2,909 research outputs found
New insights into the circuitry underlying levodopa-induced dyskinesia in rodent models of Parkinson's disease
No full textAbnormal involuntary movements (AIMs) or dyskinesias are probably the most debilitating side-effect elicited by levodopa pharmacotherapy of Parkinson’s disease. Development of levodopa-induced dyskinesias (LID) reflects a processes of sensitization to levodopa taking place primarily in striatum, and leading to the abnormal response to dopaminomimetics. Despite the growing knowledge about the intracellular pathways involved in the development of LID, little is known about the impact of antidyskinetic treatments on the basal ganglia circuitry. In the present thesis, we used microdialysis to investigate the neurochemical and behavioural changes exerted by different antidyskinetic treatments or approaches in basal ganglia. We first found that levodopa evoked AIMs, and simultaneously elevated GABA levels in the substantia nigra reticulata but not globus pallidus of dyskinetic mice and rats, suggesting the involvement of the striato-nigral “direct” GABAergic pathway in both species (Bido et al., J Neurochem 118, 1043-1055, 2011). Amantadine (the only antidyskinetic drug marketed for treating LID) attenuated AIMs expression and prevented the nigral GABA rise (Bido et al., J Neurochem 118:1043-55, 2011), suggesting nigral GABA as a neurochemical correlate of LID. To further investigate which pathway is involved in LID and in the antidyskinetic effect of amantadine, we took advantage from recent studies showing the specificity of Ras-guanine nucleotide-releasing factor 1 and 2 to selectively couple NR2B and NR2A NMDA receptor subunits, respectively. We showed that blockade of striatal expression of Ras-GRF1 using a lentiviral vector carrying a short hairpin RNA (LV Ras-GRF1) caused an attenuation of LID development and expression, which was accompanied by the lack of the increase in nigral GABA. However, in LV Ras-GRF1 mice the antidyskinetic effect of amantadine and its neurochemical correlates were lost, suggesting LV Ras-GRF1 might interfere with the antidyskinetic effect of amantadine by acting on the same target (possibly the NR2B receptor). Conversely, injection of a viral construct expressing a small hairpin directed against RasGRF2 caused only a not significant reduction of LID, and did not prevent the increase of nigral GABA following L-DOPA. In these mice, also the antidyskinetic effect of amantadine remained unaltered (Bido et al., in preparation).
To confirm the involvement of the direct pathway in LID, and dissect out the role of striatal and nigral dopamine D1 and D2 receptors we performed regional perfusion (striatum and substantia nigra pars reticulata) of selective D1 and D2 antagonists simultaneously with systemic L-DOPA
administration. Intrastriatal blockade of D1 receptor attenuated LID and prevented the accompanying rise of nigral GABA levels whereas blockade of D2 receptor was ineffective (Mela et al., Neurobiol Dis 45, 574-583, 2012). When perfused in the substantia nigra, both the D1 and D2 antagonists attenuated LID expression, although only the D1 antagonist prevented the GABA rise.
Overall, the data provide neurochemical evidence that LID is accompanied by activation of D1-receptor expressing striato-nigral GABAergic neurons, and that the antidyskinetic effect of amantadine partly relies on the modulation of this pathway, possibly through NR2B-subunit expressing NMDA receptors. Nonetheless, by using different antidyskinetic approaches we were able to cause only ~50% reduction of LID in face of a complete inhibition of the GABA rise in substantia nigra. This points to the existence of other important neurochemical modulators of LID, possibly also in brain structures outside the basal ganglia
Amantadine attenuates levodopa-induced dyskinesia in mice and rats preventing the accompanying rise in nigral GABA levels
