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

Zinc is an important trace element in biology. An important pool of zinc in the brain is the one present in synaptic vesicles in a subgroup of glutamatergic neurons. In this form it can be released by electrical stimulation and may serve to modulate responses at receptors for a number of different neurotransmitters. These include both excitatory and inhibitory receptors, particularly the NMDA and GABA(A) receptors. This pool of zinc is the only form of zinc readily stained histochemically (the chelatable zinc pool), but constitutes only about 8% of the total zinc content in the brain. The remainder of the zinc is more or less tightly bound to proteins where it acts either as a component of the catalytic site of enzymes or in a structural capacity. The metabolism of zinc in the brain is regulated by a number of transport proteins, some of which have been recently characterized by gene cloning techniques. The intracellular concentration may be mediated both by efflux from the cell by the zinc transporter ZrT1 and by complexing with apothionein to form metallothlonein. Metallothionein may serve as the source of zinc for incorporation into proteins, including a number of DNA transcription factors. However, zinc is readily released from metallothionein by disulfides, increasing concentrations of which are formed under oxidative stress. Metallothionein is a very good scavenger of free radicals, and zinc itself can also reduce oxidative stress by binding to thiol groups, decreasing their oxidation. Zinc is also a very potent inhibitor of nitric oxide synthase. Increased levels of chelatable zinc have been shown to be present in cell cultures of immune cells undergoing apoptosis. This is very reminiscent of the zinc staining of neuronal perikarya dying after an episode of ischemia or seizure activity. Thus a possible role of zinc in causing neuronal death in the brain needs to be fully investigated. intraventricular injections of calcium EDTA have already been shown to reduce neuronal death after a period of ischemia. Pharmacological doses of zinc cause neuronal death, and some estimates indicate that extracellular concentrations of zinc could reach neurotoxic levels under pathological conditions. Zinc is released in high concentrations from the hippocampus during seizures. Unfortunately, there are contrasting observations as to whether this zinc serves to potentiate or decrease seizure activity. Zinc may have an additional role in causing death in at least some neurons damaged by seizure activity and be involved in the sprouting phenomenon which may give rise to recurrent seizure propagation in the hippocampus. In Alzheimer's disease, zinc has been shown to aggregate beta-amyloid, a form which is potentially neurotoxic. The zinc-dependent transcription factors NF-kappa B and Sp1 bind to the promoter region of the amyloid precursor protein (APP) gene. Zinc also inhibits enzymes which degrade APP to nonamyloidogenic peptides and which degrade the soluble form of beta-amyloid. The changes in zinc metabolism which occur during oxidative stress may be important in neurological diseases where oxidative stress is implicated, such as Alzheimer's disease, Parkinson's disease, and amyotrophic lateral sclerosis (ALS). Zinc is a structural component of superoxide dismutase 1, mutations in which give rise to one form of familiar ALS. After HIV infection, zinc deficiency is found which may be secondary to immune-induced cytokine synthesis. Zinc is involved in the replication of the HIV virus at a number of sites. These observations should stimulate further research into the role of zinc in neuropathology.
 ...
PMID:Zinc metabolism in the brain: relevance to human neurodegenerative disorders. 936 Dec 93

The cytokine interleukin-1 (IL-1) and its endogenous antagonist (IL-1ra) have important functions in the central nervous system. Recent experimental observations have suggested that recombinant IL-1RA (rhIL-1ra) has neuroprotective properties in ischaemia, excitotoxicity, and trauma. We wished to see what effect rhIL-1ra had on kainic acid-induced neuronal death and to investigate how this might relate to changes in expression of the amyloid precursor protein gene (APP) and glial fibrillary acid protein (GFAP) using in situ hybridization. Wistar rats were treated by intracerebroventricular administration with rhIL-1ra at doses of 10, 20 and 40 microg given 10 min before and 10 min after intraperitoneal kainic acid 10 mg/kg. Behaviour was measured and, after 10 days, the brains were removed for histology and in situ hybridization. There were no anticonvulsant effects on kainic acid-induced wet dog shakes or limbic motor seizures. There were no differences in the effects of rhIL-1ra at all doses tested on hippocampal temperature, blood pressure, blood gases, pH, and glucose in comparison to control. With rhIL-1ra 10 microg given twice, there was significant protection of neurons in the CA1 and CA3 field of the hippocampus and dorsal thalamus, but not in the primary olfactory cortex-amygdaloid region. Small, but insignificant, neuroprotective effects were observed in the same anatomical regions with a dose of 20 microg given twice, and no neuroprotective effects were observed with 40 microg. The enhanced neuronal survival in CA1, CA3 and the dorsal thalamus was associated with preservation of APP 695 mRNA (neuronal form) and lack of stimulation of APP 770 (glial form) and GFAP messages. Where there was no neuroprotection APP 695 mRNA was reduced and stimulation of both APP 770 and GFAP mRNAs was observed. In conclusion, rhIL-1ra has dose- and region-dependent effects on neuronal survival after kainic acid and prevents damage-induced changes in APP and GFAP mRNAs.
 ...
PMID:The neuroprotective effects of the recombinant interleukin-1 receptor antagonist rhIL-1ra after excitotoxic stimulation with kainic acid and its relationship to the amyloid precursor protein gene. 956 1

