Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UMLS:C0011570 (depression)
 172,036 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Galanin, a neuroendocrine peptide with a multitude of functions, binds to and acts on specific G-protein coupled receptors. Only one galanin receptor subtype, GalRI, has been cloned so far, although pharmacological evidence suggests the presence of more than one galanin receptor subtype. These receptors mediate via different Gi/Go-proteins the inhibition of adenylyl cyclase, opening of K+-channels and closure of Ca2+-channels. Galanin inhibits secretion of insulin, acetylcholine, serotonin and noradrenaline, while it stimulates prolactin and growth hormone release. Determination of structural components of galanin receptors required for binding of the peptide ligand as carried out recently will facilitate the screening and design of molecules specifically acting on galaninergic systems with therapeutic potential in Alzheimer's disease, feeding disorders, pain and depression.
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PMID:Galanin receptors: involvement in feeding, pain, depression and Alzheimer's disease. 912 74

Results from preclinical studies have validated the participation of neuropeptides in sleep regulation. In recent human and clinical studies it has been shown that peripheral administration of various peptides results in specific changes in the sleep electroencephalogram in humans. Furthermore, it has been demonstrated that certain peptides are common regulators of the electrophysiological and neuroendocrine components of sleep. It is now well established that the balance between the neuropeptides growth hormone-releasing hormone (GHRH) and corticotropin-releasing hormone (CRH) plays a key role in normal and pathological sleep regulation. In young normal subjects, GHRH stimulates slow-wave sleep and growth hormone secretion but inhibits cortisol release, whereas CRH has the opposite effect. During normal aging and during acute depression, the GHRH:CRH ratio is changed in favor of CRH, resulting in disturbances in sleep endocrine activity. In addition to GHRH, galanin, growth hormone-releasing peptide, and neuropeptide Y also promote sleep, unlike ACTH(4-9), which disturbs sleep. In elderly subjects, sleep deteriorates after acute administration of somatostatin but improves after chronic treatment with vasopressin. Vasoactive intestinal polypeptide decelerates the non-rapid eye movement-rapid eye movement cycle and advances the occurrence of the cortisol nadir. The impact of delta sleep-inducing peptide, cholecystokinin, and thyrotropin-releasing hormone on human sleep regulation is not yet clear. This paper reviews recent work investigating the influence of these various neuropeptides on sleep.
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PMID:Neuropeptides and human sleep. 945 70

Administration of hormones to humans and animals results in specific effects on the sleep electroencephalogram (EEG) and nocturnal hormone secretion. Studies with pulsatile administration of various neuropeptides in young and old normal controls and in patients with depression suggest they play a key role in sleep-endocrine regulation. Growth hormone (GH)-releasing hormone (GHRH) stimulates GH and slow wave sleep (SWS) and inhibits cortisol, whereas corticotropin-releasing hormone (CRH) exerts opposite effects. Changes in the GHRH:CRH ratio contribute to sleep-endocrine aberrations during normal ageing and acute depression. In addition, galanin and neuropeptide Y promote sleep, whereas, in the elderly, somatostatin impairs sleep. The rapid eye movement (REM)-nonREM cycle is modulated by vasoactive intestinal polypeptide. Cortisol stimulates SWS and GH, probably by feedback inhibition of CRH. Neuroactive steroids exert specific effects on the sleep EEG, which can be explained by gamma-aminobutyric acid(A) receptor modulation.
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PMID:Effects of hormones on sleep. 955 Jan 12

It is thought that galanin, a 29 amino acid neuropeptide, is involved in various neuronal functions, including the regulation of food intake and hormone release. Consistent with this idea, galanin receptors have been demonstrated throughout the brain, with high levels being observed in the hypothalamus. However, little is known about the mechanisms by which galanin elicits its actions in the brain. Therefore, we studied the effects of galanin and its analogs on synaptic transmission using an in vitro slice preparation of rat hypothalamus. In arcuate nucleus neurons, application of galanin resulted in an inhibition of evoked glutamatergic EPSCs and a decrease in paired-pulse depression, indicating a presynaptic action. The fragments galanin 1-16 and 1-15 produced a robust depression of synaptic transmission, whereas the fragment 3-29 produced a lesser degree of depression. The chimeric peptides C7, M15, M32, and M40, which have been reported to antagonize some actions of galanin, all produced varying degrees of depression of evoked EPSCs. In a minority of cases, C7, M15, and M40 antagonized the actions of galanin. Analysis of mEPSCs in the presence of TTX and Cd2+, or after application of alpha-latrotoxin, indicated a site of action for galanin downstream of Ca2+ entry. Thus, our data suggest that galanin acts via several subtypes of presynaptic receptors to depress synaptic transmission in the rat arcuate nucleus.
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PMID:Galanin receptor-mediated inhibition of glutamate release in the arcuate nucleus of the hypothalamus. 957 Jul 80