No full textAmantadine is the only drug marketed for treating levodopa-induced dyskinesia. However, its impact on basal ganglia circuitry in the dyskinetic brain, particularly on the activity of striatofugal pathways, has not been evaluated. We therefore used dual probe microdialysis to investigate the effect of amantadine on behavioral and neurochemical changes in the globus pallidus and substantia nigra reticulata of 6-hydroxydopamine hemi-lesioned dyskinetic mice and rats. Levodopa evoked abnormal involuntary movements (AIMs) in dyskinetic mice, and simultaneously elevated GABA release in substantia nigra reticulata (∼3-fold) but not globus pallidus. Glutamate levels were unaffected in both areas. Amantadine (40 mg/kg, i.p.), ineffective alone, attenuated (∼50%) AIMs expression and prevented the GABA rise. Moreover, it unraveled a facilitatory effect of levodopa on pallidal glutamate levels. Levodopa also evoked AIMs expression and a GABA surge (∼2-fold) selectively in the substantia nigra of dyskinetic rats. However, different from mice, glutamate levels rose simultaneously. Amantadine, ineffective alone, attenuated (∼50%) AIMs expression preventing amino acid increase and leaving unaffected pallidal glutamate. Overall, the data provide neurochemical evidence that levodopa-induced dyskinesia is accompanied by activation of the striato-nigral pathway in both mice and rats, and that the anti-dyskinetic effect of amantadine partly relies on the modulation of this pathway. © 2011 International Society for Neurochemistry
Rozpor ako východisko, láska ako smer u Simone Weilovej (Contradiction as base, Love as direction in writings of Simone Weil)
No full textArticle is explaining contradiction and love, Simone Weil‘s essential terms of hermeneutics of human Being. It introduces close relation of these terms with her understanding of God as well as with her overall concept of religion. Author also mentions Simone Weil‘s inspirations with philosophical and spiritual concepts of the East
“I beg you to tell me what has become of Djamila”: The Political Mobilization of Simone de Beauvoir’s Readers During the Boupacha Affair
No full textBy Sophia Millman This is a condensed version of a Masters thesis dedicated to the political mobilization of Simone de Beauvoir’s readers. The citations from the letters were translated from French by the author. *** On June 2, 1960, the French government ordered all copies of the daily Algiers edition of Le Monde seized and destroyed to suppress the publication of Simone de Beauvoir’s article “Pour Djamila Boupacha.” Beauvoir, a self-professed “woman of letters”, not “of action[1]”, and one ..
Further evidence for an involvement of nociceptin/orphanin FQ in the pathophysiology of Parkinson’s disease: a behavioral and neurochemical study in reserpinized mice
No full textThe contribution of nociceptin/orphanin FQ (N/OFQ) to reserpine-induced parkinsonism was evaluated in mice. A battery of motor tests revealed that reserpine caused dose-dependent and long-lasting motor impairment. Endogenous N/OFQ sustained this response since N/OFQ peptide (NOP) receptor knockout (NOP-/-) mice were less susceptible to the hypokinetic action of reserpine than wild-type (NOP+/+) animals. Microdialysis revealed that reserpine elevated glutamate and reduced GABA levels in substantia nigra reticulata, and that resistance to reserpine in NOP-/- mice was accompanied by a milder increase in glutamate and lack of inhibition of GABA levels. To substantiate this genetic evidence, the NOP receptor antagonist 1-[(3R,4R)-1-cyclooctylmethyl-3-hydroxymethyl-4-piperidyl]-3-ethyl-1,3-dihydro-2H benzimidazol-2-one (J-113397) simultaneously reduced akinesia and nigral glutamate levels in reserpinized NOP+/+ mice, being ineffective in NOP-/- mice. Moreover, repeated J-113397 administration in reserpinized mice resulted in faster recovery of baseline motor performance which was, however, accompanied by a loss of acute antiakinetic response. The short-term beneficial effect of J-113397 was paralleled by normalization of nigral glutamate levels, whereas loss of acute response was paralleled by loss of the ability of J-113397 to inhibit glutamate levels. We conclude that endogenous N/OFQ contributes to reserpine-induced parkinsonism, and that sustained NOP receptor blockade produces short-term motor improvement accompanied by normalization of nigral glutamate release
A comparative study of form and theology in the works of Flannery O'Connor and Simone Weil
No full textIn this comparative study of the form and theology of Flannery O'Connor and Simone Weil I interrogate how Weil's philosophical writings and her theology illuminate O'Connor's use of both narrative and non-fictional forms, and her Catholicism. The Introduction analyses how Weil's concept of superposed reading provides a new method of approaching both O'Connor, her writings, and O'Connor
studies, and focuses on how such apparently different women interconnect. Chapter One explores how both Weil and O'Connor attempt to write their theologies on the
