| 1. |
- Björklund, Tomas, et al.
(författare)
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Optimization of continuous in vivo DOPA production and studies on ectopic DA synthesis using rAAV5 vectors in Parkinsonian rats
- 2009
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Ingår i: Journal of Neurochemistry. - : Wiley. - 1471-4159 .- 0022-3042. ; 111:2, s. 355-367
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Tidskriftsartikel (refereegranskat)abstract
- Viral vector-mediated gene transfer is emerging as a novel therapeutic approach with clinical utility in treatment of Parkinson's disease. Recombinant adeno-associated viral (rAAV) vector in particular has been utilized for continuous l-3,4 dihydroxyphenylalanine (DOPA) delivery by expressing the tyrosine hydroxylase (TH) and GTP cyclohydrolase 1 (GCH1) genes which are necessary and sufficient for efficient synthesis of DOPA from dietary tyrosine. The present study was designed to determine the optimal stoichiometric relationship between TH and GCH1 genes for ectopic DOPA production and the cellular machinery involved in its synthesis, storage, and metabolism. For this purpose, we injected a fixed amount of rAAV5-TH vector and increasing amounts of rAAV5-GCH1 into the striatum of rats with complete unilateral dopamine lesion. After 7 weeks the animals were killed for either biochemical or histological analysis. We show that increasing the availability of 5,6,7,8-tetrahydro-l-biopterin (BH4) in the same cellular compartment as the TH enzyme resulted in better efficiency in DOPA synthesis, most likely by hindering inactivation of the enzyme and increasing its stability. Importantly, the BH4 synthesis from ectopic GCH1 expression was saturable, yielding optimal TH enzyme functionality between GCH1 : TH ratios of 1 : 3 and 1 : 7.
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| 2. |
- Carlsson, Thomas, et al.
(författare)
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Systemic administration of Neuregulin-1ß(1) protects dopaminergic neurons in a mouse model of Parkinson's disease.
- 2011
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Ingår i: Journal of Neurochemistry. - : Wiley. - 1471-4159 .- 0022-3042. ; 117:6, s. 1066-1074
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Tidskriftsartikel (refereegranskat)abstract
- Neuregulin-1 (Nrg1) is genetically linked to schizophrenia, a disease caused by neurodevelopmental imbalance in dopaminergic function. The Nrg1 receptor ErbB4 is abundantly expressed on midbrain dopaminergic neurons. Nrg1 has been shown to penetrate blood-brain barrier, and peripherally administered Nrg1 activates ErbB4 and leads to a persistent hyperdopaminergic state in neonatal mice. These data prompted us to study the effect of peripheral administration of Nrg1 in the context of Parkinson's disease, a neurodegenerative disorder affecting the dopaminergic system in the adult brain. We observed that systemic injections of the extracellular domain of Nrg1ß(1) (Nrg1ß(1) -ECD) increased dopamine levels in the substantia nigra and striatum of adult mice. Nrg1ß(1) -ECD injections also significantly protected the mouse nigrostriatal dopaminergic system morphologically and functionally against 6-hydroxydopamine-induced toxicity in vivo. Moreover, Nrg1ß(1) -ECD also protected human dopaminergic neurons in vitro against 6-hydroxydopamine. In conclusion, we have identified Nrg1ß(1) -ECD as a neurotrophic factor for adult mouse and human midbrain dopaminergic neurons with peripheral administratability, warranting further investigation as therapeutic option for PD patients.
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| 3. |
- Carta, Manolo, et al.
(författare)
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Role of striatal l-DOPA in the production of dyskinesia in 6-hydroxydopamine lesioned rats.
- 2006
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Ingår i: Journal of Neurochemistry. - : Wiley. - 1471-4159 .- 0022-3042. ; 96:6, s. 1718-1727
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Tidskriftsartikel (refereegranskat)abstract
- We explored possible differences in the peripheral and central pharmacokinetics of L-DOPA as a basis for individual variation in the liability to dyskinesia. Unilaterally, 6-hydroxydopamine (6-OHDA) lesioned rats were treated chronically with L-DOPA for an induction and monitoring of abnormal involuntary movements (AIMs). Comparisons between dyskinetic and non-dyskinetic cases were then carried out with regard to plasma and striatal L-DOPA concentrations, tissue levels of dopamine (DA), DA metabolites, and serotonin. After a single intraperitoneal injection of L-DOPA, plasma L-DOPA concentrations did not differ between dyskinetic and non-dyskinetic animals, whereas peak levels of L-DOPA in the striatal extracellular fluid were about fivefold larger in the former compared with the latter group. Interestingly, the time course of the AIMs paralleled the surge in striatal L-DOPA levels. Intrastriatal infusion of L-DOPA by reverse dialysis concentration dependently induced AIMs in all 6-OHDA lesioned rats, regardless of a previous priming for dyskinesia. Steady-state levels of DA and its metabolites in striatal and cortical tissue did not differ between dyskinetic and non-dyskinetic animals, indicating that the observed difference in motor response to L-DOPA did not depend on the extent of lesion-induced DA depletion. These results show that an elevation of L-DOPA levels in the striatal extracellular fluid is necessary and sufficient for the occurrence of dyskinesia. Individual differences in the central bioavailability of L-DOPA may provide a clue to the varying susceptibility to dyskinesia in Parkinson's disease.
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| 4. |
- Cheng, Fang, et al.
(författare)
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Copper-dependent co-internalization of the prion protein and glypican-1.
- 2006
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Ingår i: Journal of Neurochemistry. - : Wiley. - 1471-4159 .- 0022-3042. ; 98:5, s. 1445-1457
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Tidskriftsartikel (refereegranskat)abstract
- Heparan sulfate chains have been found to be associated with amyloid deposits in a number of diseases including transmissible spongiform encephalopathies. Diverse lines of evidence have linked proteoglycans and their glycosaminoglycan chains, and especially heparan sulfate, to the metabolism of the prion protein isoforms. Glypicans are a family of glycosylphosphatidylinositol-anchored, heparan sulfate-containing, cell-associated proteoglycans. Cysteines in glypican-1 can become nitrosylated by endogenously produced nitric oxide. When glypican-1 is exposed to a reducing agent, such as ascorbate, nitric oxide is released and autocatalyses deaminative cleavage of heparan sulfate chains. These processes take place while glypican-1 recycles via a non-classical, caveolin-associated pathway. We have previously demonstrated that prion protein provides the Cu2+ ions required to nitrosylate thiol groups in the core protein of glypican-1. By using confocal immunofluorescence microscopy and immunomagnetic techniques, we now show that copper induces co-internalization of prion protein and glypican-1 from the cell surface to perinuclear compartments. We find that prion protein is controlling both the internalization of glypican-1 and its nitric oxide-dependent autoprocessing. Silencing glypican-1 expression has no effect on copper-stimulated prion protein endocytosis, but in cells expressing a prion protein construct lacking the copper binding domain internalization of glypican-1 is much reduced and autoprocessing is abrogated. We also demonstrate that heparan sulfate chains of glypican-1 are poorly degraded in prion null fibroblasts. The addition of either Cu2+ ions, nitric oxide donors, ascorbate or ectopic expression of prion protein restores heparan sulfate degradation. These results indicate that the interaction between glypican-1 and Cu2+-loaded prion protein is required both for co-internalization and glypican-1 self-pruning.
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| 5. |
- Emgård-Mattson, Mia, et al.
(författare)
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Both apoptosis and necrosis occur early after intracerebral grafting of ventral mesencephalic tissue: a role for protease activation.
- 2003
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Ingår i: Journal of Neurochemistry. - : Wiley. - 1471-4159 .- 0022-3042. ; 86:5, s. 1223-1232
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Tidskriftsartikel (refereegranskat)abstract
- Neural transplantation is an experimental treatment for Parkinson's disease. Widespread clinical application of the grafting technique is hampered by a relatively poor survival (around 10%) of implanted embryonic dopamine neurones. Earlier animal studies have indicated that a large proportion of the grafted cells die during graft tissue preparation and within the first few days after intracerebral implantation. The present study was designed to reveal the prevalence of cell death in rat intrastriatal grafts at 90 min, 1, 3, 6 and 42 days after implantation. We examined apoptotic cell death using semi-thin and paraffin sections stained with methylene blue and an antibody against activated caspase 3, respectively. We identified abundant apoptotic cell death up to 3 days after transplantation. In addition, we studied calpain activation using an antibody specific for calpain-cleaved fodrin. We report a peak in calpain activity 90 min after grafting. Surprisingly, we did not observe any significant difference in the number of dopaminergic neurones over time. The present results imply that grafted cells may be victims of either an early necrotic or a later apoptotic cell death and that there is substantial cell death as early as 90 min after implantation.
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| 6. |
- Fujimori, Ko, et al.
(författare)
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Prevention of paraquat-induced apoptosis in human neuronal SH-SY5Y cells by lipocalin-type prostaglandin D synthase.
