Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UMLS:C0036572 (seizures)
 80,221 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

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

Corticotropin-releasing factor (CRF) has been widely implicated as playing a major role in modulating the endocrine, autonomic, behavioral and immune responses to stress. The recent cloning of multiple receptors for CRF as well as the discovery of non-peptide receptor antagonists for CRF receptors have begun a new era of CRF study. Presently, there are five distinct targets for CRF with unique cDNA sequences, pharmacology and localization. These fall into three distinct classes, encoded by three different genes and have been termed the CRF1 and CRF2 receptors (belonging to the superfamily of G-protein coupled receptors) and the CRF-binding protein. The CRF2 receptor exists as three splice variants of the same gene and have been designated CRF2a CRF2b and CRF2g. The pharmacology and localization of all of these proteins in brain has been well established. The CRF1 receptor subtype is localized primarily to cortical and cerebellar regions while the CRF2a receptor is localized to subcortical regions including the lateral septum, and paraventricular and ventromedial nuclei of the hypothalamus. The CRF2b receptor is primarily localized to heart, skeletal muscle and in the brain, to cerebral arterioles and choroid plexus. The CRF2g receptor has most recently been identified in human amygdala. Expression of these receptors in mammalian cell lines has made possible the identification of non-peptide, high affinity, selective receptor antagonists. While the natural mammalian ligands oCRF and r/hCRF have high affinity for the CRF1 receptor subtype, they have lower affinity for the CRF2 receptor family making them ineffective labels for CRF2 receptors. [125I]Sauvagine has been characterized as a high affinity ligand for both the CRF1 and the CRF2 receptor subtypes and has been used in both radioligand binding and receptor autoradiographic studies as a tool to aid in the discovery of selective small molecule receptor antagonists. A number of non-peptide CRF1 receptor antagonists that can specifically and selectively block the CRF1 receptor subtype have recently been identified. Compounds such as CP 154,526 (12), NBI 27914 (129) and Antalarmin (154) inhibit CRF-stimulation of cAMP or CRF-stimulated ACTH release from cultured rat anterior pituitary cells. Furthermore, when administered peripherally, these compounds compete for ex vivo [125I]sauvagine binding to CRF1 receptors in brain sections demonstrating their ability to cross the blood-brain-barrier. In in vivo studies, peripheral administration of these compounds attenuate stress-induced elevations in plasma ACTH levels in rats demonstrating that CRF1 receptors can be blocked in the periphery. Furthermore, peripherally administered CRF1 receptor antagonists have also been demonstrated to inhibit CRF-induced seizure activity. These data clearly demonstrate that non-peptide CRF1 receptor antagonists, when administered systemically, can specifically block central CRF1 receptors and provide tools that can be used to determine the role of CRF1 receptors in various neuropsychiatric and neurodegenerative disorders. In addition, these molecules will prove useful in the discovery and development of potential orally active therapeutics for these disorders.
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PMID:Recent advances with the CRF1 receptor: design of small molecule inhibitors, receptor subtypes and clinical indications. 1021 97

Noda epileptic rat (NER) is a new epileptic rat strain, which was developed by inbreeding rats with spontaneous tonic-clonic seizures in a stock of Crj:Wistar. In the present study, possible changes of two neuropeptides, neuropeptide Y (NPY) and corticotropin-releasing factor (CRF), in the brains of NER were investigated. Increased contents of immunoreactive (IR) NPY were found in the striatum and amygdala of 8-week NERs with partial seizure, while these changes extended to the limbic region including hippocampus in 16-week NERs with fully developed generalized tonic-clonic seizure. IR-CRF were elevated only in the entorhinal and pyriform cortex of both 8-week and 16-week NERs. Generalized tonic-clonic seizure in NERs induced a transient increase of NPY mRNA in the granular layer of dentate gyrus. These results suggest that NPY metabolism in the limbic brain contributes to the seizure susceptibility in this model of epilepsy.
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PMID:Elevated neuropeptide Y and corticotropin-releasing factor in the brain of a novel epileptic mutant rat: Noda epileptic rat. 1037 6

