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)

Studies on the sigma receptor and related compounds are becoming more attractive since they were found to be closely related to higher brain functions such as memory, learning, depression, anxiety, schizophrenia and neuroprotection. Along with these pharmacological findings, the single transmembrane-type, non-metabotropic sigma binding protein has been cloned, while the presence of metabotropic sigma receptor has been also claimed. Thus, various pharmacological findings are now ready to be characterized on the molecular basis of receptor mechanisms. On the other hand, neurosteroids have higher brain functions such as non-genomic fast actions, which are similar to the actions of sigma compounds. Indeed some neurosteroids were revealed to behave as sigma agonists while others behave like antagonists of metabotropic sigma receptors. Pharmacological studies to determine if sigma compounds can be used to cure various central symptoms related to neurosteroids or steroid hormones can be expected.
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PMID:[Sigma (sigma) receptor and neurosteroids]. 1056 65

Steroids, synthesized in peripheral glands or centrally in the brain--the latter being named neurosteroids--exert an important role as modulators of the neuronal activity by interacting with different receptors or ion channels. In addition to the modulation of GABA(A), NMDA or cholinergic receptors, neuroactive steroids interact with an atypical intracellular receptor, the sigma(1) protein. This receptor has been cloned in several species, and highly selective synthetic ligands are available. At the cellular level, sigma1 agonists modulate intracellular calcium mobilization and extracellular calcium influx, NMDA-mediated responses, acetylcholine release, and alter monoaminergic systems. At the behavioral level, the sigma1 receptor is involved in learning and memory processes, the response to stress, depression, neuroprotection and pharmacodependence. Pregnenolone, dehydroepiandrosterone, and their sulfate esters behave as sigma1 agonists, while progesterone is a potent antagonist. This review will detail the physiopathological consequences of these interactions, focusing on recent results on memory and depression. The therapeutical interest of selective sigma1 receptor agonists in alleviating aging-related cognitive deficits will be discussed.
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PMID:The interaction between neuroactive steroids and the sigma1 receptor function: behavioral consequences and therapeutic opportunities. 1174 80

Sigma receptors have recently been the target of drug development related to psychiatric disorders, including schizophrenia and depression, as well as cognitive enhancers. This paper focused on the sigma-receptor-mediated modulation of neuronal activity, especially the effects on aminergic neuron and hippocampal neuron activity. Dopaminergic neuron activities in the substantia nigra and ventral tegmental area (VTA) are variously modified by the systemic administration of sigma ligands. When applied with microiontophoresis, they are reported to increase dopaminergic neuron activity in the VTA. This activity may be involved in the psychotropic or antipsychotic effects of these ligands. Moreover, serotonergic neurons in the raphe nucleus and noradrenergic neurons in the locus coeruleus were activated by sigma ligands. These effects are probably related to the antidepressant activity of sigma receptor ligands. In the hippocampus, sigma ligands suppressed CA1 neuronal activity in vitro. The effects were suggested to be due to an increase in the threshold of action potential and decreased synaptic transmission efficacy. NMDA receptor function was modified in biphasic fashion related to doses of sigma ligands, that is, a lower dose facilitated the NMDA receptor functions, and a higher dose inhibited them. These effects on the hippocampal neurons may contribute to their neuroprotective and antiamnesic actions. Further studies are needed to elucidate the relation between the physiological function of sigma receptor and psychiatric diseases by the use of sigma receptor ligands and molecular techniques.
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PMID:[Modulation of neuronal activities in the central nervous system via sigma receptors]. 1191 6

Sigma (sigma) sites are a type of nonopiate receptor whose role has been associated with several behaviours, including anxiety, depression, analgesia, learning processes and psychosis. Although there are several known sigma receptor types, only the type I receptor (sigma 1) has been cloned. To uncover the in vivo relevance of sigma-receptors, we have generated knockout mice for sigma 1. Despite the broad expression pattern found for the sigma 1-gene, homozygous mutant mice are viable, fertile and do not display any overt phenotype, compared with their wild-type litter-mates, in mixed genetic backgrounds. However, a significant decrease in the hypermotility response has been measured in knockout mice upon challenge with (+)SKF-10 047, in agreement with the involvement of sigma 1-receptors in the induction of psychostimulant actions. The activity of sigma 2-receptors seems to be unaffected in sigma 1-mutant mice. These knockout mice could contribute to better understand the in vivo role of sigma-receptors.
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PMID:Generation and phenotypic analysis of sigma receptor type I (sigma 1) knockout mice. 1462 79

