Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts: Gene/Protein Disease Symptom Drug Enzyme Compound   Target Concepts: Gene/Protein Disease Symptom Drug Enzyme Compound

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Query: EC:1.9.3.1 (cytochrome oxidase)
8,822 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Using the excitotoxic animal model of Huntington's disease, two experimental treatments were evaluated. The first experiment explored the effect of MK801 (a systemically active anticonvulsant, and noncompetitive NMDA antagonist) pretreatment on quinolinic acid (QA)-induced striatal degeneration and behavioral deficits. MK801 prevented QA-induced neuropathological changes in the striatum and the anatomical protection was correlated with the absence of deficits in the cataleptic response to haloperidol. The second experiment tested the ability of three types of fetal grafts to reverse behavioral deficits induced by kainic acid (KA) lesion. Fetal (E15-16) striatal, cortical and tectal grafts were delivered into the KA-lesioned striatum one week or one month after lesion. Animals in this experiment were evaluated on a motor coordination task, haloperidol-induced catalepsy and amphetamine-induced locomotor activity. Striatal grafts attenuated the deficits induced by KA in all of the tasks observed, and no effect of time of grafting was detected. Tectal grafts had a partial beneficial effect, attenuating the decrease in the cataleptic response to haloperidol observed after KA lesions. No effect of time of grafting was detected for these grafts. In contrast, a clear effect of time of grafting was detected for the cortical grafts. Early cortical grafts reversed the exaggerated response to amphetamine observed after KA lesions whereas late cortical grafts resulted in sham-like scores on the catalepsy test. Histochemical analysis showed that most of the grafts survived, had acetylcholinesterase (AChE) positive fibers and cell bodies, and were metabolically active as indicated by cytochrome oxidase (CO) positive staining. It is suggested that striatal grafts may have restored to some extent the striatal GABAergic control over output structures, and that trophic factors play a role in behavioral recovery as is evident from the beneficial effects of the tectal grafts. Although the mechanisms underlying the differential effects observed after early or late cortical grafts are unknown, the interaction between the cellular components and trophic factors present in the cortical grafts and the condition of the lesioned host at the time of grafting may yield a host-graft complex with a unique profile.
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PMID:Neural grafts and pharmacological intervention in a model of Huntington's disease. 196 45

Excitotoxicity and defects in neuronal energy metabolism have both been implicated in the pathogenesis of neurodegenerative disease. These two mechanisms may be linked through the NMDA receptor, activation of which is dependent on neuronal membrane potential. Because the ability to maintain membrane potential is dependent on neuronal energy metabolism, bioenergetic defects may affect NMDA receptor-mediated excitotoxicity. We now report that reversible inhibition of succinate dehydrogenase (SDH), an enzyme central to both the tricarboxylic acid cycle and the electron transport chain, produces an "excitotoxic" lesion in rat striatum that can be blocked by the NMDA antagonist MK-801. Male Sprague-Dawley rats received intrastriatal stereotaxic injections of the SDH inhibitor malonic acid (1 or 2 mumol) in combination with intraperitoneal injections of vehicle or MK-801 (5 mg/kg) 30 min before and 210 min after malonic acid. Animals were killed 72 h after surgery, and brains were processed for histology, cytochrome oxidase activity, and [3H]MK-801 and [3H]AMPA autoradiography. The higher dose of malonic acid (2 mumol) produced large lesions that were markedly attenuated by treatment with MK-801 (28.1 +/- 3.6 vs. 4.7 +/- 2.6 mm3; p < 0.001). [3H]MK-801 and [3H]AMPA binding were reduced in the lesions by 60 and 63%, respectively. One micromole of malonic acid produced smaller lesions that were almost completely blocked by MK-801 treatment (9.6 +/- 1.3 vs. 0.06 +/- 0.04 mm3; p < 0.0001). The toxic effects of malonic acid were due specifically to inhibition of SDH inasmuch as coinjection of a threefold excess of succinate with the malonic acid blocked the striatal lesions (p < 0.002).(ABSTRACT TRUNCATED AT 250 WORDS)
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PMID:Inhibition of succinate dehydrogenase by malonic acid produces an "excitotoxic" lesion in rat striatum. 836 Jun 80