- 2012
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Ingår i: Journal of Neurochemistry. - : Wiley. - 1471-4159 .- 0022-3042. ; 120, s. 279-291
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Tidskriftsartikel (refereegranskat)abstract
- Paraquat is a widely used herbicide that is structurally similar to the known dopaminergic neurotoxicant 1-methyl-4-phenyl-pyridine and acts as a potential etiologic factor for the development of Parkinson's disease. In this study, we investigated the protective roles of lipocalin-type prostaglandin (PG) D synthase (L-PGDS) against paraquat-mediated apoptosis of human neuronal SH-SY5Y cells. The treatment of SH-SY5Y cells with paraquat decreased the intracellular GSH level, and enhanced the cell death with elevation of the caspase activities. L-PGDS was expressed in SH-SY5Y cells, and its expression was enhanced with the peak at 2 h after the initiation of the treatment with paraquat. Inhibition of PGD(2) synthesis and exogenously added PGs showed no effects regarding the paraquat-mediated apoptosis. SiRNA-mediated suppression of L-PGDS expression in the paraquat-treated cells increased the cell death and caspase activities. Moreover, over-expression of L-PGDS suppressed the cell death and caspase activities in the paraquat-treated cells. The results of a promoter-luciferase assay demonstrated that paraquat-mediated elevation of L-PGDS gene expression occurred through the NF-κB element in the proximal promoter region of the L-PGDS gene in SH-SY5Y cells. These results indicate that L-PGDS protected against the apoptosis in the paraquat-treated SH-SY5Y cells through the up-regulation of L-PGDS expression via the NF-κB element. Thus, L-PGDS might potentially serve as an agent for prevention of human neurodegenerative diseases caused by oxidative stress and apoptosis.
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| 7. |
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| 8. |
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| 9. |
- Hansson, Oskar, et al.
(författare)
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Partial resistance to malonate-induced striatal cell death in transgenic mouse models of Huntington's disease is dependent on age and CAG repeat length
- 2001
-
Ingår i: Journal of Neurochemistry. - Lund Univ, Sect Neuronal Survival, Wallenberg Neurosci Ctr, Dept Physiol Sci, S-22184 Lund, Sweden. State Univ Campinas, Sch Med Sci, Dept Clin Pathol, Campinas, SP, Brazil. Univ Uppsala, Dept Neurosci, Uppsala, Sweden. GKT, Sch Med, London, England. : BLACKWELL SCIENCE LTD. - 0022-3042 .- 1471-4159. ; 78:4, s. 694-703
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Tidskriftsartikel (refereegranskat)abstract
- Transgenic, Huntington's disease (HD) mice, expressing exon I of the HD gene with an expanded CAG repeat, are totally resistant to striatal, lesion induced by excessive NMDA receptor activation. We now show that striatal lesions induced by the mitochondrial toxin malonate are reduced by 70-80% in transgenic HD mice compared with wild-type littermate controls. This occurred in 6- and 12-week-old HID mice with 150 CAG repeats (line R6/2) and in 18-week-old, but not 6-week-old, HID mice with 115 CAG repeats (line R6/1). Therefore, we show for the first time that the resistance to neurotoxin in transgenic HD mice is dependent on both the CAG repeat length and the age of the mice. Importantly, most HD patients develop symptoms in adulthood and exhibit an inverse relationship between GAG repeat length and age of onset. Transgenic mice expressing a normal CAG repeat (18 CAG) were not resistant to malonate. Although endogenous glutamate release has been implicated in malonate-induced cell death, glutamate release from striatal synaptosomes was not decreased in HID mice. Malonate-induced striatal cell death was reduced by 50-60% in wild-type mice when they were treated with either the NMDA receptor antagonist MK-801 or the caspase inhibitor zVAD-fmk. These two compounds did not reduce lesion size in transgenic R6/1 mice. This might suggest that NMDA receptor- and caspase-mediated cell death pathways are inhibited and that the limited malonate-induced cell death still occurring in HID mice is independent of these pathways. There were no changes in striatal levels of the two anti cell death proteins Bcl-X-L and X-linked Inhibitor of apoptosis protein (XIAP), before or after the lesion in transgenic HD mice. We propose that mutant huntingtin causes a sublethal grade of metabolic stress which is CAG repeat length-dependent and results in up-regulation over time of cellular defense mechanisms against impaired energy metabolism and excitotoxicity.
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| 10. |
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| 11. |
- Kolkova, K, et al.
(författare)
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Distinct roles of PKC isoforms in NCAM-mediated neurite outgrowth
- 2005
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Ingår i: Journal of Neurochemistry. - : Wiley. - 1471-4159 .- 0022-3042. ; 92:4, s. 886-894
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Tidskriftsartikel (refereegranskat)abstract
- The role of protein kinase C (PKC) isoforms in the neural cell adhesion molecule (NCAM)-mediated neurite outgrowth was tested using a co-culture system consisting of fibroblasts with or without NCAM expression upon which either primary cerebellar granular neurones (CGN) or pheochromocytoma (PC12-E2) cells were grown. The latter transiently expressed various PKC isoforms and domains derived from selected PKCs. PKC inhibitors of various specificity inhibited NCAM-stimulated neuritogenesis from CGN, indicating that PKC is involved in this process. Moreover, stimulation by the NCAM-mimetic peptide, C3d, elicited phosphorylation of PKC in CGN. Expression of kinase-deficient forms of PKCalpha, betaI and betaII blocked NCAM-mediated neurite extension, but had no effect on nerve growth factor (NGF)-mediated neurite outgrowth. Expression of two PKCepsilon constructs: (i) a fragment from PKCepsilon encompassing the pseudosubstrate, the C1a domain (including the actin-binding site, ABS), and parts of the V3 region, or (ii) the PKCepsilon-specific ABS blocked NCAM-mediated neurite extension in both cases. These two constructs also partially inhibited NGF-stimulated neuritogenesis indicating that PKCepsilon is a positive regulator of both NCAM- and NGF-mediated differentiation. We suggest that PKCepsilon is a common downstream mediator for several neuritogenic factors, whereas one or more conventional PKCs are specifically involved in NCAM-stimulated neurite outgrowth.
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| 12. |
- Konstantoulas, Constantine James, et al.
(författare)
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FoxP1 promotes midbrain identity in embryonic stem cell-derived dopamine neurons by regulating Pitx3
- 2010
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Ingår i: Journal of Neurochemistry. - : Wiley. - 1471-4159 .- 0022-3042. ; 113:4, s. 836-847
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Tidskriftsartikel (refereegranskat)abstract
- P>The robust generation of midbrain dopamine neurons from embryonic stem cells and patient-specific induced pluripotent stem cells is a prospective tool for the development of new drugs and cell based therapies, and investigations into the aetiology of Parkinson's disease. To achieve this, it is crucial to identify the fate-determining regulatory factors that influence dopamine cell fate decision and the underlying molecular machinery. We identified FoxP1 as a novel marker for midbrain dopamine neurons. Enforced expression of FoxP1 in embryonic stem cells actuates the expression of Pitx3, a homeobox protein that is exclusively expressed in midbrain dopaminergic neurons and is required for their differentiation and survival during development and from embryonic stem cells in vitro. We show that FoxP1 can be recruited to the Pitx3 locus in embryonic stem cells and regulate Pitx3 promoter activity in a dual-luciferase assay. This transcriptional regulation of Pitx3 by FoxP1 depends on the presence of two high affinity binding sites in the distal Pitx3 promoter, through which FoxP1 directly binds as demonstrated by chromatin immunoprecipitation and electrophoretic mobility shift assay. Thus, this study demonstrates for the first time a transcription regulatory role for FoxP1 on the Pitx3 gene in mammalian stem cells.
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| 13. |
- Lindgren, Hanna, et al.
(författare)
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L-DOPA-induced dopamine efflux in the striatum and the substantia nigra in a rat model of Parkinson's disease: temporal and quantitative relationship to the expression of dyskinesia.
- 2010
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Ingår i: Journal of neurochemistry. - : Wiley. - 1471-4159 .- 0022-3042. ; 112:6, s. 1465-76
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Tidskriftsartikel (refereegranskat)abstract
- Abstract L-DOPA-induced dyskinesia in Parkinson's Disease (PD) is associated with large increases in brain dopamine (DA) levels following drug dosing, but the precise significance of this phenomenon is not understood. Here we compare DA efflux and metabolism in the striatum and the substantia nigra (SN) in dyskinetic and non-dyskinetic animals following a standard dose of L-DOPA. Rats with 6-OHDA lesions were treated chronically with L-DOPA, monitored on the abnormal involuntary movements (AIMs) scale, and then subjected to intracerebral microdialysis under freely-moving conditions. Following s.c. L-DOPA injection, peak extracellular DA levels in both striatum and SN were twice as large in dyskinetic animals compared to non-dyskinetic rats. This effect was not attributable to differences in DOPA levels or DA metabolism. The larger DA efflux in dyskinetic animals was blunted by 5-HT1A/5-HT1B receptor agonists and TTX infusion, reflecting release from serotonin neurons. Striatal levels of serotonin and its main metabolite, 5-hydroxyindolacetic acid were indeed elevated in dyskinetic animals compared to non-dyskinetic rats, indicating a larger serotonergic innervation density in the former group. High DA release was, however, not sufficient to explain dyskinesia. The AIMs output per unit concentration of striatal extracellular DA was indeed much larger in dyskinetic animals compared to non-dyskinetic cases at most time points examined. The present results indicate that both a high DA release post L-DOPA administration and an increased responsiveness to DA must coexist for a full expression of dyskinesia.
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| 14. |
- Lindquist, Catarina, et al.