Rats treated with the neuroepileptic drug, kainic acid, exhibit a specific regional pattern of neurodegeneration 24 h following onset of acute limbic status epilepticus. At 24 h post-seizure, the areas undergoing neurodegeneration also exhibit substantial amounts of the neuropeptide corticotropin-releasing factor (CRF) which is not present under normal conditions. In experimental brains, CRF is localized immunocytochemically to cells and densely labeled fibers in areas with neurodegeneration. Networks of CRF fibers closely surround moribund neurons staining intensely for acid fuchsin. Acid fuchsin, an acidophilic dye, is used routinely as a marker for irreversible neuronal injury, and acid fuchsin-positive neurons are identified in specific areas affected by kainic neurotoxicity. Evidence exists in the literature that CRF functions in brain as a excitatory neurotransmitter/neuromodulator. Under certain pathological conditions (i.e., seizures, brain trauma, ischemia), it has been postulated that CRF could act as an neurotoxic agent. This study provides anatomical evidence that CRF may function following seizures as an neurotoxin because of the close proximity of CRF-labeled fibers to degenerating neurons.
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PMID:Corticotropin-releasing factor--immunolabeled fibers in brain regions with localized kainate neurotoxicity. 1060 38

Increased CNS activity in the form of electrically or chemically induced seizures is known to alter the properties of GABA(A) receptors. The tremorgen, harmaline, causes a bursting pattern of activity in inferior olivary neurons, the effects of which are transmitted throughout the olivocerebellar circuit to other regions of the CNS. In situ hybridization was used to determine the effect of this increased activity on gamma aminobutyric acid(A) (GABA(A)) receptor subunit gene expression in the cerebellar Purkinje cell layer, deep cerebellar nuclei and inferior olivary complex of adult mice. In Purkinje cells, the expression of alpha(1), beta(2), and gamma(2) mRNAs was increased only slightly (<5%) by harmaline administration, while in deep cerebellar neurons, beta(2) transcript levels were initially elevated (26%), but dropped to control levels immediately thereafter. The expression of alpha(2), alpha(4), beta(3) and gamma(1) mRNAs in olivary neurons was affected differentially by harmaline administration. The alpha(4) transcript was increased, reaching >60% above control levels at 6 h post-injection. A smaller increase was observed for alpha(2) mRNA, while beta(3) and gamma(1) transcripts dropped below control levels during the same period. The expression of corticotropin-releasing factor mRNA was also elevated in the olivary complex. These data indicate that while Purkinje cells and deep cerebellar neurons are only minimally affected, harmaline induced changes in cellular properties may result in increased numbers of alpha(4)-containing, diazepam-insensitive, GABA(A) receptors in olivary neurons.
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PMID:Harmaline-induced changes in gamma aminobutyric acid(A) receptor subunit mRNA expression in murine olivocerebellar nuclei. 1114 22

We investigated seizures in 22 children with congenital adrenal hyperplasia (CAH), eight of whom had seizures associated with fever. The follow-up period was 5-18 years. The onset of seizures ranged from 1 to 4 years of age, and the total number of seizures was one to three in all cases. Four cases had seizures twice within 24 hours. None had seizures after 5 years of age. In two of the eight cases, the seizures may have caused by hypoglycemia or hyponatremia, in the remaining six they were considered to be febrile seizures. Three of them had first-degree relatives with febrile seizures. Electroencephalogram was recorded in five cases, with normal results in all of them. One case with febrile status developed localization-related epilepsy later. None showed developmental delay during follow-up. Although seizures in CAH have been ascribed to hypoglycemia and/or metabolic disorders (hyponatremia), our findings implicate unknown factors in the pathogenesis such as excess secretion of corticotropin releasing factor (CRF) under stress, prolonged elevation of CRF during fetus life and linkage between CAH and febrile seizures on the chromosome 6.
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PMID:[Seizures associated with fever in children of congenital adrenal hyperplasia]. 1119 91

