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Sökning: WFRF:(Cenci Angela M.)

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1.
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2.
  • Björklund, Anders, et al. (författare)
  • Preface : The evolving scenario of Parkinson's research
  • 2020. - 1
  • Ingår i: Recent Advances in Parkinson's Disease. - : Elsevier Science Publishers B.V.. - 0079-6123 .- 1875-7855. - 9780444642608 ; 252
  • Bokkapitel (övrigt vetenskapligt)
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3.
  • Kuter, Katarzyna Z., et al. (författare)
  • The role of glia in Parkinson's disease : Emerging concepts and therapeutic applications
  • 2020
  • Ingår i: Recent Advances in Parkinson's Disease. - : Elsevier Science Publishers B.V.. - 0079-6123 .- 1875-7855. - 9780444642608 ; 252, s. 131-168
  • Bokkapitel (refereegranskat)abstract
    • Originally believed to primarily affect neurons, Parkinson's disease (PD) has recently been recognized to also affect the functions and integrity of microglia and astroglia, two cell categories of fundamental importance to brain tissue homeostasis, defense, and repair. Both a loss of glial supportive-defensive functions and a toxic gain of glial functions are implicated in the neurodegenerative process. Moreover, the chronic treatment with L-DOPA may cause maladaptive glial plasticity favoring a development of therapy complications. This chapter focuses on the pathophysiology of PD from a glial point of view, presenting this rapidly growing field from the first discoveries made to the most recent developments. We report and compare histopathological and molecular findings from experimental models of PD and human studies. We moreover discuss the important role played by astrocytes in compensatory adaptations taking place during presymptomatic disease stages. We finally describe examples of potential therapeutic applications stemming from an increased understanding of the important roles of glia in PD.
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4.
  • Ohlin, Elisabet, et al. (författare)
  • Vascular endothelial growth factor is upregulated by L-dopa in the parkinsonian brain: implications for the development of dyskinesia.
  • 2011
  • Ingår i: Brain. - : Oxford University Press. - 1460-2156 .- 0006-8950. ; 134, s. 2339-2357
  • Tidskriftsartikel (refereegranskat)abstract
    • Angiogenesis and increased permeability of the blood-brain barrier have been reported to occur in animal models of Parkinson's disease and l-dopa-induced dyskinesia, but the significance of these phenomena has remained unclear. Using a validated rat model of l-dopa-induced dyskinesia, this study demonstrates that chronic treatment with l-dopa dose dependently induces the expression of vascular endothelial growth factor in the basal ganglia nuclei. Vascular endothelial growth factor was abundantly expressed in astrocytes and astrocytic processes in the proximity of blood vessels. When co-administered with l-dopa, a small molecule inhibitor of vascular endothelial growth factor signalling significantly attenuated the development of dyskinesia and completely blocked the angiogenic response and associated increase in blood-brain barrier permeability induced by the treatment. The occurrence of angiogenesis and vascular endothelial growth factor upregulation was verified in post-mortem basal ganglia tissue from patients with Parkinson's disease with a history of dyskinesia, who exhibited increased microvascular density, microvascular nestin expression and an upregulation of vascular endothelial growth factor messenger ribonucleic acid. These congruent findings in the rat model and human patients indicate that vascular endothelial growth factor is implicated in the pathophysiology of l-dopa-induced dyskinesia and emphasize an involvement of the microvascular compartment in the adverse effects of l-dopa pharmacotherapy in Parkinson's disease.
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5.
