Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts:   Target Concepts:
Query: UNIPROT:P06889 (Mol)
 630,302 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Increased expression of drug efflux transporters at the blood-brain barrier accompanies epileptic seizures and complicates therapy with antiepileptic drugs. This study is concerned with identifying mechanistic links that connect seizure activity to increased P-glycoprotein expression at the blood-brain barrier. In this regard, we tested the hypothesis that seizures increase brain extracellular glutamate, which signals through an N-methyl-d-aspartate (NMDA) receptor and cyclooxygenase-2 (COX-2) in brain capillaries to increase blood-brain barrier P-glycoprotein expression. Consistent with this hypothesis, exposing isolated rat or mouse brain capillaries to glutamate for 15 to 30 min increased P-glycoprotein expression and transport activity hours later. These increases were blocked by 5H-dibenzo[a,d]cyclohepten-5,10-imine (dizocilpine maleate) (MK-801), an NMDA receptor antagonist, and by celecoxib, a selective COX-2 inhibitor; no such glutamate-induced increases were seen in brain capillaries from COX-2-null mice. In rats, intracerebral microinjection of glutamate caused locally increased P-glycoprotein expression in brain capillaries. Moreover, using a pilocarpine status epilepticus rat model, we observed seizure-induced increases in capillary P-glycoprotein expression that were attenuated by administration of indomethacin, a COX inhibitor. Our findings suggest that brain uptake of some antiepileptic drugs can be enhanced through COX-2 inhibition. Moreover, they provide insight into one mechanism that underlies drug resistance in epilepsy and possibly other central nervous system disorders.
Mol Pharmacol 2008 May
PMID:Seizure-induced up-regulation of P-glycoprotein at the blood-brain barrier through glutamate and cyclooxygenase-2 signaling. 1831 94

The mesencephalic astrocyte-derived neurotrophic factor (MANF) has been described as a survival factor for dopaminergic neurons in vitro, but its expression in mammalian tissues is poorly known. MANF and a homologous protein, the conserved dopamine neurotrophic factor (CDNF), form a novel evolutionary conserved family of neurotrophic factors. Here we used in situ hybridization and immunohistochemistry to characterize MANF expression in developing and adult mouse. MANF expression was widespread in the nervous system and non-neuronal tissues. In the brain, relatively high MANF levels were detected in the cerebral cortex, hippocampus and cerebellar Purkinje cells. After status epilepticus, Manf mRNA expression was transiently increased in the dentate granule cell layer of hippocampus, thalamic reticular nucleus and in several cortical areas. In contrast, following global forebrain ischemia changes in Manf expression were widespread in the hippocampal formation and more restricted in cerebral cortex. The widespread expression of MANF together with its evolutionary conserved nature and regulation by brain insults suggest that it has important functions both under normal and pathological conditions in many tissue types.
Mol Cell Neurosci 2008 Nov
PMID:MANF is widely expressed in mammalian tissues and differently regulated after ischemic and epileptic insults in rodent brain. 1871 66

The aim of this study was to investigate the dynamics of lipid peroxidation and the possible correlation between lipid peroxidation in different brain regions and behavioral manifestations in lindane-induced seizures in rats. Male Wistar rats were divided into the following groups: 1. control, saline-treated group; 2. dimethylsulfoxide (DMSO)-treated group; 3. lindane-treated group (8 mg/kg), intraperitoneally. Animals were sacrificed 0.5 or 4 h after treatment and the malondialdehyde level and superoxide dismutase (SOD) activity were determined in various brain regions spectrophotometrically. Behavioral changes were classified according to the descriptive scale (0--no response, 1--head nodding, lower jaw twitching; 2--myoclonic body jerks, bilateral forelimb clonus with full rearing; 3--progression to generalized clonic convulsions followed by tonic extension of fore- and hind limbs and tail; 4--status epilepticus). A significant rise in the malondialdehyde level was detected in the cerebral cortex, hippocampus, and thalamus of lindane-treated animals 0.5 and 4 h after administration (P < 0.05). SOD activity (total and mitochondrial) was significantly decreased in the hippocampus and the cortex of lindane-treated animals at both time points (P < 0.05). An initial fall in SOD activity was detected in the thalamus 4 h after lindane administration (P < 0.05). A positive correlation between seizure severity and the malondialdehyde level was found in the hippocampus at both time points (P < 0.01). These results suggest that lipid peroxidation may contribute to the neurotoxic effects of lindane in early acute lindane intoxication and that behavioral manifestations correlate with lipid peroxidation in the hippocampus of lindane-treated rats.
Mol Cell Biochem 2010 Jan
PMID:The correlation between lipid peroxidation in different brain regions and the severity of lindane-induced seizures in rats. 1969 53