The effects of exogenous and endogenous galanin on spinal flexor reflex excitability was evaluated in rats one to eight days after the induction of inflammation by subcutaneous injection of carrageenan into the sural nerve innervation area. In normal rats, electrical stimulation of C-fibres in the sural nerve elicited a brisk reflex discharge. Conditioning stimulation of C-fibres (1/s) generated a gradual increase in reflex magnitude (wind-up), which was followed by a period of reflex hyperexcitability. Intrathecal galanin dose-dependently blocked reflex hyperexcitability induced by C-fibre conditioning stimulation whereas i.t. M-35, a high-affinity galanin receptor antagonist, moderately potentiated this effect. At one to three days after the injection of carrageenen, when inflammation was at its peak, the magnitude of the reflex was significantly increased and discharge duration became prolonged. However, wind-up and reflex hyperexcitability were significantly reduced. Furthermore, reduced reflex excitability during conditioning stimulation ("wind-down") and depression of the reflex were sometimes present, which are rarely observed in normal rats. Intrathecal galanin reduced hyperexcitability during inflammation, although its potency was weaker than in normals. However, the galanin receptor antagonist M-35 strongly enhanced wind-up and reflex hyperexcitability, similarly as in normal rats. The baseline flexor reflex, wind-up and C-fibre conditioning stimulation-induced facilitation were normalized four to eight days after carrageenan injection when signs of inflammation were diminishing. Interestingly, intrathecal galanin and M-35 failed to influence spinal excitability. The results suggest a complex functional plasticity in the role of endogenous galanin in mediating spinal excitability during inflammation. There appears to be an enhanced endogenous inhibitory control by galanin on C-afferent input during the peak of inflammation, which may explain the relative ineffectiveness of exogenous galanin. During the recovery phase there may be a reduction in galanin receptors, which may impair the action of endogenous and exogenous galanin. These results further support the notion that galanin is an endogenous inhibitory peptide in nociception.
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PMID:On the role of galanin in mediating spinal flexor reflex excitability in inflammation. 963 76

The reciprocal interactions between galanin and 5-HT1A receptors in the rat brain are presented. Galanin and its NH2-terminal fragments antagonize 5-HT1A receptor-mediated transmission at the postjunctional level, whereas galanin receptor activation mimics the inhibitory action of 5-HT1A receptor activation at the soma-dendritic level, leading to reductions of 5-HT metabolism and release. These interactions have been shown in both receptor binding studies and functional studies. In view of the present findings, galanin antagonists may represent a new type of anti-depressant drug, based on the 5-HT hypothesis of depression, by enhancing 5-HT release and postjunctional 5-HT1A-mediated transmission. Moreover, following intracerebroventricular injection galanin was found to be internalized in a population of hippocampal nerve cells mainly representing GABA, somatostatin, and/or NPY-immunoreactive nerve cells. The relevance of these findings is discussed in relation to the concept of volume transmission.
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PMID:Galanin modulates 5-hydroxytryptamine functions. Focus on galanin and galanin fragment/5-hydroxytryptamine1A receptor interactions in the brain. 992 78

This paper describes a hypothesis that attempts to account for how changes in noradrenergic systems in the brain can affect depression-related behaviors and symptoms. It is hypothesized that increased activity of the locus coeruleus (LC) neurons, the principal norepinephrine (NE)-containing cells in the brain, causes release of galanin (GAL) in the ventral tegmentum (VTA) from LC axon terminals in which GAL is colocalized with NE. It is proposed that GAL release in VTA inhibits the activity of dopaminergic cell bodies in this region whose axons project to forebrain, thereby resulting in two of the principal symptoms seen in depression, decreased motor activation and decreased appreciation of pleasurable stimuli (anhedonia). The genesis of this hypothesis, which derives from studies using an animal model of depression, is described as well as recent data consistent with the hypothesis. The formulation proposed suggests that GAL antagonists may be of therapeutic benefit in the treatment of depression.
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PMID:Galanin: a significant role in depression? 992 83