The sigma receptor was originally proposed to be a subtype of the opioid receptor. However, it is now clear that sigma receptors are unique non-opioid, non-phencyclidine brain proteins. Two types of sigma receptor exist, the sigma-1 receptor and the sigma-2 receptor. sigma-1 receptors have been cloned and their distribution, physiological functions and roles in signal transduction were recently characterised. Certain sex hormones in the brain (neurosteroids) are known to interact with sigma-1 receptors. sigma-1 receptors regulate glutamate NMDA receptor function and the release of neurotransmitters such as dopamine. They are thus proposed to be involved in learning and memory as well as in certain neuropsychiatric disorders. Selective sigma-1 receptor ligands have been suggested to represent a new class of therapeutic agents for neuropsychiatric disorders, although none have yet been introduced into therapeutic use. Early studies showed that psychotomimetic benzomorphans, as well as several antipsychotics, can bind to sigma-1 receptors. As a result of these findings, sigma-1 receptor ligands have been proposed as being of potential use in the treatment of schizophrenia. Nevertheless, the relationship of sigma-1 receptors to the underlying pathogenesis of schizophrenia is still unclear. sigma-1 receptor ligands have failed to improve acute psychotic symptoms of schizophrenia in clinical trials, but, interestingly, a few studies have shown an improvement in negative symptoms in schizophrenic patients. A number of preclinical studies have shown that selective agonists of sigma-1 receptors affect higher-ordered brain functions such as learning and memory, cognition and mood. These studies indicate that sigma-1 receptor agonists may exert therapeutic effects in depression and senile dementia. Indeed, the sigma-1 receptor agonist igmesine, has been shown to improve depression in a clinical trial. The most distinctive feature of the action of sigma-1 receptor ligands is their "modulatory" role. In behavioural studies of depression and memory, they exert beneficial effects only when brain functions are perturbed. Given the recently accumulated preclinical and clinical data, it is time to reconstruct the concept of sigma-1 receptors and the associated pathophysiological conditions that ligands of these receptors target. This would allow clinical trials to be performed more efficiently, and the results may confirm a long-speculated possibility that sigma-1 receptor ligands represent a new class of therapeutic agents for neuropsychiatric disorders.
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PMID:Sigma-1 receptor ligands: potential in the treatment of neuropsychiatric disorders. 1508 13

The term "neurosteroid" (NS) was introduced by Baulieu in 1981 to name a steroid hormone, dehydroepiandrosterone sulfate (DHEAS), that was found at high levels in the brain long after gonadectomy and adrenalectomy, and shown later to be synthetized by the brain. Later, androstenedione, pregnenolone and their sulfates and lipid derivatives as well as tetrahydrometabolites of progesterone (P) and deoxycorticosterone (DOC) were identified as neurosteroids. The term "neuroactive steroid" (NAS) refers to steroids which, independent of their origin, are capable of modifying neural activities. NASs bind and modulate different types of membrane receptors. The GABA and sigma receptor complexes have been the most extensively studied, while glycine-activated chloride channels, nicotinic acetylcholine receptors, voltage-activated calcium channels, although less explored, are also modulated by NASs. Within the glutamate receptor family, N-methyl-d-aspartate (NMDA) receptors, alpha-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid (AMPA) receptors and kainate receptors have also been demonstrated to be a target for steroid modulation. Besides their membrane effects, once inside the neuron oxidation of Ring A reduced pregnanes, THP and THDOC, bind to the progesterone intracellular receptor and regulate gene expression through this path. The involvement of NASs on depression syndromes, anxiety disorders, stress responses to different stress stimuli, memory processes and related phenomena such as long-term potentiation are reviewed and critically evaluated. The importance of context for the interpretation of behavioral effects of hormones as well as for hormonal levels in body fluids is emphasized. Some suggestions for further research are given.
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PMID:Steroids, neuroactive steroids and neurosteroids in psychopathology. 1569 25

