dizocilpine-maleate has been researched along with Amyotrophic-Lateral-Sclerosis* in 13 studies
1 review(s) available for dizocilpine-maleate and Amyotrophic-Lateral-Sclerosis
1 trial(s) available for dizocilpine-maleate and Amyotrophic-Lateral-Sclerosis
12 other study(ies) available for dizocilpine-maleate and Amyotrophic-Lateral-Sclerosis
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Excess glutamate secreted from astrocytes drives upregulation of P-glycoprotein in endothelial cells in amyotrophic lateral sclerosis.
In amyotrophic lateral sclerosis (ALS), upregulation in expression and activity of the ABC transporter P-glycoprotein (P-gp) driven by disease advancement progressively reduces CNS penetration and efficacy of the ALS drug, riluzole. Post-mortem spinal cord tissues from ALS patients revealed elevated P-gp expression levels in endothelial cells of the blood-spinal cord barrier compared to levels measured in control, non-diseased individuals. We recently found that astrocytes expressing familial ALS-linked SOD1 mutations regulate expression levels of P-gp in endothelial cells, which also exhibit a concomitant, significant increase in reactive oxygen species production and NFκB nuclear translocation when exposed to mutant SOD1 astrocyte conditioned media. In this study, we found that glutamate, which is abnormally secreted by mutant SOD1 and sporadic ALS astrocytes, drives upregulation of P-gp expression and activity levels in endothelial cells via activation of N-Methyl-D-Aspartic acid (NMDA) receptors. Surprisingly, astrocyte-secreted glutamate regulation of endothelial P-gp levels is not a mechanism shared by all forms of ALS. C9orf72-ALS astrocytes had no effect on endothelial cell P-gp expression and did not display increased glutamate secretion. Utilizing an optimized in vitro human BBB model consisting of patient-derived induced pluripotent stem cells, we showed that co-culture of endothelial cells with patient-derived astrocytes increased P-gp expression levels and transport activity, which was significantly reduced when endothelial cells were incubated with the NMDAR antagonist, MK801. Overall, our findings unraveled a complex molecular interplay between astrocytes of different ALS genotypes and endothelial cells potentially occurring in disease that could differentially impact ALS prognosis and efficacy of pharmacotherapies. Topics: Amyotrophic Lateral Sclerosis; Animals; Astrocytes; ATP Binding Cassette Transporter, Subfamily B; Blood-Brain Barrier; Capillaries; Cells, Cultured; Culture Media, Conditioned; Dizocilpine Maleate; Endothelial Cells; Excitatory Amino Acid Antagonists; Glutamic Acid; Humans; Mutation; Rats; Rats, Sprague-Dawley; Receptors, N-Methyl-D-Aspartate; Superoxide Dismutase-1; Up-Regulation | 2019 |
Cerebral neurons of transgenic ALS mice are vulnerable to glutamate release stimulation but not to increased extracellular glutamate due to transport blockade.
Mechanisms of motor neuron loss in amyotrophic lateral sclerosis (ALS) are unknown, but it has been postulated that excitotoxicity due to excessive glutamatergic neurotransmission by decreased efficiency of glutamate transport may be involved in both familial (FALS) and sporadic ALS. Using microdialysis in vivo, we tested the effects of the glutamate transport inhibitor L-trans-pyrrolidine-2,4-dicarboxylate (PDC) and of 4-aminopyridine (4-AP), which stimulates glutamate release from nerve endings, in the hippocampus and motor cortex of wild type (WT) and transgenic SOD1/G93A mice, an established model of FALS. Perfusion of 4-AP induced convulsions, expression of the inducible stress-marker heat-shock protein 70 (HSP70) and hippocampal neuronal loss. These effects were similar in both WT and G93A mice, and, in both groups, they were prevented by the previous systemic administration of the NMDA receptor antagonist MK-801. In contrast, perfusion of PDC resulted in a large and long-lasting (2 h) increase of extracellular glutamate, but no convulsions, neuronal damage or HSP70 expression were observed in either the WT or the G93A mice. Our results demonstrate that SOD1 G93A mutation does not enhance the vulnerability to endogenous glutamate-mediated excitotoxicity in brain, neither by blocking glutamate transport nor by stimulating its release. Therefore, these data do not support the possibility that glutamate transport deficiency may be an important factor of brain neuronal degeneration in familial ALS. Topics: 4-Aminopyridine; Amyotrophic Lateral Sclerosis; Animals; Biological Transport; Dicarboxylic Acids; Disease Models, Animal; Dizocilpine Maleate; Excitatory Amino Acid Agonists; Excitatory Amino Acid Antagonists; Extracellular Space; Glutamic Acid; HSP72 Heat-Shock Proteins; Humans; Mice; Mice, Transgenic; Microdialysis; Neurons; Neurotransmitter Uptake Inhibitors; Pyrrolidines; Superoxide Dismutase | 2006 |
Does excitotoxic cell death of motor neurons in ALS arise from glutamate transporter and glutamate receptor abnormalities?