(författare)
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Graded response to GABA by native extrasynaptic GABA(A) receptors
- 2006
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Ingår i: Journal of Neurochemistry. - : Wiley. - 1471-4159 .- 0022-3042. ; 97:5, s. 1349-1356
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Tidskriftsartikel (refereegranskat)abstract
- GABA is the main inhibitory neurotransmitter in the mammalian CNS. GABA in the brain is commonly associated with a fast, point-to-point form of signalling called synaptic transmission (phasic inhibition), but there is growing evidence that GABA participates in another, slower and more diffuse form of signalling often referred to as tonic inhibition. Unresolved questions regarding tonic neuronal inhibition concern activation and functional properties of extrasynaptic GABA(A) receptors (GABARex) present on neurones. Extrasynaptic receptors are exposed to submicromolar GABA concentrations and may modulate the overall excitability of neurones and neuronal networks. Here, we examined GABA-activated single-channel currents in dentate gyrus granule neurones in rat hippocampal slices. We activated three types (I, II, III) of GABARex channels by nanomolar GABA concentrations (EC50 I: 27 +/- 12; II: 4 +/- 3; III: 43 +/- 19 nM). The channels opened after a delay and the single-channel conductance was graded (gamma(max) I: 61 +/- 3; II: 85 +/- 8, III: 40 +/- 3 pS). The channels were differentially modulated by 1 mu M diazepam, 200 nM zolpidem, 1 mu M flumazenil and 50 nM THDOC (3 alpha, 21-dihydroxy-5 alpha-pregnan-20-one), consistent with the following minimal subunit composition of GABARex I alpha(1)beta gamma(2), GABARex II alpha(4)beta gamma(2) and GABARex III alpha beta delta channels.
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| 15. |
- Lindquist, Catarina, et al.
(författare)
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The mechanism of SR95531 inhibition at GABA receptors examined in human alphabeta and alphabetagamma receptors.
- 2005
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Ingår i: Journal of Neurochemistry. - : Wiley. - 1471-4159 .- 0022-3042. ; 94:2, s. 491-501
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Tidskriftsartikel (refereegranskat)abstract
- We examined the interaction of GABA and the competitive inhibitor SR95531 at human α1β1γ2S and α1β1 GABAA receptors expressed in Sf9 cells. The efficacy and potency of inhibition depended on the relative timing of the GABA and SR95531 applications. In saturating (10 mm) GABA, the half-inhibitory concentrations of SR95531 (IC50) when coapplied with GABA to α1β1γ2S or α1β1 receptors were 49 and 210 µm for the peak and 18 and 130 µm for the plateau current, respectively. Our data are explained by an inhibition mechanism in which SR95531 and GABA bind to two sites on the receptor where the binding of GABA allows channel opening but SR95531 does not. The SR95531 affinity for both receptor types was ~200 nm and the binding rate was found to be 10-fold faster than that for GABA. The dual binding-site model gives insights into the differential effects of GABA and SR95531 on the peak and plateau currents. The model predicts the effect of SR95531 on GABA currents in the synapse (GABA concentration ~ mm) and at extrasynaptic (GABA concentration ≤ µm) sites. The IC50 (50–100 nm) for the synaptic response to SR95531 was insensitive to the GABA affinity of the receptors whereas the IC50 (50–800 nm) for extrasynaptic inhibition correlated with the GABA affinity.
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| 16. |
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| 17. |
- Lundblad, Martin, et al.
(författare)
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Chronic intermittent L-DOPA treatment induces changes in dopamine release
- 2009
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Ingår i: Journal of Neurochemistry. - : Wiley. - 0022-3042 .- 1471-4159. ; 108:4, s. 998-1008
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Tidskriftsartikel (refereegranskat)abstract
- 3,4-Dihydroxyphenyl-l-alanine (l-DOPA)-induced dyskinesia often develops as a side effect of chronic l-DOPA therapy. This study was undertaken to investigate dopamine (DA) release upon l-DOPA treatment. Chronoamperometric measurements were performed in unilaterally DA-depleted rats, chronically treated with l-DOPA, resulting in dyskinetic and non-dyskinetic animals. Normal and lesioned l-DOPA naïve animals were used as controls. Potassium-evoked DA releases were significantly reduced in intact sides of animals undertaken chronic l-DOPA treatment, independent on dyskinetic behavior. Acute l-DOPA further attenuated the amplitude of the DA release in the control sides. In DA-depleted striata, no difference was found in potassium-evoked DA releases, and acute l-DOPA did not affect the amplitude. While immunoreactivity to serotonin uptake transporter was higher in lesioned striata of animals displaying dyskinetic behavior, no correlation could be documented between serotonin transporter-positive nerve fiber density and the amplitude of released DA. In conclusions, the amplitude of potassium-evoked DA release is attenuated in intact striatum after chronic intermittent l-DOPA treatment. No change in amplitude was found in DA-denervated sides of either dyskinetic or non-dyskinetic animals, while release kinetics were changed. This indicates the importance of studying DA release dynamics for the understanding of both beneficial and adverse effects of l-DOPA replacement therapy.
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| 18. |
- Lundqvist, C, et al.
(författare)
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Phosphatidylethanol affects inositol 1,4,5-trisphosphate levels in NG108-15 neuroblastoma x glioma hybrid cells
- 1993
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Ingår i: Journal of Neurochemistry. - : Wiley. - 1471-4159 .- 0022-3042. ; 60:2, s. 738-744
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Tidskriftsartikel (refereegranskat)abstract
- Phosphatidylethanol is formed by phospholipase D in animal cells exposed to ethanol. Previous reports have demonstrated that the degradation of phosphatidylethanol is slow, indicating that this lipid may be present in the cells after ethanol itself has disappeared. Accumulation of an abnormal alcohol metabolite may influence cellular functions. In the present study, cultivation of NG108-15 neuroblastoma x glioma hybrid cells in the presence of ethanol resulted in an accumulation of phosphatidylethanol and a simultaneous increase in basal inositol 1,4,5-trisphosphate levels. The direct effects of phosphatidylethanol on the phosphoinositide signal transduction system were examined through incorporation of exogenous phosphatidylethanol into membranes of ethanol-naive cells. An incorporation amounting to 2.8% of cellular phospholipids was achieved after a 5-h incubation with 30 microM phosphatidylethanol. Phosphatidylethanol was found to cause a time- and dose-dependent increase in the basal levels of inositol 1,4,5-trisphosphate. The effects on inositol 1,4,5-trisphosphate levels of exogenously added phosphatidylethanol and ethanol exposure for 2 days were not additive. No effect on bradykinin-stimulated inositol 1,4,5-trisphosphate production could be detected. However, the increase in basal inositol 1,4,5-trisphosphate levels indicates that phosphatidylethanol affects inositol 1,4,5-trisphosphate turnover and emphasizes the importance of considering phosphatidylethanol as a possible mediator of ethanol-induced effects on cellular processes.
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| 19. |
- Mela, Flora, et al.
(författare)
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Antagonism of metabotropic glutamate receptor type 5 attenuates l-DOPA-induced dyskinesia and its molecular and neurochemical correlates in a rat model of Parkinson's disease.
- 2007
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Ingår i: Journal of Neurochemistry. - : Wiley. - 1471-4159 .- 0022-3042. ; 101:2, s. 483-497
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Tidskriftsartikel (refereegranskat)abstract
- Metabotropic glutamate receptor type 5 (mGluR5) modulates dopamine and glutamate neurotransmission at central synapses. In this study, we addressed the role of mGluR5 in L-DOPA-induced dyskinesia, a movement disorder that is due to abnormal activation of both dopamine and glutamate receptors in the basal ganglia. A selective and potent mGluR5 antagonist, 3-[(2-methyl-1,3-thiazol-4-yl)ethynyl] pyridine, was tested for its ability to modulate molecular, behavioural and neurochemical correlates of dyskinesia in 6-hydroxydopamine-lesioned rats treated with L-DOPA. The compound significantly attenuated the induction of abnormal involuntary movements (AIMs) by chronic L-DOPA treatment at doses that did not interfere with the rat physiological motor activities. These effects were paralleled by an attenuation of molecular changes that are strongly associated with the dyskinesiogenic action of L-DOPA (i.e. up-regulation of prodynorphin mRNA in striatal neurons). Using in vivo microdialysis, we found a temporal correlation between the expression of L-DOPA-induced AIMs and an increased GABA outflow within the substantia nigra pars reticulata. When co-administered with L-DOPA, 3-[(2-methyl-1,3-thiazol-4-yl)ethynyl] pyridine greatly attenuated both the increase in nigral GABA levels and the expression of AIMs. These data demonstrate that mGluR5 antagonism produces strong anti-dyskinetic effects in an animal model of Parkinson's disease through central inhibition of the molecular and neurochemical underpinnings of L-DOPA-induced dyskinesia.
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| 20. |
- Morota, Saori, et al.