To determine when the calcium-binding protein parvalbumin appears during development, neurons in the chick Edinger Westphal nucleus were examined for parvalbumin immunoreactivity at a variety of embryonic stages. Parvalbumin immunoreactivity appeared on embryonic day 14 (E14, Hamburger and Hamilton stage 40) in predominantly lateral Edinger Westphal neurons. Cytochrome oxidase activity within the nucleus was examined throughout development, as an indicator of physiological activity, and expression of cytochrome oxidase was compared with that of parvalbumin. Cytochrome oxidase activity was found to be uniformly high in all parts of the Edinger Westphal nucleus throughout development. Either the Edinger Westphal nucleus in physiologically active quite early in its development or other energy demands mask the correlation of cytochrome oxidase with electrical activity. Cytochrome oxidase was expressed well before parvalbumin immunoreactivity appeared. Voltage-activated calcium currents were characterized in E12 Edinger Westphal neurons. In both amplitude and composition, E12 calcium currents resemble those of E16 neurons, excluding the possibility that calcium currents appear de novo during or just prior to the appearance of parvalbumin. Both cytochrome oxidase activity and calcium currents are observed in Edinger Westphal neurons well before the appearance of parvalbumin during development. These findings do not exclude the possibility that physiological activity affects the expression of parvalbumin since other factors such as changing patterns of synaptic activity or the appearance of calcium conducting NMDA receptors have yet to be examined. However, they raise the possibility that additional factors such as an intrinsic developmental program or a change in the neuron's basal intracellular calcium requirements may also be involved.
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PMID:Development of parvalbumin immunoreactivity in the chick Edinger Westphal nucleus. 880 Dec 53

The activation of nitric oxide synthase (NOS) has been linked to excitatory input via NMDA receptors. We hypothesized that NOS-positive neurons that have NMDA receptors on their surface would have high levels of cytochrome oxidase (C.O.) as energy generator for membrane repolarization. In order to compare the distribution of these markers on the same section, we reacted rat brain sections for C.O. histochemistry followed by NOS immunogold silver staining (IGSS). Adjacent sections were reacted for NOS IGSS followed by indirect immunoperoxidase for NMDA receptor subunit R1 (NMDAR1). We found that the staining pattern varied among regions but were consistent within each region examined. There are three types of NOS immunoreactive (NOS-ir) cells: (1) NOS-ir neurons that had moderate to high levels of both NMDAR1 and C.O. staining, such as the pontine reticular nuclei, motor and mesencephalic nuclei of the trigeminal nerve, and some motor neurons in the spinal cord. (2) NOS-ir neurons that were immunoreactive for NMDAR1 (NMDAR1-ir) but had low levels of C.O. activity in thei- somata. Their dendrites, however, were both NMDAR1-ir and rich in C.O. Examples of this type include neurons in the caudate and putamen, and periglomerular cells in the olfactory bulb. (3) We also found that some NOS-ir neurons were not NMDAR1-ir and had low C.O. activity. In addition to postsynaptic neurons, C.O. and NOS levels were both high in the inner segments of retinal photoreceptor cells where energy-demanding active ion transport maintains the dark current and where NO presumably activates guanylate cyclase for the production of cGMP, which keeps the Na+ channels open in the dark. Our findings suggest that NMDA receptors are available for the majority of NOS-ir neurons, which comprise a heterogenous population with varying energy demands.
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PMID:Do nitric oxide synthase, NMDA receptor subunit R1 and cytochrome oxidase co-localize in the rat central nervous system? 887 89

A growing body of evidence supports the hypothesis that estrogens may be beneficial in Alzheimer's disease and other neurodegenerative processes. Less is known of their therapeutic potential in acute CNS insults. In this study, we assessed the effect of estrogens in three injury paradigms that may be relevant to CNS hemorrhage, trauma, and ischemia. Supraphysiologic concentrations of 17beta-estradiol, estrone, or equilin attenuated neuronal loss due to prolonged exposure to the pro-oxidant hemoglobin, with complete protection at 10 microM. Most of this effect persisted despite concomitant treatment with the antiestrogen ICI 182,780 or the protein synthesis inhibitor cycloheximide. In contrast, the non-estrogenic steroid methylprednisolone, which is currently in clinical use in spinal cord injury, reduced neuronal loss by only about 30%. High concentrations of equilin or estrone also attenuated the submaximal neuronal injury induced by 3.5-4.5 h exposure to the cytochrome oxidase inhibitor sodium azide, with near complete protection at 30 microM. Estrogens had a weaker and somewhat variable effect on pure excitotoxic injury, reducing neuronal loss due to 24 h kainate exposure by about half, and due to 24 h NMDA exposure by 15-65%; similar neuroprotection was provided by the antioxidant 21-aminosteroid U74500A. These results suggest that estrogens may be beneficial in acute CNS injuries associated with oxidative and excitotoxic stress. Investigation of high dose estrogen therapy in in vivo models of CNS hemorrhage, trauma, and ischemia is warranted.
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PMID:Estrogens attenuate neuronal injury due to hemoglobin, chemical hypoxia, and excitatory amino acids in murine cortical cultures. 929 2