Infantile spasms is an epilepsy syndrome with several distinctive features, including age specificity during infancy, characteristic semiology (epileptic spasms), specific electroencephalographic patterns (interictal hypsarrhythmia and ictal voltage suppression), and responsiveness to the adrenocorticotropic hormone (ACTH). There is no adequate animal model of infantile spasms, perhaps due to these clinically unique features, that is specific for the developing human brain. An informative animal model would provide insights into the pathophysiology of this syndrome and form the basis for the development of innovative therapies. This chapter considers criteria for an "ideal" animal model of infantile spasms, as well as "minimal" criteria that we consider essential to yield useful information. Two animal models of infantile spasms have been described in rodents: seizures induced by corticotropin-releasing factor and N-methyl-D-aspartic acid. Neither of these models conforms exactly to the human analog, but each possesses intriguing similarities that provide testable hypotheses for future investigations.
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PMID:Infantile spasms: criteria for an animal model. 1204 Sep 4

Considerable attention has been focused on the role of corticotropin releasing factor (CRF) as well as CRF-binding protein (CRF-BP) in neuropsychiatric disorders and neurodegenerative diseases including epilepsy. Therefore, in the present study, we investigated the temporal and spatial alteration of CRF and CRF-BP in the gerbil hippocampal complex in order to characterize the possible changes and associations with different sequelae of spontaneous seizure in these animals. CRF immunoreactivity was shown in the interneurons of the hippocampal complex at 30 min following seizure. Additionally, alteration of CRF-BP immunoreactivity was restricted to the entorhinal cortex after seizure. These results indicate some factors for consideration. First, in the gerbil hippocampal complex, the delayed increase of CRF immunoreactivity, in spite of its excitatory function, may attenuate seizure activity, but may not do so in epileptogenesis. Second, in contrast to the hippocampal complex, the increase in CRF-BP immunoreactivity in the entorhinal cortex following seizure may participate in feedback inhibitory modulation.
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PMID:The differential expression of corticotropin releasing factor and its binding protein in the gerbil hippocampal complex following seizure. 1244 Nov 68

Considerable attention has been focused on the role of corticotropin-releasing factor (CRF) in neuropsychiatric disorders and neurodegenerative diseases including epilepsy. Therefore, in the present study, we investigated the temporal and spatial alteration of CRF receptor in the gerbil hippocampal complex in order to characterize the possible changes and associations with different sequelae of spontaneous seizure in these animals. Thirty minutes postictal, a decline in CRF receptor immunoreactivity was observed in the granule cells and hilar neurons. In the subiculum, CRF receptor immunoreactivity was also significantly decreased at this time point. Twenty-four hours after seizure onset, the immunoreactivity in these regions recovered to the pre-seizure level. Moreover, 30 min after seizure in the entorhinal cortex, the density of CRF receptor immunoreactivity began to decrease, particularly in the layers II and III, compared to pre-seizure group. Nevertheless, 24h after seizure onset, CRF receptor immunodensity had recovered to its seizure-sensitive (SS) level. These results suggest that altered CRF receptor expression in the hippocampal complex may affect tissue excitability and seizure activity in SS gerbils.
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PMID:Altered corticotropin-releasing factor (CRF) receptor immunoreactivity in the gerbil hippocampal complex following spontaneous seizure. 1260 81

Managing patients with treatment-resistant depression (TRD) remains a major challenge for the practicing physician. Depression is considered treatment-resistant when at least two adequate monotherapy trials with drugs from different pharmacologic classes fail to elicit a therapeutic response. Although determining the stage of TRD may allow concise description of a patient's antidepressant history, management of TRD is better served by recent attempts to create a treatment algorithm that encompasses definitive diagnosis of true TRD and strategies for optimizing available therapies, including consideration of novel treatment options. Present strategies for managing TRD include optimization of the initial drug, substitution of another drug from the same or a different antidepressant class, combination of two antidepressants with different mechanisms of action, and adding an antidepressant drug from another class. Potential nonpharmacologic treatments include vagus nerve stimulation, repetitive transcranial magnetic stimulation, and magnetic seizure therapy as an alternative to electroconvulsive therapy. Several neuropeptides and their receptors have also been identified as potential targets for pharmacologic intervention, including corticotropin-releasing factor and substance P. Other treatments currently under investigation include augmentation of antidepressant therapy with an atypical antipsychotic agent such as olanzapine or risperidone. This kind of therapeutic intervention may prove to be especially useful in treating patients with TRD.
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PMID:Treatment-resistant depression: new therapies on the horizon. 1283 33


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