Topics: Amyotrophic Lateral Sclerosis; Animals; Biological Transport; Cell Death; Dicarboxylic Acids; Disease Models, Animal; Dizocilpine Maleate; Excitatory Amino Acid Antagonists; Glutamate Plasma Membrane Transport Proteins; Glutamates; Humans; Mice; Motor Neurons; Neurotransmitter Uptake Inhibitors; Pyrrolidines; Receptors, Glutamate | 2006 |
Differential cortico-motoneuron vulnerability after chronic mitochondrial inhibition in vitro and the role of glutamate receptors.
Chronic treatment of rat cortical slices with a relative low concentration of mitochondrial inhibitor malonate leads to cortical motoneuron (CMN) death. In the neurodegenerative disease amyotrophic lateral sclerosis (ALS) corticospinal neurons, CMNs projecting to the spinal cord, degenerate. In the present study we compared the effect of chronic mitochondrial inhibition on the survival of CMNs located in the dorsal cortical areas (including corticospinal neurons) with that on ventrally located CMNs (non-corticospinal neurons) in vitro. In the explant culture model used, the dorsally located CMNs were less vulnerable to a 2-week period of mitochondrial inhibition with malonate as compared to ventrally located CMNs. Treatment with 5 mM malonate resulted in 50% surviving CMNs in the dorsal part and only 16% in the ventral part. Neuroprotection of the CMNs could be achieved with co-administration of the non-NMDA antagonist CNQX, the NMDA antagonist MK-801, or the glutamate release inhibitor riluzole, suggesting that chronic energy shortage leads to excitotoxicity. In the dorsal cortical areas CNQX, MK-801, and riluzole had a neuroprotective effect on the CMNs, whereas in the ventral cortical areas only MK-801 was neuroprotective. The sensitivity to energy depletion and consequently excitotoxicity may be related to glutamate receptor density and subunit composition in various cortical areas, but also to the projection length and input of CMNs in vivo. The present investigation gives insight in mechanisms leading to excitotoxic cell death of CMNs and may therefore be important for the development of treatment strategies in protection and survival of cortical motoneurons in ALS. Topics: 6-Cyano-7-nitroquinoxaline-2,3-dione; Amyotrophic Lateral Sclerosis; Animals; Animals, Newborn; Cell Death; Cell Survival; Cerebral Cortex; Dizocilpine Maleate; Dose-Response Relationship, Drug; Drug Interactions; Energy Metabolism; Excitatory Amino Acid Antagonists; Glutamic Acid; Immunohistochemistry; Malonates; Mitochondria; Motor Neurons; Neurofilament Proteins; Neuroprotective Agents; Organ Culture Techniques; Pyramidal Tracts; Rats; Rats, Wistar; Receptors, Glutamate | 2001 |
Ca(2+)-permeable AMPA receptors and selective vulnerability of motor neurons.
