxygenase (PAM), an enzyme that is copper-dependent. We show here that alterations of copper stores in cultured cells from different origins (pancreas and hypothalamus) affect the immunoreactivity of thyrotropin-releasing hormone (TRH) and corticotropin-releasing factor (CRF) (two α-amidated peptides). This suggests that copper can affect neuropeptide biosynthesis and may play a role in the endocrine or central nervous system function.     

Involvement of the autonomic nervous system in the in vivo TRH-induced increases in the plasma levels of glucagon, insulin and glucose in rabbits

Thyrotropin-releasing hormone, TRH, increases the plasma levels of glucagon, insulin, glucose and free fatty acids in rabbits. However, TRH has no direct effects on the release of hormones neither from the endocrine pancreas in humans nor from the isolated perfused rat pancreas. The aim of the present study was to investigate if the effects of TRH in rabbits were mediated by the autonomic nervous system. The TRH "Roche"-induced hyperglucagonemia was inhibited by phentolamine (an alpha-receptor blocking drug), yohimbine (an alpha-2 -receptor blocking drug) and atropine. The TRH "Roche"-induced hyperinsulinemia was inhibited by propranolol (a beta-receptor blocking drug). The TRH "Roche"-induced hyperglycemia was inhibited by all four drugs. The TRH "Roche"-induced increases in the plasma levels of free fatty acids were not inhibited by the sympathetic and parasympathetic blocking drugs. The effects of TRH "Roche" on the plasma levels of glucagon, insulin and glucose cannot be explained by increases in the plasma levels of catecholamines. TRH, given intravenously into rabbits, may possibly act on regions in the central nervous system which control carbohydrate metabolism and the release of glucagon and insulin from the endocrine pancreas by sympathetic and parasympathetic mechanisms.     

A Brief History of Pancreatic Reg: Implications as to its Clinical Importance

Although the pancreatic regenerating (reg) gene, was first isolated from a rat regenerating islets in 1988, its protein product was originally described in the 1970s. Reg proteins arise from a multigene family with three subtypes, and have a protein structure similar to calcium dependent lectins. Reg I and II have been implicated in control of pancreatic development and may play a role in maintenance of the beta-cell mass in the mature pancreas. Administration of reg I protein has been used in experimental animals as a therapy for surgically-induced diabetes mellitus. Reg I protein is also an inhibitor of calcium carbonate crystalization, important in maintaining the fluidity of pancreatic juice. The reg III gene, whose protein product is pancreatitis associated protein, is induced during pancreatic inflammation. Serum levels of reg III protein are a sensitive marker of severity of pancreatitis. It is an endogenous pancreatic factor that prevents the bacteria infection and scavenges oxygen-derived free radicals. Reg mRNA has been detected in non-pancreatic tissue such as the enterochromaffin-like cells of the stomach, neoplastic tissues of the colon, the small intestine, nervous system, liver tumors, and pituitary. Reg proteins are mitogens to intestinal epithelial cells, pancreatic ductal, beta cells, and Schwann cells, and are likely important to the overall integrity of the pancreas and gastrointestinal tract.     

The effects of thyrotropin releasing hormone (TRH) on the gastrointestinal tract.

Thyrotropin-releasing hormone (TRH) immunoreactivity is distributed throughout the gastrointestinal tract and the pancreas. We have studied the effect of TRH on several gastrointestinal functions in intact, unanesthetized dogs. Intravenous TRH stimulated gastric action potentials (p<0.01) and transiently inhibited tetragastrin-stimulated gastric acid secretion (p<0.05). TRH had no effect on basal or secretin-stimulated pancreatic exocrine secretion. TRH did not alter water absorption in dogs with Thiry-Vella loops constructed from proximal jejunum.     

Comparative Endocrinology of Piscine Hypothalamic Hypophysiotropic Peptides: Distribution and Activity

Fishes display a variety of anatomical relationships betweenbrain and pituitary to a degree unique among vertebrates. Thisgroup is pivotal for understanding evolution of functions ofhypophysiotropic peptides. We review information concerningoccurrences, distributions and physiological activities of threeidentified peptides in fish brain, and biological propertiesof fish brain extracts. Thyrotropin releasing hormone may bepresent universally in piscine central nervous tissue; however,this peptide has not been clearly demonstrated to have hypophysiotropicactivity in fishes. Somatostatin also has been shown to occurin fish brains; studies of actions of this substance are virtuallyabsent. Gonadotropin releasing hormone is apparently of broadoccurrence in fishes; its hypophysiotropic activity is wellestablished for several teleostean species. Anatomical relationshipsbetween brain and pituitary are particularly varied among elasmobranchs.Investigations involving additional elasmobranch representatives,as well as other fishes, are needed before generalizations canbe made. Widespread extrahypothalamic distribution of hypophysiotropicpeptides in lower vertebrates and neurotransmitter (or related)functions of neurones containing these peptides provide a basisfor proposals concerning evolution of hypothalamic control ofthe pituitary gland.     

The action of FMRFamide (Phe-Met-Arg-Phe-NH2) and related peptides on mammals

First purified 11 years ago from clam ganglia, FMRFamide (Phe-Met-Arg-Phe-NH2) was quickly demonstrated to be cardioactive in several molluscan species. Subsequent discovery that FMRFamide, or FMRFamide-related peptides (FaRPs), were present in mammalian central nervous system and gastrointestinal tract prompted investigations into the effect of FMRFamide on mammals. FMRFamide has now been shown to be cardioexcitatory in mammals, to inhibit morphine-induced antinociception, and to block morphine-, defeat-, and deprivation-induced feeding. It also inhibits colonic propulsive motility, induces behavioral effects when administered intrathecally, and has been reported to have amnesic effects in rodents. A proposal has arisen that a FMRFamide-like substance is an endogenous opioid antagonist and has stimulated a search for such a substance. However, FMRFamide has only weak affinity for opioid receptors and not all the actions of FMRFamide appear to be explained by actions at opioid receptors. Alternative mechanisms have been proposed which suggest that FMRFamide acts as a neuromodulator.     

Localization of TRH-sensitive sites in rat brain mediating intestinal transit

Stereotaxic microinjection of thyrotropin releasing hormone (TRH) into 16 brain areas revealed that only three sites, the medial septum and the lateral and anterior hypothalami, were sensitive to a 1.0 ug dose in stimulating intestinal transit in anesthetized rats. The medial septum and anterior hypothalamus also responded to 0.1 ug, but not to 0.01 ug, of TRH. Because TRH and its receptors are distributed in these brain areas, the present results suggest a possible role for this peptide in the central regulation of gastrointestinal activity.