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Query: UNIPROT:P06889 (Mol)
 630,302 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Apoptosis is a programmed cell death that occurs during the development of the nervous system and in neurodegenerative disorders. Tau protein is a cytoskeletal component that promotes microtubule polymerization and stabilization. Apoptosis was induced in primary neuronal cultures by a prolonged exposure (16 h) to the NMDA (N-methyl-D-aspartate 20 microM) or by serum deprivation. The percentages of apoptotic neurons expressing phosphorylated tau (AT8) immunoreactivity are comparable in control and NMDA-exposed cultures (7.5 +/- 1.9 and 6.9 +/- 1.9%, respectively). At the opposite, the percentage of apoptotic neurons expressing de-phosphorylated tau (tau 1) immunolabelings is dramatically increased in NMDA-treated cultures (X 2.3 of controls). Similar results were also observed 48 h after serum deprivation. These results demonstrate in vitro that under these conditions, resistant and sensitive cortical neurons to apoptosis can be partly differentiated according to their phosphorylated tau immunoreactivities.
Brain Res Mol Brain Res 1997 Apr
PMID:Cultured neurons expressing phosphorylated tau are more resistant to apoptosis induced by NMDA or serum deprivation. 910 78

Data are presented that provide convincing evidence for the expression of structurally normal and functional NMDA receptors by acetylcholine-producing human LA-N-2 neuroblastoma cells in culture. Reverse transcription and polymerase chain reaction (RT-PCR), followed by cloning and DNA sequencing, revealed the presence in these cells of mRNA representing the key subunit, NMDAR1, of the receptor. This mRNA was further demonstrated by Northern analysis to be the same size as that described for human neurons. The neutral red cytotoxicity assay was utilized to examine the influence on these neuroblastoma cells of a 48-h incubation with either L-glutamic acid or the specific NMDA agonist N-phthalamoyl-L-glutamic acid (NPG). Cell cytotoxicity was shown by this assay to be increased through incubation with glutamate at 1 and 10 mM by 27 and 37%, and through incubation with NPG at 0.1 and 1 mM by 28 and 46%. A possible mechanism of these toxic effects was further evaluated using the whole-cell configuration of the patch-clamp technique and the specific NMDA agonists (+/-)1-aminocyclobutane-cis-1,3-dicarboxylic acid (ACDA) and NPG. Using this procedure, a voltage-dependent tetrodotoxin-sensitive inward sodium current was found to be increased (x 1.5) by L-glutamic acid and by both NMDA agonists in the presence of glycine. Another voltage-gated inward current, probably carried by calcium ions, was increased three- to fourfold. Hence, these glutamate activities observed in human LA-N-2 neuroblastoma cells appear to occur through the activation of functional NMDA receptors in much the same way as reported for neurons, and both glutamate and NMDA agonists can be toxic to these neuroblastoma cells. Our findings, therefore, suggest this cell line will provide a model suitable for investigating the mechanisms of NMDA-related long-term potentiation (LTP) in neurons and of the NMDA-related neurotoxic effects of glutamate in disease states that involve a reduction in cholinergic function.
Mol Chem Neuropathol
PMID:Presence of functional NMDA receptors in a human neuroblastoma cell line. 913 30

1. Protooncogene c-fos mRNA levels were determined in the rat cerebral cortex, hippocampus, and cerebellum after exposure to a combined forced swimming and confinement stress. The stress resulted in an increase in c-fos mRNA levels in all three brain areas. 2. In an effort to elucidate the neurotransmitter systems involved in this stress-induced increase, animals were injected, prior to exposure to the stress, with either diazepam, MK-801, or propranolol. 3. In both the cerebral cortex and the hippocampus the stress-induced increase in c-fos mRNA was inhibited by MK-801, suggesting that it is mediated via NMDA receptors. In the hippocampus, propranolol had a similar effect, indicating that beta-adrenergic receptors are also involved in the stress-induced increase in c-fos mRNA. 4. On the other hand, the increase in c-fos mRNA produced by the stress of the injection was inhibited in the cerebral cortex by diazepam or propranolol and in the hippocampus only by diazepam. Furthermore, administration of MK-801 resulted in an increase in c-fos mRNA in the hippocampus of the nonstressed animals. In the cerebellum no one of the three drugs employed affected c-fos mRNA levels in either stressed or nonstressed animals. 5. Our results thus show that various forms of stress activate, in different brain areas, neurons with either NMDA, beta-adrenergic, and/or GABA-A receptors.
Cell Mol Neurobiol 1997 Apr
PMID:At least three neurotransmitter systems mediate a stress-induced increase in c-fos mRNA in different rat brain areas. 914 Jun 95