To evaluate the role of excitotoxicity in the pathogenesis of amyotrophic lateral sclerosis (ALS), we compared the sensitivity of motor neurons and that of dorsal horn neurons to kainic acid (KA). Short exposure to KA resulted in the death of motor neurons, while dorsal horn neurons were unaffected. This selective motor neuron death was completely dependent on extracellular Ca(2+) and insensitive to inhibitors of voltage-operated Ca(2+) or Na(+) channels. It was also completely inhibited by the specific AMPA antagonist LY300164 and by Joro spider toxin (JSTx), a selective blocker of AMPA receptors that lack the edited GluR2 subunit. KA selectively killed those motor neurons that stained positive for the Co(2+) histochemical staining, a measure for the presence of Ca(2+)-permeable AMPA receptors. These results suggest that Ca(2+) entry via Ca(2+)-permeable AMPA receptors is responsible for the selective motor neuron death. As the Ca(2+) permeability of the AMPA receptor is regulated by its GluR2 subunit, we stained motor neurons for GluR2. Immunoreactivity was present in all motor neurons, albeit to a variable degree. However, double-staining experiments demonstrated that motor neurons clearly expressing GluR2, also expressed Ca(2+)-permeable AMPA receptors. This indicates that despite the abundant expression of GluR2, this subunit is excluded from a subset of AMPA receptors and that the activation of these receptors is responsible for the selective motor neuron death. Topics: 6-Cyano-7-nitroquinoxaline-2,3-dione; Amyotrophic Lateral Sclerosis; Animals; Benzodiazepines; Calcium Channels; Cell Survival; Cells, Cultured; Dizocilpine Maleate; Excitatory Amino Acid Antagonists; Kainic Acid; Motor Neurons; Neurotoxins; Nifedipine; Posterior Horn Cells; Rats; Rats, Wistar; Receptors, AMPA; Spider Venoms | 2000 |
Altered calcium homeostasis and ultrastructure in motoneurons of mice caused by passively transferred anti-motoneuronal IgG.
Calcium homeostasis and ultrastructure are altered in motor axon terminals (AT) of amyotrophic lateral sclerosis (ALS) patients and in mice injected with ALS IgG and exhibit increased density of synaptic vesicles and increased intracellular calcium. To develop an immune-mediated passive transfer experimental model of both systemic weakness and altered morphology, mice were inoculated intraperitoneally with anti-motoneuronal IgG. Animals initially manifested muscle stiffness and evidence of autonomic cholinergic hyperactivity. Electron microscopic cytochemistry within 12 hours (h) demonstrated significantly increased density of synaptic vesicles and calcium both in axon terminals of neuromuscular junctions and synaptic boutons on spinal motoneurons. After 24 h the mice were severely weak and premorbid. The number of synaptic vesicles was still larger than normal, but calcium was depleted from axon terminals and synaptic boutons. The motoneuron perikarya demonstrated the dilatation of the Golgi system and the rough endoplasmic reticulum with an increased amount of calcium. The NMDA receptor antagonist, MK-801, and the L-type calcium channel antagonist, Diltiazem, prevented clinical symptoms and some morphological alterations. These data demonstrate that high titer anti-motoneuronal IgG can induce severe weakness and produce similar ultrastructural features of motor axon terminals in human ALS and in mice injected with ALS IgG, and support a key role for calcium in selective vulnerability of motoneurons. Topics: Amyotrophic Lateral Sclerosis; Animals; Axons; Calcium; Calcium Channel Blockers; Cattle; Diltiazem; Disease Models, Animal; Dizocilpine Maleate; Goats; Homeostasis; Humans; Immunization, Passive; Immunoglobulin G; Male; Mice; Mice, Inbred BALB C; Microscopy, Electron; Motor Neuron Disease; Motor Neurons; Neuroprotective Agents; Receptors, N-Methyl-D-Aspartate; Spinal Cord; Synaptic Vesicles | 1997 |
Abnormal dephosphorylation effect on NMDA receptor regulation in ALS spinal cord.