(författare)
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Spinal cord mitochondria display lower calcium retention capacity compared with brain mitochondria without inherent differences in sensitivity to cyclophilin D inhibition
- 2007
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Ingår i: Journal of Neurochemistry. - : Wiley. - 1471-4159 .- 0022-3042. ; 103:5, s. 2066-2076
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Tidskriftsartikel (refereegranskat)abstract
- The mitochondrial permeability transition (mPT) is a potential pathogenic mechanism in neurodegeneration. Varying sensitivity to calcium-induced mPT has been demonstrated for regions within the CNS possibly correlating with vulnerability following insults. The spinal cord is selectively vulnerable in e.g. amyotrophic lateral sclerosis and increased mPT sensitivity of mitochondria derived from the spinal cord has previously been demonstrated. In this study, we introduce whole-body hypothermia prior to removal of CNS tissue to minimize the effects of differential tissue extraction prior to isolation of spinal cord and cortical brain mitochondria. Spinal cord mitochondria were able to retain considerably less calcium when administered as continuous infusion, which was not related to a general increased sensitivity of the mPT to calcium, its desensitization to calcium by the cyclophilin D inhibitor cyclosporin-A, or to differences in respiratory parameters. Spinal cord mitochondria maintained a higher concentration of extramitochondrial calcium during infusion than brain mitochondria possibly related to an increased set-point concentration for calcium uptake. A hampered transport and retention capacity of calcium may translate into an increased susceptibility of the spinal cord to neurodegenerative processes involving calcium-mediated damage.
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| 21. |
- Nevalainen, Nina, et al.
(författare)
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Dopamine release from serotonergic nerve fibers is reduced in L-DOPA-induced dyskinesia
- 2011
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Ingår i: Journal of Neurochemistry. - : Wiley. - 0022-3042 .- 1471-4159. ; 118:1, s. 12-23
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Tidskriftsartikel (refereegranskat)abstract
- L-DOPA is the most commonly used treatment for symptomatic control in patients with Parkinson's disease. Unfortunately, most patients develop severe side-effects, such as dyskinesia, upon chronic l-DOPA treatment. The patophysiology of dyskinesia is unclear; however, involvement of serotonergic nerve fibers in converting l-DOPA to dopamine has been suggested. Therefore, potassium-evoked dopamine release was studied after local application of l-DOPA in the striata of normal, dopamine- and dopamine/serotonin-lesioned l-DOPA naïve, and dopamine-denervated chronically l-DOPA-treated dyskinetic rats using in vivo chronoamperometry. The results revealed that local l-DOPA administration into normal and intact hemisphere of dopamine-lesioned l-DOPA naïve animals significantly increased the potassium-evoked dopamine release. l-DOPA application also increased the dopamine peak amplitude in the dopamine-depleted l-DOPA naïve striatum, although these dopamine levels were several-folds lower than in the normal striatum, whereas no increased dopamine release was found in the dopamine/serotonin-denervated striatum. In dyskinetic animals, local l-DOPA application did not affect the dopamine release, resulting in significantly attenuated dopamine levels compared with those measured in l-DOPA naïve dopamine-denervated striatum. To conclude, l-DOPA is most likely converted to dopamine in serotonergic nerve fibers in the dopamine-depleted striatum, but the dopamine release is several-fold lower than in normal striatum. Furthermore, l-DOPA loading does not increase the dopamine release in dyskinetic animals as found in l-DOPA naïve animals, despite similar density of serotonergic innervation. Thus, the dopamine overflow produced from the serotonergic nerve fibers appears not to be the major cause of dyskinetic behavior.
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| 22. |
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| 23. |
- Paquet-Durand, Francois, et al.
(författare)
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PKG activity causes photoreceptor cell death in two retinitis pigmentosa models
- 2009
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Ingår i: Journal of Neurochemistry. - : Wiley. - 1471-4159 .- 0022-3042. ; 108:3, s. 796-810
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Tidskriftsartikel (refereegranskat)abstract
- Photoreceptor degeneration in retinitis pigmentosa is one of the leading causes of hereditary blindness in the developed world. Although causative genetic mutations have been elucidated in many cases, the underlying neuronal degeneration mechanisms are still unknown. Here, we show that activation of cGMP-dependent protein kinase (PKG) hallmarks photoreceptor degeneration in rd1 and rd2 human homologous mouse models. When induced in wild-type retinae, PKG activity was both necessary and sufficient to trigger cGMP-mediated photoreceptor cell death. Target-specific, pharmacological inhibition of PKG activity in both rd1 and rd2 retinae strongly reduced photoreceptor cell death in organotypic retinal explants. Likewise, inhibition of PKG in vivo, using three different application paradigms, resulted in robust photoreceptor protection in the rd1 retina. These findings suggest a pivotal role for PKG activity in cGMP-mediated photoreceptor degeneration mechanisms and highlight the importance of PKG as a novel target for the pharmacological intervention in RP.
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| 24. |
- Rytter, Anna, et al.
(författare)
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The temperature dependence and involvement of mitochondria permeability transition and caspase activation in damage to organotypic hippocampal slices following in vitro ischemia.
- 2005
-
Ingår i: Journal of Neurochemistry. - : Wiley. - 1471-4159 .- 0022-3042. ; 95:4, s. 1108-1117
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Tidskriftsartikel (refereegranskat)abstract
- The aggravating effect of hyperglycemia on ischemic brain injury can be mimicked in a model of in vitro ischemia (IVI) using murine hippocampal slice cultures. Using this model, we found that the damage in the CA1 region following IVI in the absence or presence of 40 mM glucose (hyperglycemia) is highly temperature dependent. Decreasing the temperature from 35 to 31 degrees C during IVI prevented cell death, whereas increasing the temperature by 2 degrees C markedly aggravated damage. As blockade of the mitochondrial permeability transition (MPT) is equally effective as hypothermia in preventing ischemic cell death in vivo, we investigated whether inhibition of MPT or of caspases was protective following IVI. In the absence of glucose, the MPT blockers cyclosporin A and MeIle(4)-CsA but not the immunosuppressive compound FK506 diminished cell death. In contrast, following hyperglycemic IVI, MPT blockade was ineffective. Also, the pan-caspase inhibitor Boc-Asp(OMe)fluoromethyl ketone did not decrease cell death in the CA1 region following IVI or hyperglycemic IVI. We conclude that cell death in the CA1 region of organotypic murine hippocampal slices following IVI is highly temperature dependent and involves MPT. In contrast, cell death following hyperglycemic IVI, although completely prevented by hypothermia, is not mediated by mechanisms that involve MPT or caspase activation
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| 25. |
- Smith, Ruben, et al.
(författare)
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Loss of SNAP-25 and rabphilin 3a in sensory-motor cortex in Huntington's disease.
- 2007
-
Ingår i: Journal of Neurochemistry. - : Wiley. - 1471-4159 .- 0022-3042. ; 103:1, s. 115-123
-
Tidskriftsartikel (refereegranskat)abstract
- Huntington’s disease (HD) is an autosomal dominant neurodegenerative disorder caused by a CAG-expansion in the gene encoding the protein huntingtin. The disease is characterized by progressive motor disturbances, cognitive defects, dementia, and weight loss. Using western blotting and immunohistochemistry we have assessed the expression levels and patterns of a number of proteins involved in neurotransmitter release in post-mortem frontal cortex samples from 10 HD cases with different disease grades. We report a loss of the soluble N-ethylmaleimide-sensitive factor attachment protein receptor (SNARE) protein, synaptosome-associated protein 25 (SNAP 25) in HD brains of grades I–IV. Moreover, in brains of grade III and IV we found a reduction in rabphilin 3a, a protein involved in vesicle docking and recycling. These losses appear to be specific and not due to a general loss of synapses in the HD cortex. Thus, levels of synaptobrevin II, syntaxin 1, rab3a or synaptophysin are unaltered in the same patient samples. SNAP 25 and rabphilin 3a are crucial for neurotransmitter release. Therefore, we suggest that a deficient pre-synaptic transmitter release may underlie some of the symptoms of HD.
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| 26. |
- Valastro, Barbara, et al.
(författare)
-
Proteomic analysis of striatal proteins in the rat model of l-DOPA-induced dyskinesia.
- 2007
-
Ingår i: Journal of Neurochemistry. - : Wiley. - 1471-4159 .- 0022-3042. ; 102:4, s. 1395-1409
-
Tidskriftsartikel (refereegranskat)abstract
- L-DOPA-induced dyskinesia (LID) is among the motor complications that arise in Parkinson's disease (PD) patients after a prolonged treatment with L-DOPA. To this day, transcriptome analysis has been performed in a rat model of LID [Neurobiol. Dis., 17 (2004), 219] but information regarding the proteome is still lacking. In the present study, we investigated the changes occurring at the protein level in striatal samples obtained from the unilaterally 6-hydroxydopamine-lesion rat model of PD treated with saline, L-DOPA or bromocriptine using two-dimensional difference gel electrophoresis and mass spectrometry (MS). Rats treated with L-DOPA were allocated to two groups based on the presence or absence of LID. Among the 2000 spots compared for statistical difference, 67 spots were significantly changed in abundance and identified using matrix-assisted laser desorption/ionization time-of-flight MS, atmospheric pressure matrix-assisted laser desorption/ionization and HPLC coupled tandem MS (LC/MS/ MS). Out of these 67 proteins, LID significantly changed the expression level of five proteins: alpha beta-crystalin, gamma-enolase, guanicloacetate methyltransferase, vinculin, and proteasome alpha-2 subunit. Complementary techniques such as western immunoblotting and immunohistochernistry were performed to investigate the validity of the data obtained using the proteomic approach. In conclusion, this study provides new insights into the protein changes occurring in LID.
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| 27. |
- Agardh, Carl-David, et al.