Recently published work using MRI to image the human brain has revealed that the hippocampal formation undergoes a selective atrophy in diverse conditions such as Cushing's syndrome, post-traumatic stress disorder, recurrent depressive illness, normal aging preceding dementia and in Alzheimer's disease. Hippocampal shrinkage is usually accompanied by deficits in declarative, episodic, spatial and contextual memory performance and the hippocampal changes provide a neural substrate for changes in cognitive function that have been recognized to accompany these various conditions. The hippocampus has long been known as a target of stress hormones, and it is an especially plastic and vulnerable region of the brain. However, the prominence of the hippocampus as a glucocorticoid target has obscured the fact that other factors besides glucocorticoid hormones are involved in the process of hippocampal atrophy. Excitatory amino acids and NMDA receptors are prominent in their involvement in an animal model of hippocampal atrophy as well as in neuronal death. Further-more, the finding of hippocampal atrophy does not necessarily imply a permanent loss of cells, and this aspect deserves careful investigation, both to analyze the underlying anatomical changes and to investigate the possibility of pharmacological treatment to reverse the process. In cases where atrophy is due to cell loss, the time course of the disease process will provide much useful information about mechanism and offer the possibility of early intervention to arrest or slow the pathological process.
Mol Psychiatry 1997 May
PMID:Possible mechanisms for atrophy of the human hippocampus. 915 91

1. Cultured dorsal root ganglion of rat pups were depolarized by exposure to 50 mM K+ and the rise of [Ca2+]i was measured using fura-2 as an indicator. 2. Lead in the extracellular solution reduced the rise of [Ca2+]i in a concentration-dependent manner, with a threshold concentration of 0.25 microM. More than 80% of the calcium entry was prevented by approximately 5 microM lead. The IC50 and the Hill coefficient were 3.1 microM and 1, respectively. 3. This effect was considered to be due to a reduction of VACCCs, since applications of NMDA did not result in any rise of [Ca2+]i. 4. Since Pb2+ itself changes the fura-2 signal in a typical and characteristic manner, fura-2 is also an indicator for Pb2+. No changes in fura-2 signals were detected when lead (5 microM) was applied for several minutes in the absence of calcium, indicating that Pb2+ did not enter the cells. 5. Thus it is concluded that lead prevents calcium entry by reducing VACCCs but does not cross the cell membrane itself.
Cell Mol Neurobiol 1997 Jun
PMID:Lead reduces depolarization-induced calcium entry in cultured DRG neurons without crossing the cell membrane: fura-2 measurements. 918 87

To address the issue of the cytotoxicity of glutamate antagonists, we administered representative agents to rats and used HSP72 immunocytochemistry as a measure of neuronal injury in the brain. The doses studied spanned the reported neuroprotective range for each compound. Some, but not all, glutamate antagonists induce neuronal injury in the brain. The non-competitive NMDA antagonists (MK801 and dextrorphan) demonstrate maximum toxicity. Competitive NMDA antagonists (CGS 19755 and MDL 100,453) may or may not induce neuronal injury depending on the particular compound. The polyamine site (SL 82.0715-10) antagonist does not result in neuronal injury. Cingulate and retrosplenial cortex neurotoxicity is not a ubiquitous feature of neuroprotective agents that block excitotoxcity, but is limited to NMDA antagonists and may depend upon the duration and completeness of the blockade of the NMDA receptor.
Brain Res Mol Brain Res 1997 Jun
PMID:Induction of heat-shock protein (HSP72) in the cingulate and retrosplenial cortex by drugs that antagonize the effects of excitatory amino acids. 919 Nov 5

Dopamine is the neurotransmitter most often implicated in the pathogenesis of schizophrenia. However, glutamatergic antagonists can cause psychotic symptoms in otherwise normal humans, and exacerbate these symptoms in schizophrenics. These findings have led to a model of dopamine-glutamate interactions in limbic cortex and striatum as a potential substrate for symptom production in schizophrenia. From this model, we might expect that cortical and striatal expression of non-NMDA ionotropic glutamate receptors would be differentially regulated by antipsychotic treatment. To begin to address this question, we examined the regulation of mRNA levels of the AMPA (gluR1-gluR4), low affinity kainate (gluR5-gluR7), and high affinity kainate (KA1-KA2) receptor subunits by clozapine (20 mg/kg/day) and haloperidol (2 mg/kg/day) treatment for 2 weeks. Both clozapine and haloperidol caused region-specific alterations in the mRNA levels of these subunits, but there was no differential regulation in the cortex vs. the striatum. Haloperidol caused a decrease in gluR2 and gluR4 mRNA levels in both cortex and striatum and an increase in KA2 mRNA levels in the striatum only. However, clozapine treatment caused an increase in gluR7 mRNA expression, and a decrease in gluR3 mRNA expression, in both cortex and striatum while causing an increase in KA2 mRNA levels, and a decrease in gluR4 mRNA levels, in the striatum only. These dissimilarities may represent an interesting mechanism for some of the differential therapeutic or toxic effects of clozapine and haloperidol, and also may be relevant to our understanding of dopamine-glutamate interactions in schizophrenia.
Brain Res Mol Brain Res 1997 Jul
PMID:Clozapine and haloperidol differentially affect AMPA and kainate receptor subunit mRNA levels in rat cortex and striatum. 922 32