Previous studies have demonstrated a significant reduction of N-methyl-D-aspartate (NMDA) receptor binding in spinal cord sections from patients who died with amyotrophic lateral sclerosis (ALS) compared to that in control patients. The reduction in NMDA receptor binding in ALS could be increased toward control values by treatment with phorbol ester, suggesting a role for receptor protein phosphorylation in this disorder. In the present study we have evaluated the time course of recovery of [3H]MK-801 binding following phorbol ester treatment to assess protein phosphatase activity in spinal cord sections from ALS and control subjects. Phorbol ester-stimulated changes in [3H]MK-801 binding returned to untreated values significantly faster in ALS tissue compared to control and could not be blocked by the coapplication of the protein phosphatase inhibitors sodium vanadate or sodium beta-D-glycerol phosphate. Okadaic acid coapplication blocked recovery in both ALS and control tissue at a concentration range at which phosphatase 2B (calcineurin) would likely be inhibited. The results suggest that abnormal levels or activity of protein phosphatases, including calcineurin, may be involved in the abnormal levels of NMDA receptors in ALS and may play some role in the pathogenesis of the disease. Topics: Aged; Aged, 80 and over; Amyotrophic Lateral Sclerosis; Binding, Competitive; Carcinogens; Dizocilpine Maleate; Enzyme Inhibitors; Excitatory Amino Acid Antagonists; Humans; Middle Aged; Okadaic Acid; Phorbol Esters; Phosphoric Monoester Hydrolases; Phosphorylation; Receptors, N-Methyl-D-Aspartate; Spinal Cord; Tritium | 1997 |
Muscarinic, N-methyl-D-aspartate (NMDA) and benzodiazepine receptor binding sites in cortical membranes from amyotrophic lateral sclerosis patients.
Amyotrophic lateral sclerosis (ALS) is a progressive neurodegenerative disorder causing marked pathology in the motoneuron system. The pathophysiology of the selective degeneration of motor neurons in the disease is as yet unknown, but evidence suggests that excitotoxic mechanisms might be involved. The present study was undertaken to determine whether defects in neurotransmitter receptors are involved in the disease, analyzing uniformly sampled specimens from neocortex and motorcortex. The binding to benzodiazepine, muscarinic cholinergic, and NMDA receptors in ALS brains was compared to that in control brains, using a single radioligand concentration of [3H]Ro 15-1788, [3H]QNB and [3H]MK-801. The benzodiazepine and the muscarinic cholinergic receptor binding was unaffected in any cortical region from the ALS subjects compared to controls. NMDA receptor binding labeled by [3H]MK-801 was significantly increased in several neocortical regions in the ALS group compared to the control group. Scatchard analysis of [3H]MK-801 binding in frontal cortex revealed a single binding site with an unaltered maximal binding capacity but an increased binding affinity of the site in the ALS group compared to the controls. The generalized alteration in the affinity of the binding site for [3H]MK-801 in the ALS cortex may indicate a modification of the NMDA receptor due to different sensitivity for endogenous modulators or to a different subunit composition of the NMDA receptor in ALS with altered functional properties. These findings may reflect a pathophysiological phenomenon in ALS. Topics: Aged; Amyotrophic Lateral Sclerosis; Binding Sites; Brain Chemistry; Dizocilpine Maleate; Excitatory Amino Acid Antagonists; Female; Flumazenil; GABA Modulators; Humans; Male; Middle Aged; Motor Cortex; Muscarinic Antagonists; Quinuclidinyl Benzilate; Radioligand Assay; Receptors, GABA-A; Receptors, Muscarinic; Receptors, N-Methyl-D-Aspartate; Tritium | 1996 |
Cell culture evidence for neuronal degeneration in amyotrophic lateral sclerosis being linked to glutamate AMPA/kainate receptors.
Amyotrophic lateral sclerosis (ALS) is a neurodegenerative disorder affecting motor neurons. Glutamate, a potent central-nervous-system toxin, has been proposed as one possible factor in this motoneuron disease. Serum from patients with ALS is known to be toxic when added to neurons in culture. We report on the toxicity to rat neurons in culture of cerebrospinal fluid (CSF) from patients with ALS. CSF were obtained from 10 ALS patients, 10 neurological controls, and 10 other controls. ALS CSF was added at dilutions of 50%, 20%, or 10% and neuron survival was assessed after 24 h. The neuroprotective effects of antagonists to two glutamate receptors were also assessed. ALS CSF was significantly neurotoxic, with a neuronal survival rate of only 47% compared with 80% or so for control CSF. This neurotoxicity was blocked by CNQX, an antagonist to the alpha-amino-3-hydroxy-5-methyl-4-isoxazole propionic acid (AMPA)/kainate receptor but not by two N-methyl-D-aspartate (NMDA) antagonists. ALS CSF contains a specific neurotoxic factor which is AMPA/kainate-like which could have a role in the neuronal degeneration of this disease. Topics: 2-Amino-5-phosphonovalerate; 6-Cyano-7-nitroquinoxaline-2,3-dione; Aged; Amino Acids; Amyotrophic Lateral Sclerosis; Animals; Cell Survival; Cells, Cultured; Dizocilpine Maleate; Dose-Response Relationship, Drug; Humans; Middle Aged; Motor Neurons; Nerve Degeneration; Quinoxalines; Rats; Receptors, AMPA; Receptors, Glutamate; Receptors, Kainic Acid | 1993 |
Amyotrophic lateral sclerosis: quantitative autoradiography of [3H]MK-801/NMDA binding sites in spinal cord.
