1,720,969 research outputs found
Parkinson's disease: no NOP, new hope
No full textIn conclusion, we feel that data obtained through
a clinically-driven protocol in two different PD models
(neurotoxic and etiologic) and animal species (mouse and
rat), convey a solid proof-of-concept that NOP receptor
antagonists protect/rescue DA neurons from PD-like
neurodegeneration. Although more evidence needs to be
collected to claim that endogenous N/OFQ contributes to
DA cell loss also in human PD, NOP receptor antagonists
hold promise as symptomatic and disease-modifying
agents in PD therap
Eltoprazine prevents levodopa‐induced dyskinesias by reducing striatal glutamate and direct pathway activity
No full textBackground. Preclinical and clinical evidence that the serotonergic system plays a major role in levodopa-induced dyskinesias has been provided. Selective serotonin (5-hydroxytryptamine, 5-HT) 5-HT1A or 5-HT1B receptor agonists, and, very recently, the mixed 5-HT1A/5-HT1B receptor agonist eltoprazine, proved effective in inhibiting levodopa-induced dyskinesias in experimental animals and parkinsonian patients. Here we investigate the mechanisms underlying this effect. Methods. Microdialysis was employed in 6-hydroxydopamine hemilesioned rats chronically treated with levodopa alone or in combination with eltoprazine. Gamma-aminobutyric acid (GABA) and glutamate levels were monitored ON levodopa in the dopamine-depleted striatum and ipsilateral substantia nigra reticulata. Motor activity on the rotarod was assessed, both OFF and ON levodopa. Western blot was used to quantify ex-vivo striatal levels of phosphorylated extracellular signal regulated kinase 1 and 2. Striatal and nigral amino acid levels, as well as striatal dopamine levels were also monitored in levodopa-primed dyskinetic rats acutely challenged with levodopa and eltoprazine. Results. Eltoprazine attenuated the development and expression of dyskinesias, preserving motor coordination on the rotarod. Eltoprazine prevented the rise of nigral amino acids and striatal glutamate levels, as well as the increase in striatal phosphorylated extracellular signal regulated kinase 1 and 2, associated with dyskinesias. However, eltoprazine did not affect the levodopa-induced increase in striatal dopamine. Conclusions. Eltoprazine inhibits the sensitization of striato-nigral medium-sized gamma-aminobutyric acid spiny neurons (the direct pathway) to levodopa and their overactivation associated with dyskinesias appearance. Activation of 5-HT1A and 5-HT1B receptors regulating striatal glutamate transmission but not striatal ectopic dopamine release might underlie the symptomatic effect of eltoprazine
Going Beyond Counting First Authors in Author Co-citation Analysis
Full text linkThe present study examines one of the fundamental aspects of author co-citation analysis (ACA) - the way co-citation
counts are defined. Co-citation counting provides the data on which all subsequent statistical analyses and mappings
are based, and we compare ACA results based on two different types of co-citation counting - the traditional type that
only counts the first one among a cited work's authors on the one hand and a non-traditional type that takes into
account the first 5 authors of a cited work on the other hand. Results indicate that the picture produced through this non-traditional author co-citation counting contains more coherent author groups and is therefore considerably clearer. However, this picture represents fewer specialties in the research field being studied than that produced through the traditional first-author co-citation counting when the same number of top-ranked authors is selected and analyzed. Reasons for these effects are discussed
Variations on the Author