  • Fieblinger, Tim, et al. (författare)
  • Mechanisms of Dopamine D1 Receptor-Mediated ERK1/2 Activation in the Parkinsonian Striatum and Their Modulation by Metabotropic Glutamate Receptor Type 5
  • 2014
  • Ingår i: Journal of Neuroscience. - : Society for Neuroscience. - 0270-6474 .- 1529-2401. ; 34:13, s. 4728-4740
  • Tidskriftsartikel (refereegranskat)abstract
    • In animal models of Parkinsons disease, striatal overactivation of ERK1/2 via dopamine (DA) D1 receptors is the hallmark of a supersensitive molecular response associated with dyskinetic behaviors. Here we investigate the pathways involved in D1 receptor-dependent ERK1/2 activation using acute striatal slices from rodents with unilateral 6-hydroxydopamine (6-OHDA) lesions. Application of the dopamine D1-like receptor agonist SKF38393 induced ERK1/2 phosphorylation and downstream signaling in the DA-denervated but not the intact striatum. This response was mediated through a canonical D1R/PKA/MEK1/2 pathway and independent of ionotropic glutamate receptors but blocked by antagonists of L-type calcium channels. Coapplication of an antagonist of metabotropic glutamate receptor type 5 (mGluR5) or its downstream signaling molecules (PLC, PKC, IP3 receptors) markedly attenuated SKF38393-induced ERK1/2 activation. The role of striatal mGluR5 in D1-dependent ERK1/2 activation was confirmed in vivo in 6-OHDA-lesioned animals treated systemically with SKF38393. In one experiment, local infusion of the mGluR5 antagonistMTEPin the DA-denervated rat striatum attenuated the activation of ERK1/2 signaling by SKF38393. In another experiment, 6-OHDA lesions were applied to transgenic mice with a cell-specific knockdown of mGluR5 in D1 receptor-expressing neurons. These mice showed a blunted striatal ERK1/2 activation in response to SFK38393 treatment. Our results reveal that D1-dependent ERK1/2 activation in the DA-denervated striatum depends on a complex interaction between PKA-and Ca2+ -dependent signaling pathways that is critically modulated by striatal mGluR5.
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6.
  • Francardo, Veronica, et al. (författare)
  • Impact of the lesion procedure on the profiles of motor impairment and molecular responsiveness to L-DOPA in the 6-hydroxydopamine mouse model of Parkinson's disease.
  • 2011
  • Ingår i: Neurobiology of Disease. - : Elsevier. - 0969-9961. ; 42:3, s. 327-40
  • Tidskriftsartikel (refereegranskat)abstract
    • 6-Hydroxydopamine (6-OHDA) lesions are being used in the mouse for basic research on Parkinson's disease and L-DOPA-induced dyskinesia. We set out to compare unilateral lesion models produced by intrastriatal or intramesencephalic injections of a fixed 6-OHDA concentration (3.2μg/μl) in C57BL/6 mice. In the first experiment, toxin injections were performed either at two striatal coordinates (1 or 2μl per site, termed "striatum(2×1μl)" and "striatum(2×2μl)" models), in the medial forebrain bundle (MFB), or in the substantia nigra pars compacta (SN) (1μl per site). All the four lesion models produced significant forelimb use asymmetry, but spontaneous turning asymmetry only occurred in the MFB and striatum(2×2μl) models. After the behavioral studies, the induction of phosphorylated extracellular signal-regulated kinases 1 and 2 (pERK1/2) by acute L-DOPA (30mg/kg) was used as a marker of post-synaptic supersensitivity. Striatal pERK1/2 expression was sparse in the SN and striatum(2×1μl) groups, but pronounced in the striatum(2×2μl) and MFB-lesioned mice. In further experiments, mice with MFB and striatal(2×2μl) lesions were used to compare behavioral and molecular responses to chronic L-DOPA treatment (12days at 3 and 6mg/kg/day). Maximally severe abnormal involuntary movements (AIMs) occurred in all MFB-lesioned mice, whereas only 35% of the mice with striatal lesions developed dyskinesia. Striatal tissue levels of dopamine were significantly lower in the dyskinetic animals (both MFB and striatum(2×2μl) groups) in comparison with the non-dyskinetic ones. Noradrenaline levels were significantly reduced only in MFB lesioned animals and did not differ among the dyskinetic and non-dyskinetic cases with striatal lesions. In all groups, the L-DOPA-induced AIM scores correlated closely with the number of cells immunoreactive for tyrosine hydroxylase or FosB/∆FosB in the striatum. In conclusion, among the four lesion procedures examined here, only the MFB and striatum(2×2μl) models yielded a degree of dopamine denervation sufficient to produce spontaneous postural asymmetry and molecular supersensitivity to L-DOPA. Both lesion models are suitable to reproduce L-DOPA-induced dyskinesia, although only MFB lesions yield a pronounced and widespread expression of post-synaptic supersensitivity markers in the striatum.
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7.
  • Janelidze, Shorena, et al. (författare)
  • Increased CSF biomarkers of angiogenesis in Parkinson disease
  • 2015
  • Ingår i: Neurology. - : Lippincott Williams & Wilkins. - 0028-3878. ; 85:21, s. 1834-1842
  • Tidskriftsartikel (refereegranskat)abstract
    • To study biomarkers of angiogenesis in Parkinson disease (PD), and how these are associated with clinical characteristics, blood-brain barrier (BBB) permeability, and cerebrovascular disease.