The neurochemistry of feeding was a highlight of this meeting. A number of peptides are now known to participate in the control of nutrient balance, and many of them featured in the meeting, including the feeding suppressors alpha-melanocyte-stimulating hormone, leptin and corticotrophin releasing hormone, and the orexigenic agents, melanin-concentrating hormone, Agouti-related peptide, orexin A and neuropeptide Y. Other substances that play a role in feeding are amylin and its antagonist, AC-187, histamine, dopamine, serotonin, opiates, galanin and CART peptides. The hypothalamic and extrahypothalamic localization of these feedingrelated substances and their interactions with one another, and other brain regions, are beginning to be understood. Another symposium focused on sigma receptor ligands, such as (+)-pentazocine, PRE-084, the neurosteroid pregnanolone sulfate, NE-100, igmesine (JO-1784) and BD-1008 and related compounds. Results showed that sigma ligands may affect Ca(2+) signaling via two modes of action, one being at the endoplasmic reticulum and the other at the plasma membrane. Sigma receptors have been implicated in learning and memory, and may play a role in anxiety and depression.
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PMID:International Behavioral Neuroscience Society - Ninth meeting. Neurochemistry of feeding. 1608 42

Based on a medicinal-chemistry-guided approach, three novel series of druglike cycloalkyl-annelated pyrazoles were synthesized and display high affinity (pKi>8) for the sigma1 receptor. Structure-affinity relationships were established, and the different scaffolds were optimized with respect to sigma1 binding and selectivity versus the sigma2 receptor and the hERG channel, resulting in selective compounds that have Ki values (for sigma1) in the subnanomolar range. Selected compounds were screened for cytochrome P450 inhibition (CYP1A2, CYP2A6, CYP2B6, CYP2C8, CYP2C9, CYP2C19, CYP2D6, CYP2E1, CYP3A4), metabolic stability (rat and human liver microsomes), and cell-membrane permeability (Caco-2). They showed favorable in vitro ADME properties as well as favorable calculated druglike and experimental physicochemical properties. Furthermore, compounds 7 f and 17 a, for example, displayed high selectivity (affinity) for the sigma1 receptor against a wide range of other receptors (>60). With these valuable tool compounds in hand, we are further exploring the role of the sigma1 receptor in relevant animal models corresponding to such medicinal indications as drug abuse, pain, depression, anxiety, and psychosis.
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PMID:A medicinal-chemistry-guided approach to selective and druglike sigma 1 ligands. 1689 45

Neurosteroids (NS) are steroids synthesized by the brain. Neuroactive steroids (NAS) refers to steroids that, independent of their origin, are capable of modifying neural activities. NAS bind and modulate different types of membrane receptors. The gamma amino butyric acid (GABA) and sigma receptor complexes have been the most extensively studied. Oxidized ring A reduced pregnanes, tetrahydroprogesterone (THP), and tetrahydrodeoxycorticosterone (THDOC) bind to the progesterone intracellular receptor (PR), and in this way can also regulate gene expression. Animal experimentation showed that salient symptoms of depression, viz., anxiety, sleep disturbances, and memory and sexual dysfunctions, are modulated by NAS. In turn, psychotropic drugs modulate NS and NAS levels. NS levels as well as NAS plasma concentrations change in patients with depression syndromes, the levels return to normal baseline with recovery, but normalization is not necessary for successful therapy. Results from current studies on the evolution of nervous systems, including evolutionary developmental biology as well as anatomical and physiological findings, almost preclude a categorical classification of the psychiatric ailments the human brain succumbs to. The persistence in maintaining such essentialist classifications may help to explain why up to now the search for biological markers in psychiatry has been an unrewarding effort. It is proposed that it would be more fruitful to focus on relationships between NAS and symptoms of psychiatric disorders, rather than with typologically defined disorders.
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PMID:Neurosteroids, neuroactive steroids, and symptoms of affective disorders. 1696 51

Sigma receptors are classified into sigma(1) and sigma(2) subtypes. These subtypes display a different tissue distribution and a distinct physiological and pharmacological profile in the central and peripheral nervous system. The characterization of these subtypes and the discovery of new specific sigma receptor ligands demonstrated that sigma receptors are novel targets for the therapeutic treatment of neuropsychiatric diseases (schizophrenia, depression, and cognition), brain ischemia, and cocaine addiction. Furthermore, imaging of sigma(1) receptors in the human brain using specific PET radioligands has started. In addition, the two sigma receptor subtypes are also expressed on tumor cells, where they could be of prognostic relevance. The ability of sigma(2) receptor agonists to inhibit tumor cell proliferation through mechanisms that might involve apoptosis, intracellular Ca(2+), and sphingolipids has promoted the development of sigma(2) receptor agonists as novel therapeutic drugs for treating cancer. Consequently, sigma(2) receptor ligands have been demonstrated to be potentially useful tumor imaging ligands. In this article, we focus on the sigma receptor ligands as therapeutic agents and as radiopharmaceuticals.
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PMID:Sigma receptor ligands: possible application as therapeutic drugs and as radiopharmaceuticals. 1707 84


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