This work has explored the relationship between excitotoxicity and the amyloid precursor protein gene (APP) which may be relevant to future therapeutic developments in Alzheimer's disease. The excitotoxic effects of kainic acid (KA) and pentylenetetrazole (PTZ) have been compared and contrasted on the two major mRNA isoforms of APP using in situ hybridization and quantitative analysis of gene expression in rat brain. The Kunitz Protease Inhibitor containing isoform APP 770 KPI+, the major glial cell isoform, has been shown to be stimulated after KA and was related to neuronal loss and astrocyte activation as gauged by GFAP mRNA. This was associated with reduced expression of APP695 KPI- isoform, the major neuronal isoform. These changes were not observed after PTZ where there was no neuronal loss and no glial reaction. The KA induced changes in APP were prevented by pretreatment with the non-competitive NMDA receptor antagonist dizocilpine and the barbiturate pentobarbitone, but not with the kappa-opioid receptor agonist enadoline. These findings were related to the suppression of seizures and the survival of neurons. In conclusion, excitotoxic stimulation leading to neuronal death was associated with increased expression of APP KPI+ mRNA and decreased APP KPI- mRNA, a finding which may relate to the plasticity of the central nervous system.
 ...
PMID:The effects of excitotoxicity on the expression of the amyloid precursor protein gene in the brain and its modulation by neuroprotective agents. 972 Sep 74

Secreted forms of the beta-amyloid precursor protein (beta-APP) have neuroprotective properties in vitro and may be involved in the containment of neuronal excitation. To test whether loss of secreted forms of beta-APP (sAPPs) may enhance excitotoxic responses, we injected mice homozygous for a targeted mutation of the beta-APP gene (beta-APPDelta/Delta) intraperitoneally with kainic acid. We found that in these mice, kainic acid induced seizures initiated earlier, and acute mortality was enhanced compared to isogenic wild-type mice independently from the callosal agenesis phenotype observed to occur at increased frequency in APP mutant mice. Expression of c-fos in cortex and cingulate gyrus was enhanced in beta-APPDelta/Delta mice, although the amount of structural damage and apoptosis in the hippocampal pyramidal cell layer and cortex was similar to that of controls. When cerebellar granule cell cultures and cortical neuronal cultures were challenged with glutamate receptor agonists, the rates of cell death and apoptosis of beta-APPDelta/Delta mice were indistinguishable from those of controls. Therefore, deficiency of sAPPs causes facilitation of seizure activity in the absence of enhanced cell death. Since enhanced seizures were observed also in mice homozygous for a deletion of the entire beta-APP gene, this phenotype results from a loss of APP rather than from a dominant effect of APPDelta.
 ...
PMID:Hypersensitivity to seizures in beta-amyloid precursor protein deficient mice. 1020 85