(författare)
-
Cerebral metabolic changes in profound, insulin-induced hypoglycemia, and in the recovery period following glucose administration
- 1978
-
Ingår i: Journal of Neurochemistry. - : Wiley. - 1471-4159 .- 0022-3042. ; 31:5, s. 1135-1142
-
Tidskriftsartikel (refereegranskat)abstract
- Severe hypoglycemia was induced by insulin in lightly anaesthetized (70°o N2O) and artificially ventilated rats. Brain tissue was frozen in situ after spontaneous EEG potentials had disappeared for 5. 10. 15 or 30 min and cerebral cortex concentrations of labile organic phosphates, glycolytic metabolites, ammonia and amino acids were determined. In other experiments, recovery was induced by glucose injection at the end of the period of EEG silence. All animals with an isoelectric EEG showed extensive deterioration of the cerebral energy state. and gross perturbation of amino acid concentrations. The latter included a 4-fold rise in aspartate concentration and reductions in glutamate and glutamine concentrations to 20 and 5oo of control levels respectively. There was an associated rise in ammonia concentration to about 3μmol-g-1. Administration of glucose brought about extensive recovery of cerebral energy metabolism. For example, after an isoelectric period of 30 min tissue concentrations of phosphocreatine returned to or above normal, the accumulation of ADP and AMP was reversed, there was extensive resynthesis of glycogen and glutamine and full normalisation of tissue concentrations of pyruvate. α-ketoglutarate. GABA and ammonia. However, even after 3 h of recovery there was a reduction in the ATP concentration and thereby in adenine nucleotide pool, moderate elevations of lactate content and the lactate pyruvate ratio, and less than complete restoration of the amino acid pool. It is concluded that some cells may have been irreversibly damaged by the hypoglycemia.
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| 28. |
- Agardh, Carl-David, et al.
(författare)
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Endogenous substrates utilized by rat brain in severe insulin-induced hypoglycemia
- 1981
-
Ingår i: Journal of Neurochemistry. - : Wiley. - 1471-4159 .- 0022-3042. ; 36:2, s. 490-500
-
Tidskriftsartikel (refereegranskat)abstract
- Several previous studies have demonstrated that severe hypoglycemia is accompanied by consumption of endogenous brain substrates (glycolytic and citric acid cycle metabolites and free amino acids) and some have shown a loss of structural components as well, notably phospholipids. In the present study, on paralysed and artificially ventilated rats, we measured cerebral oxygen and glucose consumption during 30 min of hypoglycemic coma (defined as hypoglycemia of sufficient severity to cause cessation of spontaneous EEG activity) and calculated the non-glucose oxygen consumption. In an attempt to estimate the missing substrate we measured tissue concentrations of phospholipids and RNA. After 5 min of hypoglycemic coma, tissue phospholipid content decreased by about 8% with no further change during the subsequent 55 min. A similar reduction remained after 90 min of recovery, induced by glucose administration following 30 min of coma. Since no preferential loss of polyenoic fatty acids or of ethanolamine phosphoglycerides occurred, it is concluded that loss of phospholipids was due to phospholipase activity rather than to peroxidative degradation. The free fatty acid concentration increased sixfold after 5 min of coma and remained elevated during the course of hypoglycemia. A 9% reduction in tissue RNA content was observed after 30 min of hypoglycemia. Calculations indicated that available endogenous carbohydrate and amino acid substrates were essentially consumed after 5 min of coma, and that other non-glucose substrates must have accounted for approximately 50μmol·g−1 of oxygen (8.3 μmol·g−1 in terms of glucose equivalents) within the 5–30 min period. The 10% reduction in phospholipid-bound fatty acids was more than sufficient (in four- to fivefold excess) to account for this oxygen consumption. However, since no further degradation occurred in the 5–30 min period, there is no simple, direct, quantitative relationship between oxygen consumption and cortical fatty acid oxidation during this interval. The possibility thus remains that unmeasured exogenous or endogenous substrates were utilized.
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| 29. |
- Agardh, Carl-David, et al.
(författare)
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Influence of severe hypoglycemia on mitochondrial and plasma membrane function in rat brain
- 1982
-
Ingår i: Journal of Neurochemistry. - : Wiley. - 1471-4159 .- 0022-3042. ; 38:3, s. 662-668
-
Tidskriftsartikel (refereegranskat)abstract
- Abstract: Previous experiments have shown that severe hypoglycemia disrupts cerebral energy state in spite of a maintained cerebral oxygen consumption, suggesting uncoupling of oxidative phosphorylation. Other studies have demonstrated that hypoglycemia leads to loss of cerebral cortical phospholipids and phospholipid-bound fatty acids. The objective of the present study was, therefore, to study respiratory characteristics of brain mitochondria during severe hypoglycemia and to correlate respiratory activity to mitochondrial phospholipid composition. Mitochondria were isolated after 30 or 60 min of hypoglycemia with ceased EEG activity, and after a 90-min recovery period, and their resting (state 4) and ADP-stimulated (state 3) oxygen consumption rates and phospholipids and phospholipid-bound fatty acid content were measured. After 30 min of hypoglycemia, state 3 respiration decreased without any increase in state 4 respiration or change in ADP/O ratio. This decrease, which occurred with glutamate plus malate—but not with succinate—as substrates, was partly reversed by addition of bovine serum albumin and KCI. Chemical analyses of isolated mitochondria did not reveal changes in their phospholipid or fatty acid content. The results thus failed to account for the dissociation of cerebral energy state and oxygen consumption. It is emphasized, though, that uncoupling may well occur in vivo due to accumulation of free fatty acids and "futile cycling" of K+ and Ca2+. After 60 min of hypoglycemia, a moderate decrease in state 3 respiration was observed also with succinate as substrate, and there was some decrease in ADP/O ratios in KCI-containing media. However, the changes in ADP/O ratios were more conspicuous during recovery; in addition, state 4 respiration increased significantly. It is concluded that changes in mitochondrial function after 30 min of hypoglycemia are potentially reversible but that true mitochondrial failure develops in the recovery period following 60 min of hypoglycemia. This conclusion was corroborated by results demonstrating incomplete recovery of cerebral energy state. Since EEG and sensory evoked potentials return after 30 min but not after 60 min of hypoglycemia it seemed difficult to explain failure of return of electrophysiological function after 60 min of hypoglycemia solely by mitochondrial dysfunction; plasma membrane function was therefore assessed by measurements of extracellular potassium activity ([K+]e). The results showed that whereas [K+]e remained close to control in the recovery period following 30 min of hypoglycemia it rose progressively during recovery following 60 min of hypoglycemia. Possibly, inhibition of Na+ K+–activated ATPase could contribute to the permanent loss of spontaneous or evoked electrical activity.
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| 30. |
- Araujo, IM, et al.
(författare)
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Calpain activation is involved in early caspase-independent neurodegeneration in the hippocampus following status epilepticus
- 2008
-
Ingår i: Journal of Neurochemistry. - : Wiley. - 1471-4159 .- 0022-3042. ; 105:3, s. 666-676
-
Tidskriftsartikel (refereegranskat)abstract
- Evidence for increased calpain activity has been described in the hippocampus of rodent models of temporal lobe epilepsy. However, it is not known whether calpains are involved in the cell death that accompanies seizures. In this work, we characterized calpain activation by examining the proteolysis of calpain substrates and in parallel we followed cell death in the hippocampus of epileptic rats. Male Wistar rats were injected with kainic acid (KA; 10 mg/kg) intraperitoneally and sacrificed 24h later, after development of grade 5 seizures. We observed a strong Fluoro-Jade labelling in the CA1 and CA3 areas of the hippocampus in the rats that received KA, as compared to saline-treated rats. Immunohistochemistry and Western blot analysis for the calpain-derived breakdown products of spectrin (SBDP) showed evidence of increased calpain activity in the same regions of the hippocampus where cell death is observed. No evidence was found for caspase activation, in the same conditions. Treatment with the calpain inhibitor MDL 28170 significantly prevented the neurodegeneration observed in CA1. Taken together, our data suggest that early calpain activation, but not caspase activation, is involved in neurotoxicity in the hippocampus after status epilepticus.
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| 31. |
- Bekku, Yoko, et al.
(författare)
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Brevican distinctively assembles extracellular components at the large diameter nodes of Ranvier in the CNS
- 2009
-
Ingår i: Journal of Neurochemistry. - : Wiley. - 1471-4159 .- 0022-3042. ; 108:5, s. 1266-1276
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Tidskriftsartikel (refereegranskat)abstract
- Brevican is known to be an abundant extracellular matrix component in the adult brain and a structural constituent of perineuronal nets. We herein show that brevican, tenascin-R (TN-R) and phosphacan are present at the nodes of Ranvier on myelinated axons with a particularly large diameter in the central nervous system. A brevican deficiency resulted in a reorganization of the nodal matrices, which was characterized by the shift of TN-R, and concomitantly phosphacan, from an axonal diameter-dependent association with nodes to an axonal diameter independent association. Supported by the co-immunoprecipitation results, these observations indicate that the presence of TN-R and phosphacan at nodes is normally brevican-dependent, while in the absence of brevican these molecules can also be recruited by versican V2. The versican V2 and Bral1 distribution was not affected, thus indicating a brevican-independent role of these two molecules for establishing hyaluronan-binding matrices at the nodes. Our results revealed that brevican plays a crucial role in determining the specialization of the hyaluronan-binding nodal matrix assemblies in large diameter nodes.
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| 32. |
- Benveniste, Helene, et al.