Full text link“Variations on the Author” discusses two of Eduardo Coutinho’s recent films (Um Dia na Vida, from 2010, and Últimas Conversas, posthumously released in 2015) and their contribution to the general question of documentary authorship. The director’s filmography is characterized by a consistent yet self-effacing form of authorial self-inscription: Coutinho often features as an interviewer that rather than express opinions propels discourses; an interviewer that is good at listening. This mode of self-inscription characterizes him as an author who is not expressive but who is nonetheless markedly present on the screen. In Um Dia na Vida, however, Coutinho is completely absent form the image, while Últimas Conversas, on the contrary, includes a confessional prologue that moves the director from the margins to the center of his films. This article examines the ways in which these works stand out in the filmography of a director who offers new insights into the notion of cinematic authorship
Appropriate Similarity Measures for Author Cocitation Analysis
Full text linkWe provide a number of new insights into the methodological discussion about author cocitation analysis. We first argue that the use of the Pearson correlation for measuring the similarity between authors’ cocitation profiles is not very satisfactory. We then discuss what kind of similarity measures may be used as an alternative to the Pearson correlation. We consider three similarity measures in particular. One is the well-known cosine. The other two similarity measures have not been used before in the bibliometric literature. Finally, we show by means of an example that our findings have a high practical relevance.information science;Pearson correlation;cosine;similarity measure;author cocitation analysis
Viral mediated α-synuclein overexpression results in greater transgene levels and α-synuclein overload in mice bearing kinase dead mutation of LRRK2
Full text linkAbstract The relationship between LRRK2 mutations and susceptibility to synuclein pathology in Parkinson’s disease (PD) is still unclear. We here investigate whether the mice carrying the D1994S kinase-dead (KD) mutation of LRRK2 show enhanced susceptibility to synucleinopathy. Twelve-month-old LRRK2 KD and WT mice were injected with AAV2/9 carrying human A53T α-synuclein (AAV-h-A53Tα-syn) or AAV2/9-GFP as a control. Three months after injection, α-synuclein pathology and nigrostriatal dopaminergic neuron degeneration were assessed along with motor behaviour. AAV-h-A53Tα-syn-injected LRRK2 KD mice showed a decline in stepping activity in the drag test compared to baseline levels and AAV-GFP-injected controls. This was associated with higher transgene levels and Serine129 α-syn phosphorylation in striatum and substantia nigra measured by immunohistochemistry. Total α-synuclein levels were also elevated in the substantia nigra but not striatum of AAV-h-A53Tα-syn LRRK2 KD mice compared to AAV-h-A53Tα-syn controls. Stereological counting of nigral dopaminergic neurons and densitometric analysis of striatal dopaminergic terminals did not reveal overt nigrostriatal degeneration. We conclude that silencing of kinase activity results in greater α-syn load due to greater viral transduction and/or defective α-syn clearance, possibly related to autophagy-lysosomal pathway impairment, however, with no consequence upon dopaminergic neuron survival in the mouse
Dopamine Transporter, PhosphoSerine129 alpha-Synuclein and alpha-Synuclein Levels in Aged LRRK2 G2019S Knock-In and Knock-Out Mice
Full text linkThe G2019S mutation in leucine rich-repeat kinase 2 (LRRK2) is a major cause of familial Parkinson's disease. We previously reported that G2019S knock-in mice manifest dopamine transporter dysfunction and phosphoSerine129 alpha-synuclein (pSer129 alpha-syn) immunoreactivity elevation at 12 months of age, which might represent pathological events leading to neuronal degeneration. Here, the time-dependence of these changes was monitored in the striatum of 6, 9, 12, 18 and 23-month-old G2019S KI mice and wild-type controls using DA uptake assay, Western analysis and immunohistochemistry. Western analysis showed elevation of membrane dopamine transporter (DAT) levels at 9 and 12 months of age, along with a reduction of vesicular monoamine transporter 2 (VMAT2) levels at 12 months. DAT uptake was abnormally elevated from 9 to up to 18 months. DAT and VMAT2 level changes were specific to the G2019S mutation since they were not observed in LRRK2 kinase-dead or knock-out mice. Nonetheless, dysfunctional DAT uptake was not normalized by acute pharmacological inhibition of LRRK2 kinase activity with MLi-2. Immunoblot analysis showed elevation of pSer129 alpha-syn levels in the striatum of 12-month-old G2019S KI mice, which, however, was not confirmed by immunohistochemical analysis. Instead, total alpha-syn immunoreactivity was found elevated in the striatum of 23-month-old LRRK2 knock-out mice. These data indicate mild changes in DA transporters and alpha-syn metabolism in the striatum of 12-month-old G2019S KI mice whose pathological relevance remains to be established.LMN