A mutant amyloid precursor protein (APP/RK) designed to interfere with processing by alpha-secretase caused a severe phenotype in transgenic mice, including behavioural abnormalities, i.e. neophobia, aggression, hypersensitivity to kainic acid, hyposensitivity to N-methyl-D-aspartate, and premature death [Moechars D. et al. (1996) Eur. molec. Biol. Org. J. 15, 1265-1274]. We now demonstrated that the APP/RK transgene did not disturb the expression of several other genes, i.e. endogenous amyloid precursor protein and amyloid precursor protein-like proteins, members of the low density lipoprotein receptor lipoprotein receptor family and several of their ligands, including apolipoprotein E, but expression of alpha-2-macroglobulin was never detected. Neither amyloid deposits nor neurofibrillary tangles were detected in the brain of APP/RK transgenic mice, even when 15-months-old. The tendency for seizures and hyposensitivity for N-methyl-D-aspartate was not due to or reflected in the distribution of the three major types of glutamate receptors. The major and consistent finding in transgenic APP/RK mice that died prematurely was extensive neurodegeneration and apoptosis, mainly in hippocampus and cortex, and accompanied by astrocytosis throughout the brain. Reduced synaptic density and dendritic damage was only observed in three transgenic mice that were killed shortly after positive observation of seizures. In addition, the distribution of cathepsin D and ubiquitin was abnormal in these mice.
 ...
PMID:Premature death in transgenic mice that overexpress a mutant amyloid precursor protein is preceded by severe neurodegeneration and apoptosis. 1039 65

While neuropathological studies have established the pathology of dementia pugilistica to be similar to that of Alzheimer's disease, there is little information about the early histological changes caused by the repetitive trauma that eventually produces dementia pugilistica. We have examined the brains of four young men and a frontal lobectomy specimen from a fifth, age range 23-28 years, all of whom suffered mild chronic head injury. There were two boxers, a footballer, a mentally subnormal man with a long history of head banging, and an epileptic patient who repeatedly hit his head during seizures. The four autopsy cases were widely sampled; the lobectomy specimen was serially sliced after fixation. Routine stains were performed; inmmunostaining included beta-amyloid precursor protein, amyloid beta-protein (Abeta), tau and apolipoprotein E (apoE). Pathological findings in all five cases were of neocortical neurofibrillary tangles (NFTs) and neuropil threads, with groups of tangles consistently situated around blood vessels in the worst affected regions. No Abeta immunoreactivity was detected. The amount of neuronal apoE expression varied widely between the cases with no clear relation to the NFTs. The apoE genotype was determined in only two cases (both epsilon3/epsilon3). It appears that repetitive head injury in young adults is initially associated with neocortical NFT formation in the absence of Abeta deposition. The distribution of the tau pathology suggests that the pathogenesis of cytoskeletal abnormalities may involve damage to blood vessels or perivascular elements.
 ...
PMID:Neuronal cytoskeletal changes are an early consequence of repetitive head injury. 1044 57

Muscarinic acetylcholine receptors (mAChR) in the central nervous system are involved in learning and memory, epileptic seizures, and processing the amyloid precursor protein. The M(1) receptor is the predominant mAChR subtype in the cortex and hippocampus. Although the five mAChR fall into two broad functional groups, all five subtypes, when expressed in recombinant systems, can activate the mitogen-activated protein kinase (MAPK) pathway. The MAPK pathway has been implicated in learning and memory, amyloid protein processing, and neuronal plasticity. We used M(1) knock-out mice to determine the role of this receptor subtype in signal transduction in the mouse forebrain. In primary cortical cultures from mice lacking the M(1) mAChR, agonist-stimulated phosphoinositide hydrolysis was reduced by more than 60% compared with cultures from wild type mice. Although muscarinic agonists induced robust activation of MAPK in cortical cultures from wild type mice, mAChR-mediated activation of MAPK was virtually absent in cultures from M(1)-deficient mice. These results indicate that the M(1) mAChR is the major subtype that mediates activation of phospholipase C and MAPK in mouse forebrain.
 ...
PMID:The M1 receptor is required for muscarinic activation of mitogen-activated protein (MAP) kinase in murine cerebral cortical neurons. 1127 34