(författare)
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Determination of Brain Interstitial Concentrations by Microdialysis
- 1989
-
Ingår i: Journal of Neurochemistry. - : Wiley. - 1471-4159 .- 0022-3042. ; 52:6, s. 1741-1750
-
Tidskriftsartikel (refereegranskat)abstract
- Microdialysis is an extensively used technique for the study of solutes in brain interstitial space. The method is based on collection of substances by diffusion across a dialysis membrane positioned in the brain. The outflow concentration reflects the interstitial concentration of the substance of interest, but the relationship between these two entities is at present unclear. So far, most evaluations have been based solely on calibrations in saline. This procedure is misleading, because the ease by which molecules in saline diffuse into the probe is different from that of tissue. We describe here a mathematical analysis of mass transport into the dialysis probe in tissue based on diffusion equations in complex media. The main finding is that diffusion characteristics of a given substance have to be included in the formula. These include the tortuosity factor (λ) and the extracellular volume fraction (α). We have substantiated this by studies in a welldefined complex medium (red blood cell suspensions) as well as in brain. We conclude that the traditional calculation procedure results in interstitial concentrations that are too low by a factor of λ2/α for a given compound.
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| 33. |
- Blomqvist, Photjanee, et al.
(författare)
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Cyclic AMP Concentrations in Rat Neocortex and Hippocampus During and Following Incomplete Ischemia : Effects of Central Noradrenergic Neurons, Prostaglandins, and Adenosine
- 1985
-
Ingår i: Journal of Neurochemistry. - : Wiley. - 0022-3042 .- 1471-4159. ; 44:5, s. 1345-1353
-
Tidskriftsartikel (refereegranskat)abstract
- Abstract: The concentrations of cyclic AMP, noradrenaline, glycogen, glucose, lactate, pyruvate, labile phosphate compounds, and free fatty acids were investigated in the rat neocortex and hippocampus during and following cerebral ischemia. An incomplete ischemia of 5 and 15 min duration was induced by bilateral carotid clamping combined with hypotension. The postischemic events were studied after 5, 15, and 60 min of recirculation. Five minutes of ischemia did not significantly alter the neocortical or hippocampal concentrations of cyclic AMP. After 15 min of ischemia the neocortical levels decreased significantly below control values. In the recirculation period following ischemia a significant elevation of the cyclic AMP concentrations was observed. Following 5 min of recirculation after 5 min of ischemia the levels increased from 2.53 ± 0.21 nmol ± g−1 to 5.18 ± 0.09 nmol ± g−1 in the neocortex and from 2.14 ± 0.16 nmol ± g−1 to 3.52 ± 0.35 nmol ± g−1 in the hippocampus. Five minutes of recirculation following 15 min of ischemia led to a significant increase in the levels of cyclic AMP, to 12.86 ± 1.43 nmol ± g−1 in the neocortex to 5.58 ± 0.57 nmol ± g−1 in the hippocampus. With longer recirculation periods the cyclic AMP levels progressively decreased and were similar to control values after 60 min. Depletion of cortical noradrenaline by at least 95% was performed by injections of 6‐hydroxydopamine into the ascending axon bundles from the locus ceruleus. The lesion did not significantly change the ischemic or postischemic neocortical and hippocampal levels of cyclic AMP, glycogen, or free fatty acids including arachidonic acid. Treatment of the animals with theophyllamine (23, 46, and 92 mg ± kg−1) or indomethacin (10 mg ± kg−1) did not affect the postischemic levels of cyclic AMP. It is concluded that central noradrenergic neurons, prostaglandins, and adenosine are not of major importance for the observed postischemic elevations of cyclic AMP and that the changes in the concentrations of free fatty acids measured during and following ischemia are not mediated by noradrenergic neurons.
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| 34. |
- Cardell, Monika, et al.
(författare)
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Time Course of the Translocation and Inhibition of Protein kinase C During Complete Cerebral Ischemia in the Rat
- 1993
-
Ingår i: Journal of Neurochemistry. - : Wiley. - 0022-3042 .- 1471-4159. ; 61:4, s. 1308-1314
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Tidskriftsartikel (refereegranskat)abstract
- Abstract: The time course for the ischemia‐induced changes in the subcellular distribution of protein kinase C (PKC) (α), (β311). and (γ) and the activity of PKC were studied in the neocortex of rats subjected to 1, 2, 3, 5, 10, and 15 min of global cerebral ischemia. In the particulate fraction, a 14‐fold increase in PKC (γ) levels was seen at 3 min of ischemia, which further increased at 5–15 min of ischemia. At 15 min of ischemia, PKC (γ) and (βll) levels had increased two‐ and six‐fold, respectively. In the cytosolic fraction, a transient early 1.4‐fold increase in PKC (βll) and PKC (γ) levels was seen, whereas no change in the levels PKC (α) was noted. PKC (γ) levels then progressively declined, reaching 50% at 15 min of ischemia. At 5 min of ischemia, a 43% decrease in PKC activity was seen in the particulate fraction, reaching 50% at 15 min of ischemia concomitant with a 27% decrease in the cytosolic fraction. There was no change in the activator‐independent PKC activity. Pretreatment with the ganglioside AGF2 prevented the redistribution of PKC (γ) in the particulate fraction at 5 min. but not at 10 min of ischemia. The observed time course for the translocation of PKC (γ) parallels the ischemia‐induced release of neurotransmitters and increased levels of diacylglycerols, arachidonate, and intra‐cellular calcium and delineates this subspecies as especially ischemia‐sensitive. Ganglioside pretreatment delayed the translocation of PKC (γ), possibly by counteracting the effects of ischemia‐induced factors that favor PKC binding to cell membranes.
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| 35. |
- Cenci Nilsson, Angela, et al.
(författare)
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Post- versus presynaptic plasticity in L-DOPA-induced dyskinesia.
- 2006
-
Ingår i: Journal of Neurochemistry. - : Wiley. - 1471-4159 .- 0022-3042. ; 99:2, s. 381-392
-
Tidskriftsartikel (refereegranskat)abstract
- L-3,4-dihydroxyphenylalanine (L-DOPA) remains the most efficacious drug for the treatment of Parkinson's disease (PD), but causes adverse effects that limit its utility. L-DOPA-induced dyskinesia (abnormal involuntary movements) is a significant clinical problem that attracts growing scientific interest. Current notions attribute the development of dyskinesia to two main factors, viz. the loss of nigrostriatal dopamine (DA) projections and the maladaptive changes produced by L-DOPA at sites postsynaptic to the nigrostriatal neuron. Basic research in the past 15 years has placed a lot of emphasis on the postsynaptic plasticity associated with dyskinesia, but recent experimental work shows that also some presynaptic factors, involving the regulation of L-DOPA/DA release and metabolism in the brain, may show plasticity during treatment. This review summarizes significant studies of L-DOPA-induced dyskinesia in patients and animal models, and outlines directions for future experiments addressing mechanisms of presynaptic plasticity. These investigations may uncover clues to the varying susceptibility to L-DOPA-induced dyskinesia among PD patients, paving the way for tailor-made treatments.
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| 36. |
- Ding, Wei-Qun, et al.
(författare)
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Stimulation of muscarinic receptors induces expression of individual fos and jun genes through different transduction pathways
- 1998
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Ingår i: Journal of Neurochemistry. - : Wiley. - 1471-4159 .- 0022-3042. ; 70:4, s. 1722-1729
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Tidskriftsartikel (refereegranskat)abstract
- The transduction pathways coupling muscarinic receptors to induction of fos and jun genes were investigated in neuroblastoma SH-SY5Y cells. Stimulation with carbachol induced expression of c-fos, fosB, c-jun, junB, and junD. This effect was abolished by pretreatment with atropine, indicating an involvement of muscarinic receptors. These genes were also induced by activation of protein kinase C with phorbol ester or by elevating the intracellular Ca2+ concentration with a Ca2+ ionophore. The Ca2+ effect was inhibited by KN-62, suggesting an induction through Ca2+/calmodulin-dependent kinase II. Inhibition of protein kinase C with GF109203X suppressed the carbachol-stimulated increase in mRNA levels of c-fos, fosB, and junB by approximately 70% but had only minor effects on the expression of c-jun and junD. On the other hand, preincubation with KN-62 attenuated the carbachol-induced increase in c-jun and junD expression by 70% but had no effect on c-fos, fosB, and junB mRNA levels. Simultaneous inhibition of both protein kinase C and Ca2+/calmodulin-dependent kinase II completely abolished the carbachol-stimulated expression of c-jun and junD, but c-fos, fosB, and junB were still expressed to a certain extent under this condition. Comparison of the inhibitory effects of GF109203X and Go 6976 suggests the involvement of classical protein kinase C isozymes in muscarinic receptor-stimulated expression of fos and jun genes. These results demonstrate that the muscarinic receptor-induced expression of individual fos and jun genes is regulated via different pathways, primarily protein kinase C or Ca2+/calmodulin-dependent kinase II.
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| 37. |
- Dong, Yan, et al.
(författare)
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Amperometric measurements of catecholamine release from single vesicles in MN9D cells.