While current medications for epilepsy are primarily symptomatic treatments that suppress seizures, one of the main goals of future drug development in epilepsy is the identification of antiepileptogenic or disease-modifying therapies that can completely prevent epilepsy or slow its progression. A rational antiepileptogenic strategy is to target primary cell signaling pathways that initially trigger the downstream mechanisms causing epileptogenesis. Recent work implicates the mammalian target of rapamycin (mTOR) pathway as mediating epileptogenesis in a genetic epilepsy, Tuberous Sclerosis Complex (TSC), and suggests that mTOR inhibitors, such as rapamycin, may have antiepileptogenic properties for epilepsy in TSC. As mTOR regulates multiple cellular functions that may contribute to epileptogenesis in general, including ion channel expression, synaptic plasticity, and programmed cell death, mTOR inhibitors might also represent an effective antiepileptogenic therapy for other, more common types of epilepsy, such as acquired epilepsies due to brain injuries. Here, we describe evidence from a recently-published study that mTOR mediates epileptogenesis in a popular animal model of acquired limbic epilepsy due to brain injury following kainate-induced status epilepticus, and that rapamycin has antiepileptogenic effects in this model. Furthermore, putative pathways and mechanisms upstream and downstream from mTOR involved in epileptogenesis in the kainite model are considered, identifying possible additional therapeutic targets. Finally, the potential translational applications of this and other animal model data for developing antiepileptogenic therapies for people with acquired epilepsy due to brain injury are discussed.
Mol Cell Pharmacol 2009 Jan 01
PMID:Developing Antiepileptogenic Drugs for Acquired Epilepsy: Targeting the Mammalian Target of Rapamycin (mTOR) Pathway. 2041 51

The activity of the neuronal-specific potassium chloride co-transporter KCC2 allows neurons to maintain low intracellular Cl(-) concentrations. These low Cl(-) concentrations are critical in mediating fast synaptic inhibition upon the activation of Cl(-)-permeable ligand-gated ion channels such as type A gamma-aminobutyric acid receptors (GABA(A)Rs). Deficits in KCC2 functional expression thus play central roles in the etiology of epilepsy and ischemia. It is emerging that KCC2 is phosphorylated on tyrosine residues, but the molecular substrates for this covalent modification within KCC2 and its functional significance remain poorly understood. Here we demonstrate that in HEK-293 cells the principal sites of tyrosine phosphorylation within KCC2 are residues 903 and 1087 (Y903/1087), which lie within the major C-terminal intracellular domain of KCC2. Phosphorylation of Y903/1087 decreases the cell surface stability of KCC2 principally by enhancing their lysozomal degradation. We further demonstrate that in cultured hippocampal neurons prolonged activation of muscarinic acetylcholine receptors (mAChRs) enhances KCC2 tyrosine phosphorylation and lysozomal degradation. Consistent with our in vitro studies, induction of status epilepticus (SE) in mice using pilocarpine, a mAChR agonist, induces large deficits in the cell surface stability of KCC2 together with enhanced tyrosine phosphorylation. Tyrosine phosphorylation of KCC2 is thus likely to play a key role in regulating the degradation of KCC2, a process that may be responsible for pathological losses of KCC2 function that are evident in SE and other forms of epilepsy.
Mol Cell Neurosci 2010 Oct
PMID:Tyrosine phosphorylation regulates the membrane trafficking of the potassium chloride co-transporter KCC2. 2060 Sep 29