Neuropeptides: corticotropin releasing factor (CRF), neuropeptide Y (NPY) and somatostatin (STS) have been associated with depression and anxiety, while neurotensin (NT), calcitonin gene-related peptide (CGRP) and tachykinins [neurokinin A (NKA) and substance P (SP)] are presumed to also play a role in the function of the dopaminergic system. Moreover, investigations in the past decade have shown that psychotomimetics and antipsychotic drugs as well as lithium affect brain synthesis, tissue concentrations, and release of some neuropeptides. In view of the above, experiments were carried out to explore whether changes in neuropeptides constitute one of the mechanisms of action of electroconvulsive treatment (ECT). Human cerebrospinal fluid (CSF) was studied before and after ECT, and brains from healthy and models of depression rats were investigated in electroconvulsive stimuli (ECS)-treated and sham-treated animals. The major findings were that a series of ECTs, in parallel to clinical recovery, increased CSF concentrations of NPY-like immunoreactivity (-LI), STS-LI, and CRF-LI, and in one study endothelin-LI. A series of ECS, but not a single treatment, reproducibly elevated concentrations of NPY-LI, NKA-LI, and STS-LI--but not NT-LI, SP-LI, galanin-LI, or CGRP-LI--in hippocampus, frontal cortex, and occipital cortex. No changes were measured in other regions, e.g., striatum. NPY and STS mRNAs were also increased indicating that ECS affects peptide synthesis. Generalized seizures induced by, e.g., kainic acid or pentylenetetrazole, had similar effects on neuropeptides. The changes persisted for at least 1 week after the last treatment. Pretreatment with compounds reducing seizures, such as benzodiazepines and MK-801; had no effect on magnitude of neuropeptide changes although the seizure duration was decreased by > 50%. On the basis of these findings, it is suggested that neuropeptides are involved in ECT's mechanisms of action. Since ECT is therapeutically efficient in both schizophrenia and depression and, taking into account that antipsychotic drugs and psychotomimetics as well as lithium selectively affect some neuropeptides, it is hypothesized that distinct combinations of neuropeptide and monoamine changes in selected neuronal populations constitute the underpinnings of ECT's effects on specific disease symptoms, conceivably independent of diagnosis.
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PMID:Neuropeptides and electroconvulsive treatment. 1018 19

In the present brief overview we summarize results from several studies focusing on two neuropeptides, galanin and neuropeptide Y (NPY) in discrete neuronal systems, where they coexist with classic transmitters. On the basis of studies in different animal models we propose that these peptides may be involved in regulation of certain CNS functions and that drugs acting on their receptors may be of use in new therapeutic strategies. At the spinal level galanin and NPY are regulated in DRG neurons by nerve injury and in dorsal horn neurons by inflammation. It is possible that this leads to attenuation of pain sensitivity. Moreover, both peptides may exert trophic effects, for example to enhance regeneration. In the hypothalamic arcuate nucleus NPY and its receptors are part of the feeding circuitry, and we suggest that derangement of these NPY neurons may at least in part underlay the lethal phenotype of anorectic mice, which die 22 days postnatally after showing decreased food intake and growth retardation. Expression of NPY and NPY receptors is changed in the hippocampus of mice comparatively early after prion inoculation, indicating that this peptide system is affected in this spongiform degenerative disease in a region of importance for learning and memory. Finally, galanin is co-localized with classic monoamine transmitters in two central systems, the dorsal raphe serotonin neurons and the locus coeruleus noradrenergic neurons. In both cases galanin causes hyperpolarization (at high concentrations) and prolongs monoamine-induced outward currents (at low concentrations), thus modulating activity in two systems of importance for many brain functions including mood regulation. It may therefore be interesting to analyse to what extent drugs affecting galaninergic transmission also may be efficient in the treatment of, for example, depression.
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PMID:Galanin and NPY, two peptides with multiple putative roles in the nervous system. 1042 30

The neuropeptide galanin modulates several physiological functions such as cognition, learning, feeding behavior, and depression, probably via the galanin 1 receptor (GAL-R1). Using an HTS assay based on 125I-human galanin binding to the human galanin-1 receptor (hGAL-R1), we discovered a series of 1,4-dithiin and dithiipine-1,1,4,4-tetroxides that exhibited binding affinity IC50's to hGAL-R1 ranging from 190 to 2700 nM. Two of the dithiepin analogues, 7 and 23, behaved pharmacologically as hGAL-R1 antagonists in secondary assays involving adenylate cyclase activity and GTP binding to G-proteins. Analogues 7 and 23 were also active in functional assays involving galanin, reversing the inhibitory effect of galanin on acetylcholine (ACh) release in rat brain hippocampal slices and electrically-stimulated guinea pig ileum twitch.
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PMID:2,3-Dihydro-dithiin and -dithiepine-1,1,4,4-tetroxides: small molecule non-peptide antagonists of the human galanin hGAL-1 receptor. 1089 15


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