- 2008
-
Ingår i: Journal of neurochemistry. - : Wiley. - 1471-4159 .- 0022-3042. ; 107:6, s. 1589-95
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Tidskriftsartikel (refereegranskat)abstract
- MN9D cells have been used as a successful model to investigate dopamine pharmacology and to test the specific effects of drugs for the treatment of Parkinson's disease. However, quantitative measurements of quantal release from these cells have not been carried out. In this work, we used amperometry to investigate catecholamine release from MN9D cells. Amperometric events were observed in both undifferentiated and differentiated (butyric acid-treated) cells. An increase in quantal size and half-width was observed for differentiated cells versus undifferentiated cells; however, the number of events per cell and the amplitude remained constant. In transmission electron microscopy images, no obvious cluster of small synaptic vesicles was observed, and large dense-core vesicles were present in the cell body of undifferentiated cells; however, after differentiation, vesicles were concentrated in the cell processes. In differentiated cells, l-DOPA caused an increase in quantal size and half-width, which could be blocked by the vesicular monoamine transporter inhibitor, reserpine.
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| 38. |
- Ekström, Per, et al.
(författare)
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Calmodulin‐Binding Proteins Within the Slow Phase of Axonal Transport in the Rabbit Vagus Nerve Per Ekstrom and Martin Kanje
- 1987
-
Ingår i: Journal of Neurochemistry. - : Wiley. - 0022-3042 .- 1471-4159. ; 49:1, s. 146-151
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Tidskriftsartikel (refereegranskat)abstract
- Abstract: : Calmodulin‐binding proteins (CBPs) in the rabbit vagus nerve were studied by means of calmodulin‐Sepha‐rose affinity chromatography and polyacrylamide gel electrophoresis. The soluble fraction (105g supernatant) of a nerve homogenate contained four CBPs with molecular weights of 44, 55, 91, and 93 kD, respectively. Slowly transported proteins were recovered in the vagus 3 days after injection of [35S]methionine into the nodose ganglion. Four labelled CBPs with molecular weights of 44, 55, 69, and 83 kD, respectively were found. The nodose ganglion con tained two labelled CBPs, 44 and 55 kD. The 55‐kD CBP was identified as tubulin after immunoblotting. In separate experiments it was also shown that bovine brain tubulin bound to the calmodulin column.
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| 39. |
- Ekström, Per, et al.
(författare)
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Inhibition of Fast Axonal Transport by erythro‐9‐[3‐(2‐Hydroxynonyl)]Adenine
- 1984
-
Ingår i: Journal of Neurochemistry. - : Wiley. - 0022-3042 .- 1471-4159. ; 43:5, s. 1342-1345
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Tidskriftsartikel (refereegranskat)abstract
- Abstract: erythro‐9‐[3‐(2‐Hydroxynonyl)]adenine, an inhibitor of protein carboxylmethylation and dynein‐ATPase activity, inhibited fast axonal transport in vitro in frog sciatic nerves. Its site of action might be associated with an ATPase on which transport depends, since specific carboxylmethylation inhibitors lacked effects on transport. The levels of high energy phosphates and protein synthesis were unaffected by the drug at a transport‐inhibiting concentration, making disturbances due to metabolic effects less likely. An erythro‐9‐[3‐(2‐hy‐droxynonyl)]adenine‐sensitive ATPase was looked for in various nerve fractions but has so far not been resolved.
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| 40. |
- Engelsen, Bernt, et al.
(författare)
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Effect of Insulin‐Induced Hypoglycemia on the Concentrations of Glutamate and Related Amino Acids and Energy Metabolites in the Intact and Decorticated Rat Neostriatum
- 1986
-
Ingår i: Journal of Neurochemistry. - : Wiley. - 0022-3042 .- 1471-4159. ; 47:5, s. 1634-1641
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Tidskriftsartikel (refereegranskat)abstract
- Abstract The glutamate (Glu) terminals in rat neostriatum were removed by a unilateral frontal decortication. One to two weeks later the effects of insulin‐induced hypoglycemia on the steady‐state levels of amino acids [Glu, glutamine (Gin), aspartate (Asp), γ‐aminobutyric acid (GABA), tau‐rine] and energy metabolites (glucose, glycogen, α‐ketoglu‐tarate, pyruvate, lactate, ATP, ADP, AMP, phosphocre‐atine) were examined in the intact and decorticated neostriatum from brains frozen in situ. The changes in the metabolite levels were examined during normoglycemia, hypoglycemia with burst‐suppression (BS) EEG, after 5 and 30 min of hypoglycemic coma with isoelectric EEG, and 1 h of recovery following 30 min of isoelectric EEG. In normoglycemia Glu decreased and Gin and glycogen increased significantly on the decorticated side. During the BS period no significant differences in the measured compounds were noted between the two sides. After 5 min of isoelectric EEG Glu, Gin, GABA, and ATP levels were significantly lower and Asp higher on the intact than on the decorticated side. No differences between the two sides were found after 30 min of isoelectric EEG. After 1 h of recovery from 30 min of isoelectric EEG Glu, Gin, and glycogen had not reached their control levels. Glu was significantly lower, and Gin and glycogen higher on the decorticated side. The Asp and GABA levels were not significantly different from control levels. The results indicate that the turnover of Glu is higher in the intact than in decorticated neostriatum during profound hypoglycemia.
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| 41. |
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| 42. |
- Giorgi, O, et al.
(författare)
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Differential neurochemical properties of central serotonergic transmission in Roman high- and low-avoidance rats
- 2003
-
Ingår i: Journal of Neurochemistry. - : Wiley. - 1471-4159 .- 0022-3042. ; 86:2, s. 422-431
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Tidskriftsartikel (refereegranskat)abstract
- The selective breeding of Roman high- (RHA/Verh) and low-avoidance (RLA/Verh) rats for rapid versus poor acquisition of active avoidant behaviour has produced two behavioural phenotypes with different performances in a variety of animal models of anxiety, in which RLA/Verh rats are consistently more fearful than RHA/Verh rats. In addition, these two lines display different functional properties of brain neurotransmitters like serotonin (5-HT), known to be involved in the expression of anxiety- and depression-related behaviours. Therefore, we used brain microdialysis and [(3) H]-citalopram binding autoradiography to characterize further the neurochemical properties of 5-HTergic transmission in the two lines. No significant line-related differences were detected in the basal 5-HT output in the frontoparietal cortex (FPCx). In contrast, the increase in the cortical 5-HT output elicited by the systemic administration or the local application, via reverse dialysis, of chlorimipramine and fluoxetine was more robust in RHA/Verh than in RLA/Verh rats. Moreover, the binding signal of [(3) H]-citalopram to 5-HT re-uptake sites was more intense in the FPCx of RHA/Verh rats than in their RLA/Verh counterparts. These findings suggest that the functional tone of the 5-HTergic projection to the FPCx is stronger in the RHA/Verh line relative to the RLA/Verh line. It is proposed that RLA/Verh rats may be used as a model with heuristic value for studying the role of 5-HTergic transmission in anxiety and in the anxiolytic effects of monoamine re-uptake inhibitors.
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| 43. |
- Hu, Bing Ren, et al.
(författare)
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Casein Kinase II Activity in the Postischemic Rat Brain Increases in Brain Regions Resistant to Ischemia and Decreases in Vulnerable Areas
- 1993
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Ingår i: Journal of Neurochemistry. - : Wiley. - 0022-3042 .- 1471-4159. ; 60:5, s. 1722-1728
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Tidskriftsartikel (refereegranskat)abstract
- Abstract: Casein kinase II (CKII) is a protein kinase acting in the intracellular cascade of reactions activated by growth factor receptors, and that has a profound influence on cell proliferation and survival. In this investigation, we studied the changes in the activity and levels of CKII in the rat brain exposed to 10. 15 and 20 min of transient forebrain ischemia followed by variable periods of reperfusion. The cytosolic CKII activity decreased during reperfusion by ∼ 30 and ∼ 50% in the selectively vulnerable areas, striatum and the CA1 region of the hippocampus, respectively. In the resistant CA3 region of hippocampus and neocortex, the activity increased by ∼ 20 and ∼ 60%, respectively. The postischemic changes in CKII activity were dependent on the duration of the ischemic insult. The levels of CKII did not change after ischemia, suggesting that the enzyme is modulated by covalent modification or is interacting with an endogenous inhibitor/activator. Treatment of the cytosolic fraction from cortex of rats exposed to ischemia and 1 h of reperfusion with agarose‐bound phosphatase decreased the activity of CKII to control levels, suggesting that CKII activation after ischemia involves a phosphorylation of the enzyme. The correlation between postischemic CKII activity and neuronal survival implies that preservation or activation of CKII activity may be important for neuronal survival after cerebral ischemia.
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| 44. |
- Hu, Bing Ren, et al.
(författare)
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Depression of Neuronal Protein Synthesis Initiation by Protein Tyrosine Kinase Inhibitors
- 1993
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Ingår i: Journal of Neurochemistry. - : Wiley. - 0022-3042 .- 1471-4159. ; 61:5, s. 1789-1794
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Tidskriftsartikel (refereegranskat)abstract
- Abstract— Growth factors stimulate cellular protein synthesis, but the intracellular signaling mechanisms that regulate initiation of mRNA translation in neurons have not been clarified. A rate‐limiting step in the initiation of protein synthesis is the formation of the ternary complex among GTP, eukaryotic initiation factor 2 (elF‐2), and the initiator tRNA. Here we report that genistein, a specific tyrosine kinase inhibitor, decreases tyrosine kinase activity and the content of phosphotyrosine proteins in cultured primary cortical neurons. Genistein inhibits protein synthesis by >80% in a dose‐dependent manner (10–80 μg/ml) and concurrently decreases ternary complex formation by 60%. At the doses investigated, genistein depresses tyrosine kinase activity and concomitantly stimulates PKC activity. We propose that a protein tyrosine kinase participates in the initiation of protein synthesis in neurons, by affecting the activity of elF‐2 directly or through a protein kinase cascade.