We have characterized a high-affinity binding site for [3H]MK-801, an NMDA receptor ion channel antagonist, in cervical spinal cords from patients who have died with amyotrophic lateral sclerosis (ALS) and from control subjects. In cervical spinal cord [3H]MK-801 labelled at least two binding sites, the highest affinity site having a Kd of between 9-16 nM. No significant differences in affinity were observed between spinal cords from ALS patients or controls. In spinal cords from ALS patients, large reductions in [3H]MK-801 receptor binding (between 30-40% reductions) were detected in both the dorsal and ventral horns. These data may reflect the death of receptor-bearing cells, or a form of receptor regulation. Topics: Adult; Aged; Amyotrophic Lateral Sclerosis; Autoradiography; Dizocilpine Maleate; Down-Regulation; Humans; Kinetics; Middle Aged; Receptors, N-Methyl-D-Aspartate; Spinal Cord | 1993 |
Activation of PKC reverses apparent NMDA receptor reduction in ALS.
The binding of [3H]MK-801 to NMDA receptors was reduced by 40-45% in the dorsal and ventral horns of spinal cords from patients who died with amyotrophic lateral sclerosis (ALS) compared with controls. These results reflect either neurone death with concomitant receptor loss or regulation-related receptor decreases independent of motoneurone degeneration. To distinguish between these possibilities we explored aspects of NMDA receptor regulation using phorbol ester to activate protein kinase C (PKC). Spinal cord sections were exposed to phorbol ester before incubation with [3H]MK-801 to determine levels of NMDA binding. Phorbol ester treatment increased [3H]MK-801 binding in both ALS and control tissue to almost identical levels of specific binding for both groups. The increased [3H]MK-801 binding could be completely blocked by concurrent exposure of spinal cord sections to H-7, a general protein kinase inhibitor. These results suggest that NMDA receptors in ALS spinal cord are decreased as a result of abnormal enzyme activity independent of motoneurone degeneration. Topics: 1-(5-Isoquinolinesulfonyl)-2-Methylpiperazine; Aged; Amyotrophic Lateral Sclerosis; Autoradiography; Dizocilpine Maleate; Enzyme Activation; Humans; In Vitro Techniques; Isoquinolines; Phorbol 12,13-Dibutyrate; Piperazines; Protein Kinase C; Receptors, N-Methyl-D-Aspartate; Spinal Cord | 1993 |
Excitatory amino acid receptor antagonist in murine motoneuron disease (the wobbler mouse).
Recent evidence has suggested a potential role for involvement of excitatory amino acids (EAA) in the pathogenesis of the neuron loss in motoneuron diseases. We have examined the ability of an antagonist of N-methyl-D-aspartate (NMDA) receptors to halt or retard the progression of neurological symptoms in a murine form of motoneuron disease. The wobbler mouse is an autosomal recessive mutant which develops progressive neurological symptoms secondary to motoneuron loss. Treatment of wobbler mice with the NMDA receptor antagonist (+)-5-methyl-10,11-dihydro-5H-dibenzo(a,d)cyclohepten-5, 10-imine maleate (MK-801) did not retard neurological deterioration as assessed by a semiquantitative clinical scale. We conclude that NMDA receptor activation is probably not involved in the pathogenesis of motoneuron loss in the wobbler mouse. Topics: Amyotrophic Lateral Sclerosis; Animals; Dizocilpine Maleate; Mice; Mice, Inbred C57BL; Mice, Neurologic Mutants; Motor Neuron Disease; Receptors, N-Methyl-D-Aspartate | 1992 |