Neuron-restrictive silencer factor (NRSF) and its isoforms are differentially regulated in rodent models of self-sustaining status epilepticus (SSSE). NRSF isoforms regulate genes associated with SSSE, including the proconvulsant tachykinins, brain-derived neurotrophic factor and multiple ion channels. NRSF isoforms may direct distinct gene expression patterns during SSSE, and the ratio of each isoform may be a causative factor in traumatic damage to the central nervous system. Here, we analysed global gene expression changes by microarray in human SK-N-AS neuroblastoma cells following the over-expression of NRSF and a truncated isoform, HZ4. We used bioinformatics software to analyse the microarray dataset and correlated these data with epilepsy candidate gene pathways. Findings were validated by reverse transcriptase-polymerase chain reaction. We demonstrated that NRSF and HZ4 direct overlapping as well as distinct gene expression patterns, and that they differentially modulated gene expression patterns associated with epilepsy. Finally, we revealed that NRSF gene expression may be modulated by the anticonvulsant, phenytoin. We have interpreted our data to reflect altered gene expression directed by NRSF that might be relevant for SSSE.
J Mol Neurosci 2011 Jun
PMID:Distinct gene expression profiles directed by the isoforms of the transcription factor neuron-restrictive silencer factor in human SK-N-AS neuroblastoma cells. 2065 37

Recurrent seizures can induce mossy fiber sprouting (MFS), of the hippocampal dentate gyrus, and synaptic reorganization in mature brain. This changes local circuits and provides a structural basis for epileptogenesis in the hippocampus. However, the mechanisms of MFS and synaptic reorganization still remain unclear. Neural-cadherin (N-cadherin), a calcium adhesion molecule, plays an important role in neurite outgrowth, pathfinding, and synaptic specificity of early central nervous system development. It is unknown whether N-cadherin is involved in MFS after seizures in mature brain. To further examine the correlation between MFS and N-cadherin expression, we separately labeled MFS and N-cadherin with Timm staining and antibody in adult rats after status epilepticus (SE). Timm staining revealed that MFS is observed in the inner molecular layer of dentate gyrus of rats 2 and 4 weeks after SE. The observed MFS migrated from the hilus to the granule cell layer, gradually extending axons into the inner molecular layer to form an intense band. Immunohistochemical staining of N-cadherin revealed that the upregulated expression of N-cadherin was concentrated in the position of mossy fiber axonal sprouts of rats 1-4 weeks after SE, and that it was earlier than MFS. The spatial and temporal distribution consistence of N-cadherin and Timm staining supported the correlation that exists between N-cadherin expression and the process of aberrant MFS. This result suggests that N-cadherin may be involved in the pathfinding and synaptic specificity of MFS in mature brain after seizures, and can play an important role in the targeted growth of mossy fibers.
Mol Cell Biochem 2011 Dec
PMID:Spatiotemporal profile of N-cadherin expression in the mossy fiber sprouting and synaptic plasticity following seizures. 2172 Jul 65

There is a growing concern about the effects of chemicals on the developing nervous system. Chemical exposure at critical periods of development can be associated with effects ranging from subtle to profound on the structure and/or function of the nervous system. Understanding critical biological molecular targets, which underlie chemical-induced neurotoxicity, will provide a scientific basis for risk assessment. Cell signaling molecules such as protein kinase C (PKC) have been shown to play critical roles in motor activity, development of the nervous system, and in learning and memory. PKC also has been shown to be associated with several neurological disorders including Alzheimer's disease, status epilepticus, and cerebellar ataxia. In the literature, there is abundant information linking PKC to cognitive function, long-term potentiation, or brain structural changes. Here, we show the relationship between changes in PKC (as assayed using radioactive material or by western blots) and the neurotoxic effects caused by environmental chemicals in vitro and in vivo.
Methods Mol Biol 2011
PMID:Cell signaling and neurotoxicity: protein kinase C in vitro and in vivo. 2181 75