Metabotropic glutamate (mGlu) receptors have been considered as potential targets for neuroprotective drugs, but the lack of specific drugs has limited the development of neuroprotective strategies in experimental models of acute or chronic central nervous system (CNS) disorders. The advent of potent and centrally available subtype-selective ligands has overcome this limitation, leading to an extensive investigation of the role of mGlu receptor subtypes in neurodegeneration during the last 2 years. Examples of these drugs are the noncompetitive mGlu1 receptor antagonists, CPCCOEt and BAY-36-7620; the noncompetitive mGlu5 receptor antagonists, 2-methyl-6-(phenylethynyl)pyridine, SIB-1893, and SIB-1757; and the potent mGlu2/3 receptor agonists, LY354740 and LY379268. Pharmacologic blockade of mGlu1 or mGlu5 receptors or pharmacologic activation of mGlu2/3 or mGlu4/7/8 receptors produces neuroprotection in a variety of in vitro or in vivo models. MGlu1 receptor antagonists are promising drugs for the treatment of brain ischemia or for the prophylaxis of neuronal damage induced by synaptic hyperactivity. MGlu5 receptor antagonists may limit neuronal damage induced by a hyperactivity of N-methyl-d-aspartate (NMDA) receptors, because mGlu5 and NMDA receptors are physically and functionally connected in neuronal membranes. A series of observations suggest a potential application of mGlu5 receptor antagonists in chronic neurodegenerative disorders, such as amyotrophic lateral sclerosis and Alzheimer disease. MGlu2/3 receptor agonists inhibit glutamate release, but also promote the synthesis and release of neurotrophic factors in astrocytes. These drugs may therefore have a broad application as neuroprotective agents in a variety of CNS disorders. Finally, mGlu4/7/8 receptor agonists potently inhibit glutamate release and have a potential application in seizure disorders. The advantage of all these drugs with respect to NMDA or AMPA receptor agonists derives from the evidence that mGlu receptors do not "mediate," but rather "modulate" excitatory synaptic transmission. Therefore, it can be expected that mGlu receptor ligands are devoid of the undesirable effects resulting from the inhibition of excitatory synaptic transmission, such as sedation or an impairment of learning and memory.
 ...
PMID:Metabotropic glutamate receptor subtypes as targets for neuroprotective drugs. 1152 8

To characterize the effects of the familial Alzheimer's disease-causing Swedish mutations of amyloid precursor protein (SwAPP) on the vulnerability of central nervous system neurons, we induced epileptic seizures in transgenic mice expressing SwAPP. The transgene expression did not change the seizure threshold, but consistently more neurons degenerated in brains of SwAPP mice as compared with wild-type littermates. The degenerating neurons were stained both by terminal deoxynucleotidyl transferase-mediated dUTP nick end-labeling and by Gallyas silver impregnation. A susceptible population of neurons accumulated intracellular Abeta and immunoreacted with antibodies against activated caspase-3. To demonstrate that increased Abeta levels mediated the increased vulnerability, we infused antibodies against Abeta and found a significant reduction in neuronal loss that was paralleled by decreased brain levels of Abeta. Because the SwAPP mice exhibited no amyloid plaques at the age of these experiments, transgenic overproduction of Abeta in brain rendered neurons susceptible to damage much earlier than the onset of amyloid plaque formation. Our data underscore the possibility that Abeta is toxic, that it increases the vulnerability of neurons to excitotoxic events produced by seizures, and that lowering Abeta by passive immunization can protect neurons from Abeta-related toxicity.
 ...
PMID:Passive immunization against beta-amyloid peptide protects central nervous system (CNS) neurons from increased vulnerability associated with an Alzheimer's disease-causing mutation. 1206 9

Reports suggest that Alzheimer's disease (AD) patients show a high life-time prevalence of seizure-like disorders. The transgenic CRND8 (TgCRDN8) is a mouse model of AD-like amyloid pathogenesis that expresses a double-mutant form of human amyloid precursor protein 695 (K670N/M671L and V717F). We have previously reported that post-plaque TgCRND8 mice exhibited a lower threshold to seizure with a more severe seizure type when challenged with pentylenetetrazole (PTZ) intravenously. Here, we now report that pre-plaque TgCRND8 mice also demonstrate an increased sensitivity to PTZ-induced seizures with a more severe seizure type over age-matched littermate controls. A lower threshold and more severe seizure type in TgCRND8 mice prior to and after plaque deposition suggest that this genotype difference may be due to beta-amyloid (Abeta) toxicity rather than plaque formation. Thus, the TgCRND8 mice are not only a model for Abeta production and plaque deposition, but may also be useful for AD associated seizure.
 ...
PMID:Increased seizure threshold and severity in young transgenic CRND8 mice. 1533 Nov 44


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