Cultured mouse cortical neurons undergo apoptosis when exposed to staurosporine. The cell-permeable caspase inhibitor Z-Val-Ala-Asp fluoromethylketone (Z-VAD.FMK) attenuated this death, without altering overall protein synthesis. Z-VAD.FMK also attenuated cortical neuronal apoptosis induced by removal of serum. However, Z-VAD.FMK did not attenuate the excitotoxic necrosis induced by 5-min exposure to 100 microM NMDA, 24-h exposure to 100 microM kainate, or 90-min exposure to oxygen-glucose deprivation. We have previously shown that blockade of the excitotoxic component of oxygen-glucose deprivation-induced neuronal death with glutamate antagonists unmasks an apoptotic death. Treatment with Z-VAD.FMK, but not the cathepsin-B protease inhibitor Z-Phe-Ala fluoromethylketone (Z-FA.FMK), also attenuated this oxygen-glucose deprivation-induced neuronal apoptosis. These data support the idea that brain caspases mediate the apoptotic component of oxygen-glucose deprivation-induced neuronal death and raise the possibility that combining caspase inhibitors with glutamate antagonists might attenuate brain damage induced by hypoxic-ischemic insults in vivo.
Mol Cell Neurosci 1997
PMID:Caspase inhibition selectively reduces the apoptotic component of oxygen-glucose deprivation-induced cortical neuronal cell death. 924 99

Glycine is a major inhibitory neurotransmitter in the spinal cord and brainstem of vertebrates. Glycine is accumulated into synaptic vesicles by a proton-coupled transport system and released to the synaptic cleft after depolarization of the presynaptic terminal. The inhibitory action of glycine is mediated by pentameric glycine receptors (GlyR) that belong to the ligand-gated ion channel superfamily. The synaptic action of glycine is terminated by two sodium- and chloride-coupled transporters, GLYT1 and GLYT2, located in the glial plasma membrane and in the presynaptic terminals, respectively. Dysfunction of inhibitory glycinergic neurotransmission is associated with several forms of inherited mammalian myoclonus. In addition, glycine could participate in excitatory neurotransmission by modulating the activity of the NMDA subtype of glutamate receptor. In this article, we discuss recent progress in our understanding of the molecular mechanisms that underlie the physiology and pathology of glycinergic neurotransmission.
Mol Neurobiol 1997 Jun
PMID:Molecular biology of glycinergic neurotransmission. 929 60

Excitotoxicity, mitochondrial dysfunction and free radical induced oxidative damage have been implicated in the pathogenesis of several different neurodegenerative diseases, such as amyotrophic lateral sclerosis, Parkinson's disease (PD), Alzheimer's disease (AD), and Huntington's disease. Much of the interest in the association of neurodegeneration with mitochondrial dysfunction and oxidative damage emerged from animal studies using mitochondrial toxins. Within mitochondria 1-methyl-4-phenylpyridinium (MPP+), the active metabolite of 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP), acts to inhibit NADH-coenzyme Q reductase (complex I) of the electron transport chain. MPTP produces Parkinsonism in humans, primates, and mice. Similarly, lesions produced by the reversible inhibitor of succinate dehydrogenase (complex II), malonate, and the irreversible inhibitor, 3-nitropropionic acid (3-NP), closely resemble the histologic, neurochemical and clinical features of HD in both rats and non-human primates. The interruption of oxidative phosphorylation results in decreased levels of ATP. A consequence is partial neuronal depolarization and secondary activation of voltage-dependent NMDA receptors, which may result in excitotoxic neuronal cell death (secondary excitotoxicity). The increase in intracellular Ca2+ concentration leads to an activation of Ca2+ dependent enzymes, including the constitutive neuronal nitric oxide synthase (cnNOS) which produces NO.. NO. may react with the superoxide anion to from peroxynitrite. We show that systemic administration of 7-nitroindazole (7-NI), a relatively specific inhibitor of cnNOS in vivo. attenuates lesions produced by striatal malonate injections or systemic treatment with 3-NP or MPTP. Furthermore 7-NI attenuated increases in lactate production and hydroxyl radical and 3-nitrotyrosine generation in vivo, which may be a consequence of peroxynitrite formation. Our results suggest that neuronal nitric oxide synthase inhibitors may be useful in the treatment of neurologic diseases in which excitotoxic mechanisms play a role.
Mol Cell Biochem 1997 Sep
PMID:The role of mitochondrial dysfunction and neuronal nitric oxide in animal models of neurodegenerative diseases. 930 87


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