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8.
  • Lundblad, Martin, et al. (författare)
  • Chronic intermittent L-DOPA treatment induces changes in dopamine release
  • 2009
  • Ingår i: Journal of Neurochemistry. - : Wiley-Blackwell. - 1471-4159 .- 0022-3042. ; 108:4, s. 998-1008
  • 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 naive 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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9.
  • Lundblad, Martin, et al. (författare)
  • Pharmacological validation of behavioural measures of akinesia and dyskinesia in a rat model of Parkinson's disease.
  • 2002
  • Ingår i: European Journal of Neuroscience. - : Wiley-Blackwell. - 1460-9568 .- 0953-816X. ; 15:1, s. 120-132
  • Tidskriftsartikel (refereegranskat)abstract
    • In an attempt to define clinically relevant models of akinesia and dyskinesia in 6-hydroxydopamine (6-OHDA)-lesioned rats, we have examined the effects of drugs with high (L-DOPA) vs. low (bromocriptine) dyskinesiogenic potential in Parkinson's disease on three types of motor performance, namely: (i) abnormal involuntary movements (AIMs) (ii) rotational behaviour, and (iii) spontaneous forelimb use (cylinder test). Rats with unilateral 6-OHDA lesions received single daily i.p. injections of L-DOPA or bromocriptine at therapeutic doses. During 3 weeks of treatment, L-DOPA but not bromocriptine induced increasingly severe AIMs affecting the limb, trunk and orofacial region. Rotational behaviour was induced to a much higher extent by bromocriptine than L-DOPA. In the cylinder test, the two drugs initially improved the performance of the parkinsonian limb to a similar extent. However, L-DOPA-treated animals showed declining levels of performance in this test because the drug-induced AIMs interfered with physiological limb use, and gradually replaced all normal motor activities. L-DOPA-induced axial, limb and orolingual AIM scores were significantly reduced by the acute administration of compounds that have antidyskinetic efficacy in parkinsonian patients and/or nonhuman primates (-91%, yohimbine 10 mg/kg; -19%, naloxone 4-8 mg/kg; -37%, 5-methoxy 5-N,N-dimethyl-tryptamine 2 mg/kg; -30%, clozapine 8 mg/kg; -50%, amantadine 40 mg/kg). L-DOPA-induced rotation was, however, not affected. The present results demonstrate that 6-OHDA-lesioned rats do exhibit motor deficits that share essential functional similarities with parkinsonian akinesia or dyskinesia. Such deficits can be quantified using novel and relatively simple testing procedures, whereas rotometry cannot discriminate between dyskinetic and antiakinetic effects of antiparkinsonian treatments.
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10.
  • Westin, J. E., et al. (författare)
  • Persistent changes in striatal gene expression induced by long-term L-DOPA treatment in a rat model of Parkinson's disease
  • 2001
  • Ingår i: European Journal of Neuroscience. - : Wiley-Blackwell. - 0953-816X .- 1460-9568. ; 14:7, s. 1171-1176
  • Tidskriftsartikel (refereegranskat)abstract
    • Current knowledge of the molecular changes induced by dopamine denervation and subsequent treatment with L-DOPA is based on studies performed on relatively acute and young animal models of parkinsonism. It is highly warranted to ask how well these models simulate the state of chronic denervation and sustained L-DOPA pharmacotherapy which are typical of advanced Parkinson's disease. This study investigates the effects of time postdenervation and L-dopa treatment duration on the striatal expression of opioid precursor mRNAs and FosB/DFosB-related proteins. Unilaterally 6-hydroxydopamine-lesioned rats were treated with therapeutical doses of L-DOPA for one year (long-term group) or a few weeks (short-term group). Age-matched lesioned rats received injections of vehicle or bromocriptine, an antiparkinsonian compound which does not produce dyskinesia when administered de novo. The lesion-induced up-regulation of preproenkephalin mRNA expression persisted at more than one year postlesion, and was unaffected by the pharmacological treatments applied. L-DOPA, but not bromocriptine, induced high striatal levels of FosB/DFosB immunoreactivity and prodynorphin mRNA, and these did not differ between short-term and long-term L-DOPA-treated rats. The present data provide the first demonstration that L-DOPA maintains high striatal levels of fosB and prodynorphin gene expression during a prolonged course of treatment, which simulates the clinical practice in Parkinson's disease more closely than the short-treatment paradigms studied thus far.
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  • Resultat 1-10 av 47
  • [1]2345Nästa

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