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| 45. |
- Hu, Bing‐Ren ‐R, et al.
(författare)
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Persistent Translocation of Ca2+/Calmodulin‐Dependent Protein Kinase II to Synaptic Junctions in the Vulnerable Hippocampal CA1 Region Following Transient Ischemia
- 1995
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Ingår i: Journal of Neurochemistry. - : Wiley. - 0022-3042 .- 1471-4159. ; 64:1, s. 277-284
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Tidskriftsartikel (refereegranskat)abstract
- Abstract: The influence of brain ischemia on the subcellular distribution and activity of Ca2+/calmodulin‐dependent protein kinase II (CaM kinase II) was studied in various cortical rat brain regions during and after cerebral ischemia. Total CaM kinase II immunoreactivity (IR) and calmodulin binding in the crude synaptosomal fraction of all regions studied increase but decrease in the microsomal and cytosolic fractions, indicative of a translocation of CaM kinase II to synaptosomes. The translocation of CaM kinase II to synaptic junctions occurs but not to synaptic vesicles. The translocation in neocortex and CA3/DG (dentate gyrus) is transient, whereas in the hippocampal CA1 region, it persists for at least 1 day of reperfusion. The Ca2+/calmodulin‐dependent activity of CaM kinase II in the subsynaptosomal fractions of neocortex is persistently decreased by up to 85%, despite the increase in CaM kinase II IR. The decrease in activity is more pronounced than the decline in IR, suggesting that CaM kinase II is covalently modified in the postischemic phase. The persistent translocation of CaM kinase II in the vulnerable ischemic CA1 region indicates that a pathological process is sustained in the area after the reperfusion phase and this may be of significance for ischemic brain injury.
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| 46. |
- Karlsson, J E, et al.
(författare)
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Glial and neuronal marker proteins in the silicone chamber model for nerve regeneration
- 1993
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Ingår i: Journal of Neurochemistry. - : Wiley. - 0022-3042 .- 1471-4159. ; 60:3, s. 1098-1104
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Tidskriftsartikel (refereegranskat)abstract
- In the present study, neuronal and Schwann cell marker proteins were used to biochemically characterize the spatiotemporal progress of degeneration/regeneration in the silicone chamber model for nerve regeneration. Rat sciatic nerves were transected and the proximal and distal stumps were inserted into a bridging silicone chamber with a 10-mm interstump gap. Using dot immunobinding assays, S-100 protein and neuronal intermediate filament polypeptides were measured in different parts of the nerve 0-30 days after transection. In the most proximal nerve segment, all the measured proteins were transiently increased. In the proximal and distal stumps adjacent to the transection, the studied proteins were decreased indicating degeneration of the nerve. Within the silicone chamber, the regenerating nerve expressed the Schwann cell S-100 protein already at 7 days, whereas the neurofilament polypeptides appeared later. These observations are corroborated by previous morphological studies. The biochemical method described provides a new and fast approach to the study of nerve regeneration.
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| 47. |
- Kobylecki, Christopher, et al.
(författare)
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Calcium-permeable AMPA receptors are involved in the induction and expression of l-DOPA-induced dyskinesia in Parkinson's disease
- 2010
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Ingår i: Journal of Neurochemistry. - : Wiley. - 1471-4159 .- 0022-3042. ; 114:2, s. 499-511
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Tidskriftsartikel (refereegranskat)abstract
- P>Overactivity of striatal alpha-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid (AMPA) glutamate receptors is implicated in the pathophysiology of l-DOPA-induced dyskinesia (LID) in Parkinson's disease (PD). In this study, we evaluated the behavioural and molecular effects of acute and chronic blockade of Ca2+-permeable AMPA receptors in animal models of PD and LID. The acute effects of the Ca2+-permeable AMPA receptor antagonist 1-trimethylammonio-5-(1-adamantane-methylammoniopentane) dibromide hydrobromide (IEM 1460) on abnormal involuntary movements (AIMs) in the 6-hydroxydopamine (6-OHDA)-lesioned rat and LID in the MPTP-lesioned non-human primate were assessed. Subsequently, the effects of chronic treatment of 6-OHDA-lesioned rats with vehicle, l-DOPA/benserazide (6/15 mg/kg, i.p.) + vehicle or l-DOPA + IEM 1460 (3 mg/kg, i.p.) on behavioural and molecular correlates of priming for LID were evaluated. In the 6-OHDA-lesioned rat and MPTP-lesioned non-human primate, acute treatment with IEM 1460 (1-3 mg/kg) dose-dependently reduced LID without adverse effects on motor performance. Chronic co-treatment for 21 days with IEM 1460 reduced the induction of AIMs by l-DOPA in the 6-OHDA-lesioned rat without affecting peak rotarod performance, and attenuated AIMs score by 75% following l-DOPA challenge (p < 0.05). Chronic IEM 1460 treatment reversed l-DOPA-induced up-regulation of pre-proenkephalin-A, and normalised pre-proenkephalin-B mRNA expression in the lateral striatum, indicating an inhibition of both behavioural and molecular correlates of priming. These data suggest that Ca2+-permeable AMPA receptors are critically involved in both the induction and subsequent expression of LID, and represent a potential target for anti-dyskinetic therapies.
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| 48. |
- Kukhtina, V, et al.
(författare)
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Intracellular domain of nicotinic acetylcholine receptor: the importance of being unfolded.
- 2006
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Ingår i: Journal of Neurochemistry. - : Wiley. - 1471-4159 .- 0022-3042. ; 97:Suppl 1, s. 63-67
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Tidskriftsartikel (refereegranskat)abstract
- Bioinformatics methods with subsequent verification by experimental data were applied to the structural investigation of the intracellular loop of the d-subunit of the nicotinic acetylcholine receptor (nAChR). Three complementary methods were used: prediction of secondary structure elements, prediction of ordered/disordered protein regions and prediction of short functional binding motifs. The output of five different algorithms was used for the secondary structure construction. Most of the intracellular domain is predicted to be unfolded. The predictions correlate well with the experimental data of limited proteolysis and NMR performed on the mostly monomeric fraction of heterologously expressed Torpedo intracellular domain protein. Twelve functional binding motifs within the disordered regions of the nAChR intracellular domain are predicted. Identification of proteins that interact with the intracellular domain will provide a better understanding of protein–protein interactions involved in nAChR assembly, trafficking and clustering.
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| 49. |
- Kurihara, Junichi, et al.
(författare)
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Changes in the Tyrosine Phosphorylation of Mitogen‐Activated Protein Kinase in the Rat Hippocampus During and Following Severe Hypoglycemia
- 1994
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Ingår i: Journal of Neurochemistry. - : Wiley. - 0022-3042 .- 1471-4159. ; 63:6, s. 2346-2348
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Tidskriftsartikel (refereegranskat)abstract
- Abstract: The changes in the levels of tyrosine‐phosphorylated proteins in the cytosolic fraction of the rat hippocampus subjected to severe hypoglycemia were analyzed. A marked increase in tyrosine phosphorylation of a 43‐kDa protein was observed at 30 min of isoelectric EEG and 30 min and 1 h of recovery. Immunostaining of the same blot with antibody against mitogen‐activated protein (MAP) kinase demonstrated a double band of ∼42 and 43 kDa. The increased tyrosine phosphorylation of MAP kinase during hypoglycemic coma and the early recovery period suggests that MAP kinase may be involved in neuronal degeneration and repair.
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| 50. |
- Larsson, Christer, et al.
(författare)
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Activation of protein kinase C in permeabilized human neuroblastoma SH-SY5Y cells
- 1992
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Ingår i: Journal of Neurochemistry. - : Wiley. - 1471-4159 .- 0022-3042. ; 59:2, s. 644-651
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Tidskriftsartikel (refereegranskat)abstract
- The activation of protein kinase C was investigated in digitonin-permeabilized human neuroblastoma SH-SY5Y cells by measuring the phosphorylation of the specific protein kinase C substrate myelin basic protein4-14. The phosphorylation was inhibited by the protein kinase C inhibitory peptide PKC19-36 and was associated to a translocation of the enzyme to the membrane fractions of the SH-SY5Y cells. 1,2-Dioctanoyl-sn-glycerol had no effect on protein kinase C activity unless the calcium concentration was raised to concentrations found in stimulated cells (above 100 nM). Calcium in the absence of other activators did not stimulate protein kinase C. Phorbol 12-myristate 13-acetate was not dependent on calcium for the activation or the translocation of protein kinase C. The induced activation was sustained for 10 min, and thereafter only a small net phosphorylation of the substrate could be detected. Calcium or dioctanoylglycerol, when applied alone, only caused a minor translocation, whereas in combination a marked translocation was observed. Arachidonic acid (10 microM) enhanced protein kinase C activity in the presence of submaximal concentrations of calcium and dioctanoylglycerol. Quinacrine and p-bromophenacyl bromide did not inhibit calcium- and dioctanoylglycerol-induced protein kinase C activity at concentrations which are considered to be sufficient for phospholipase A2 inhibition.
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