Mitochondrial electron transport chain (ETC) function is selectively reduced in multiple tissues, including brain, from patients with Parkinson's disease (PD) and Alzheimer's disease (AD). The ETC defects are specific to each illness, involve complex I in PD and complex IV in AD, are transferable with mitochondrial DNA (mtDNA) and lead to increased production of reactive oxygen species (ROS) in mtDNA-deficient clonal neuronal cells hybridized with mtDNA ('cybrids') from PD or AD patients. C57BL/6 mice treated with MPTP developed elevated tissue hydroxyl radical ('OH) levels in striatum and ventral midbrain but not cerebellum. In brain microdialysis in awake rats, striatal 'OH output increased 3-5-fold after infusion of methylpyridinium ion (MPP+), a complex I inhibitor, or sodium azide, a complex IV inhibitor. Elevated 'OH after MPP+ was blocked stereospecifically by infusion of the nitric oxide synthase (NOS) inhibitor nitro-L-arginine or by the NMDA channel blocker MK801. Neither NOS inhibition nor NMDA blockade altered azide-induced 'OH production. ETC inhibition in vivo increases production of toxic 'OH, but the underlying mechanisms vary as a function of which ETC complex is inhibited. These results support the concept of developing oxygen free radical scavengers for both AD and PD and further suggest that inhibition of NOS and blockade of NMDA receptor function may alter progression of idiopathic PD.
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PMID:Mitochondrial toxins in models of neurodegenerative diseases. I: In vivo brain hydroxyl radical production during systemic MPTP treatment or following microdialysis infusion of methylpyridinium or azide ions. 931 90

The present study examined the relationship between an important energy-generating enzyme (cytochrome oxidase; CO), a key energy-consuming enzyme (Na+ K+ ATPase) and neurochemicals associated with excitatory glutamatergic synapses (NMDAR1 and neuronal nitric oxide synthase, nNOS) in the adult macaque retina. Polyclonal antibodies against neuronal nitric oxide synthase and N-methyl-D-aspartate receptor subunit I were generated for immunohistochemical examination and labeled sites not previously reported were found. We have also isolated cDNAs for cytochrome oxidase subunits III (mitochondrial-encoded) and IV (nuclear-encoded), as well as for a fragment of neuronal nitric oxide synthase, from a human cDNA library. The distributions of mRNAs of these genes were analyzed by in situ hybridization. We found that three or more of the markers examined coexisted in a number of sites: (a) In the inner segments of photoreceptors, high energy demand for maintaining the dark current was placed by Na+ K+ ATPase. This was partially met by ATP-generating enzymes such as CO. Neuronal NOS was also present there for the synthesis of NO and the cascading event leading to the generation of cGMP and the gating of channels for visual transduction. (b) Both the outer and inner plexiform layers had detectable amounts of all four markers, although the levels varied among them. This was most likely due to the presence of depolarizing glutamatergic synapses arising from photoreceptors and bipolar cells and such synaptic events were energy-demanding. The involvement of NMDA receptors and nNOS in these synaptic layers is strongly implicated in the present study. (c) All four markers were present in the majority of retinal ganglion cells, with some inherent heterogeneity related to intensity and size. Retinal ganglion cells are known to receive excitatory synapses from glutamatergic bipolar cells and are themselves highly active. The presence of both NMDAR1 and nNOS in these cells were verified in the present study and the energy demands related to these synaptic activities were necessarily high. Thus, active ion transporting functions related to synaptic or non-synaptically induced repolarization from the basis for an interrelationship between the neurochemicals/enzymes studied. Finally, (d) all four markers and the gene expression of CO and nNOS in the macaque retina were regulated by neuronal activity.
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PMID:Neurochemical organization of the macaque retina: effect of TTX on levels and gene expression of cytochrome oxidase and nitric oxide synthase and on the immunoreactivity of Na+ K+ ATPase and NMDA receptor subunit I. 966 11