Enhancement of D1 dopaminergic responses in aged LRRK2 G2019S knock-in mice
Full text linkLRRK2 G2019S is associated with familial and sporadic Parkinson's disease and G2019S knock-in mice represent a valuable model to study early changes of basal ganglia transmission associated with Parkinson's disease. Here, we performed behavioral, biochemical and neurochemical analysis in 3-month-old and 12-month-old G2019S knock-in (KI) mice to investigate whether the G2019S mutation is associated with changes of D1 transmission during ageing. Behavioral analysis revealed no difference across genotypes at 3 months but elevated grooming activity in 12-month-old G2019S KI mice compared to wild-type and LRRK2 kinase-dead mice. Immunoblotting revealed a two-fold increase of the levels of phosphorylated GluA1 subunit of the AMPA receptor in 12-month-old G2019S KI mice challenged with the D1 receptor agonist SKF-81297 (5 mg/Kg), compared to wild-type mice. In vivo dual probe microdialysis revealed elevations of basal striatal and nigral extracellular glutamate levels and reduction of nigral GABA levels in 12-month-old G2019S KI mice. Systemic administration of the D1 receptor agonist SKF-81297 did not affect neurotransmitter release whereas reverse dialysis of the D1 receptor antagonist SCH-23390 (10–1000 nM) elevated striatal GABA release in 12-month-old G2019S KI but not wild-type mice. Intrastriatal SCH-233390 was also associated with a prolonged reduction of glutamate release in the substantia nigra reticulata in both genotypes. Finally, 12-month-old G2019S KI mice showed a more prolonged hypokinetic response to intraperitoneal administration of SCH-23390 (1 mg/Kg) compared to wild-type mice. We conclude that the LRRK2 G2019S mutation is associated with age-dependent enhancement of D1 dopaminergic responses, possibly due to elevated endogenous D1 transmission in striatum, that might be instrumental to sustain motor and cognitive function over ageing and help explain the slower and more benign course of G2019S-associated Parkinson's disease
Morphine and Fentanyl Differently Affect MOP and NOP Gene Expression in Human Neuroblastoma SH-SY5Y Cells.
No full textMorphine is widely used for the treatment of severe acute and chronic pain, but long-term therapy rapidly leads to tolerance. Morphine effects are mediated by μ opioid receptor (MOP) activation as well as for fentanyl that, in contrast to morphine, induces less tolerance to analgesia. The mechanisms underlying opioid tolerance involve complex processes, such as MOP desensitization, internalization, and/or changes of gene expression. The development of morphine tolerance also involves adaptive changes of the anti-opioid nociceptin/orphanin FQ-nociceptin receptor system, as suggested by the reduction of morphine tolerance in nociceptin opioid receptor (NOP) knockout mice. The aim of the present study was to investigate the MOP and NOP gene expression in the SH-SY5Y cells following morphine and fentanyl exposure. Results showed that cell exposure to 10 μM morphine for 5 h induced a significant decrease of MOP and NOP gene expression and that the MOP downregulation was reverted by the pretreatment with naloxone. Conversely, SH-SY5Y cells exposed to 0.1 and 1 μM fentanyl for 5 and 72 h showed a significant MOP upregulation, also reverted by naloxone pretreatment. Fentanyl induced no changes of NOP gene expression. The present findings showed a different effect by morphine and fentanyl on MOP mRNA levels that contributes to define the role of MOP gene expression changes in the mechanisms underlying the tolerance. Morphine also triggers an altered NOP-related signaling confirming that the nociceptin/orphanin FQ-nociceptin receptor system also plays a significant role in the development of morphine tolerance
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