The anticonvulsant effect of cyano-carvone, a monoterpene monocyclic, was investigated in epilepsy model induced by pilocarpine. Cyano-carvone at doses of 25, 50 or 75 mg/kg promoted a reduction of 16.7, 33 and 66.7%, respectively, against pilocarpine-induced seizures, and it was efficacious in increasing both the latency to first seizures and the survival percentage, resulting in 33.3, 67 and 91.7% of protection against death induced by seizures, respectively (P < 0.05). The reference drug atropine (25 mg/kg) also produced a significant protection (100%). Its monoterpene, at 25, 50 and 75 mg/kg, was also capable to increase the latency for installation of status epilepticus induced by pilocarpine, and presented a significant protection against lipid peroxidation and nitrite formation in mice hippocampus (P < 0.05). In addition, it was observed that the cyano-carvone pretreatment increased the acetylcholinesterase activity in mice hippocampus after pilocarpine-induced seizures. The present results clearly indicate the anticonvulsant ability of cyano-carvone, which can be, at least in part, explained by the increased activity of the acetylcholinesterase enzyme. Our data suggest that the action mechanism can also be due to a direct activation of the antioxidant enzymes that could be associated with a reduction observed in oxidative stress in mice hippocampus, probably involving an inhibition of free radical production.
Cell Mol Neurobiol 2012 May
PMID:Anticonvulsant and antioxidant effects of cyano-carvone and its action on acetylcholinesterase activity in mice hippocampus. 2237 95

Recent studies show a key role of brain inflammation in epilepsy. However, the mechanisms controlling brain immune response are only partly understood. In the periphery, acetylcholine (ACh) release by the vagus nerve restrains inflammation by inhibiting the activation of leukocytes. Recent reports suggested a similar anti-inflammatory effect for ACh in the brain. Since brain cholinergic dysfunctions are documented in epileptic animals, we explored changes in brain cholinergic gene expression and associated immune response during pilocarpine-induced epileptogenesis. Levels of acetylcholinesterase (AChE) and inflammatory markers were measured using real-time RT-PCR, in-situ hybridization and immunostaining in wild type (WT) and transgenic mice over-expressing the "synaptic" splice variant AChE-S (TgS). One month following pilocarpine, mice were video-monitored for spontaneous seizures. To test directly the effect of ACh on the brain's innate immune response, cytokines expression levels were measured in acute brain slices treated with cholinergic agents. We report a robust up-regulation of AChE as early as 48 h following pilocarpine-induced status epilepticus (SE). AChE was expressed in hippocampal neurons, microglia, and endothelial cells but rarely in astrocytes. TgS mice overexpressing AChE showed constitutive increased microglial activation, elevated levels of pro-inflammatory cytokines 48 h after SE and accelerated epileptogenesis compared to their WT counterparts. Finally we show a direct, muscarine-receptor dependant, nicotine-receptor independent anti-inflammatory effect of ACh in brain slices maintained ex vivo. Our work demonstrates for the first time, that ACh directly suppresses brain innate immune response and that AChE up-regulation after SE is associated with enhanced immune response, facilitating the epileptogenic process. Our results highlight the cholinergic system as a potential new target for the prevention of seizures and epilepsy.
Front Mol Neurosci 2012
PMID:Acetylcholinesterase loosens the brain's cholinergic anti-inflammatory response and promotes epileptogenesis. 2263 69


<< Previous 1 2 3 4 5 6 7 8 9 10 Next >>