Glutamate is an excitotoxin responsible for causing neuronal damage associated with mitochondria dysfunction. We have analyzed the relationship between the mitochondrial respiratory rate, the membrane potential (delta psi) and the activity of mitochondrial complexes in retinal cells in culture, used as neuronal models. Glutamate (10 microM-10 mM) dose-dependently decreased the O2 consumption and the membrane potential. A linear correlation was found between these parameters, suggesting that the mitochondrial respiratory function was affected. Exposure to glutamate (100 microM) for 10 min, in the absence of Mg2+, inhibited the activity of complex I (26.3%), complexes II/III (22.2%) and complex IV (26.7%). MK-801 ((+)-5-methyl-10,11-dihydro-5H-dibenzo[a,d]-cyclohepten-5,10-imine hydrogen maleate), a non-competitive antagonist of the NMDA (N-methyl-D-aspartate) receptors, completely reversed the effect exerted by 100 microM glutamate at the level of complexes I, II/III and IV. These results suggest that NMDA receptor-mediated inhibition of mitochondrial respiratory chain complexes may be responsible for the alteration in the respiratory rate of chick retinal cells submitted to glutamate.
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PMID:Glutamate-mediated inhibition of oxidative phosphorylation in cultured retinal cells. 1067 80

Our previous studies showed a differential distribution of the glutamatergic terminals in cytochrome oxidase-rich and -poor regions of the visual cortex. The NMDA type of glutamate receptors have been proposed to be involved in the activation of nitric oxide synthase to produce nitric oxide, the neurotransmitter. In the present study, we hypothesized that the expressions of glutamate receptor, NMDA receptors (NMDAR1) and neuronal nitric oxide synthase (nNOS) were colocalized and were also correlated with that of cytochrome oxidase (CO) in a subset of neurons. We used primary cultures of postnatal rat visual cortical neurons as a model system, so that we could examine both the somatic and dendritic expressions of these neurochemicals in individual neurons. We found a difference in the sequence of developmental expressions of NMDAR1, nNOS, CO, and Na(+)/K(+) ATPase. Triple labeling showed that all nNOS-positive neurons were immunoreactive for NMDAR1, and a subpopulation of them had high CO activity. The expression of NMDAR1 was positively correlated with CO activity. This is consistent with our previous finding that CO activity is strongly governed by excitatory glutamatergic synapses. After 40 hours of depolarizing potassium chloride treatment, CO activity was increased, and NMDAR1and nNOS levels were up-regulated in parallel. One week of tetrodotoxin significantly decreased the expression of NMDAR1, nNOS, and CO activity. Our results demonstrate that NMDA receptors and nNOS do co-exist in a subset of neurons that have high CO activity and their expressions are under the control of neuronal activity.
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PMID:Expression and regulation of NMDA receptor subunit R1 and neuronal nitric oxide synthase in cortical neuronal cultures: correlation with cytochrome oxidase. 1080 Feb 3

Beta amyloid (Abeta) peptides accumulate in Alzheimer's disease and are neurotoxic possibly through the production of oxygen free radicals. Using brain microdialysis we characterized the ability of Abeta to increase oxygen radical production in vivo. The 1-40 Abeta fragment increased 2,3-dehydroxybenzoic acid efflux more than the 1-28 fragment, in a manner dependent on nitric oxide synthase and NMDA receptor channels. We then examined the effects of Abeta peptides on mitochondrial function in vitro. Induction of the mitochondrial permeability transition in isolated rat liver mitochondria by Abeta(25-35) and Abeta(35-25) exhibited dose dependency and required calcium and phosphate. Cyclosporin A prevented the transition as did ruthenium red, chlorpromazine, or N-ethylmaleimide. ADP and magnesium delayed the onset of mitochondrial permeability transition. Electron microscopy confirmed the presence of Abeta aggregates and swollen mitochondria and preservation of mitochondrial structure by inhibitors of mitochondrial permeability transition. Cytochrome c oxidase (COX) activity was selectively inhibited by Abeta(25-35) but not by Abeta(35-25). Neurotoxic Abeta peptide can increase oxidative stress in vivo through mechanisms involving NMDA receptors and nitric oxide sythase. Increased intracellular Abeta levels can further exacerbate the genetically driven complex IV defect in sporadic Alzheimer's disease and may precipitate mitochondrial permeability transition opening. In combination, our results provide potential mechanisms to support the feed-forward hypothesis of Abeta neurotoxicity.
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PMID:Neurotoxic Abeta peptides increase oxidative stress in vivo through NMDA-receptor and nitric-oxide-synthase mechanisms, and inhibit complex IV activity and induce a mitochondrial permeability transition in vitro. 1118 24


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