souls of their readers yet are each subject to constraints imposed by form. Weil's concept of locating equilibrium between incommensurates is discussed, and her
distinctively philosophical approach to fictions and fictionality is used to investigate O'Connor's notion of prophetic fictions and the writer's role. Chapter Two assesses how both writers revivify Christian paradoxes. Weil's monstrous concept of affiiction, and O'Connor's use of the grotesque genre to jolt secular man into an
awareness of the sacred are scrutinised. Chapter Three studies how both writers consider an encounter between God and man is possible through the action of grace. My Conclusion interrogates how Weil's work can deepen our understanding of O'Connor's writings, and examines how successful O'Connor is at realising a truly
Christian literature. I conclude that despite being a writer of powerful fictions, O'Connor can not be totally successful in her mission as writer-prophet because
ultimately fiction escapes orthodoxy
In vivo evidence for a differential contribution of striatal and nigral D1 and D2 receptors to l-DOPA induced dyskinesia and the accompanying surge of nigral amino acid levels
No full textEvidence for an involvement of striatal D1 receptors in levodopa-induced dyskinesia has been presented whereas the contribution of striatal D2 receptors remains controversial. In addition, whether D1 and D2 receptors located in the substantia nigra reticulata shape the response to levodopa remains unknown. We therefore used dual probe microdialysis to unravel the impact of striatal and nigral D1 or 02 receptor blockade on abnormal involuntary movements (AIMS) and striatal output pathways in unilaterally 6-hydroxydopamine lesioned dyskinetic rats. Regional perfusion of D1/D5 (SCH23390) and D2/D3 (raclopride) receptor antagonists was combined with systemic administration of levodopa. Levodopa-induced AIMS coincided with a prolonged surge of GABA and glutamate levels in the substantia nigra reticulata. Intrastriatal SCH23390 attenuated the levodopa-induced AIM scores (similar to 50%) and prevented the accompanying neurochemical response whereas raclopride was ineffective. When perfused in the substantia nigra, both antagonists attenuated AIM expression (similar to 21-40%). However, only intranigral SCH23390 attenuated levodopa-induced nigral GABA efflux, whereas raclopride reduced basal GABA levels without affecting the response to levodopa. In addition, intranigral raclopride elevated amino acid release in the striatum and revealed a (mild) facilitatory effect of levodopa on striatal glutamate. We conclude that both striatal and nigral D1 receptors play an important role in dyskinesia possibly via modulation of the striato-nigral direct pathway. In addition, the stimulation of nigral D2 receptors contributes to dyskinesia while modulating glutamate and GABA efflux both locally and in the striatum. (C) 2011 Elsevier Inc. All rights reserved
Microlinices benthovus Simone 2014
No full textbenthovus, Microlinices Simone, 2014 Microlinices benthovus Simone, 2014: 575–578 (figs 6A–J, 7A–H, 11A–C). Gastropoda, Naticidae Paratypes (22 spc): MZSP 105269. Paratypes 1 (15 spc): MZSP 105270. Paratypes 2 (16 spc): MZSP 105271. Paratypes 3 (7 spc): MZSP 105272. Localities: Brazil, Espírito Santo, off Itaúnas, Abrolhos Slope, 18°59' S, 37°50' W, MD55 sta. DC 73, 637 m depth, 27 May 1987; 1) 19°00' S, 37°48' W, MD55 sta. DC72, 950– 1050 m, 27 May 1987; 2) off Regência, 19°40' S, 37°48' W, MD55 sta. CB77, 790– 940 m depth, 27 May 1987; 3) off Itaúnas, Abrolhos Slope, 19°01' S, 37°47' W, MD55 sta. CB79, 1500–1575 m depth, 28 May 1987. Collectors: P. Bouchet, J.H. Leal and B. Métivier. Preservation: Dry. Remarks: Former MNHN, Paris. The catalogue number MZSP 105250 is mentioned twice in Simone’s (2014) paper, among the paratypes of M. ibitingus Simone, 2014 and M. benthovus. This duplicity was a mistake by the author: the latter is an erroneous designation and should be disregarded. The only valid paratype lots for M. benthovus are the ones shown above.Published as part of Cavallari, Daniel C., Dornellas, Ana Paula S. & Simone, Luiz Ricardo L., 2016, Second annotated list of type specimens of molluscs deposited in the Museu de Zoologia da Universidade de São Paulo, Brazil, pp. 1-59 in European Journal of Taxonomy 213 on page 10, DOI: 10.5852/ejt.2016.213, http://zenodo.org/record/384012
Was bringt die Föderalismusreform? Wahrscheinliche Effekte der geänderten Zustimmungspflicht
No full textThe recently enacted reform of German federalism is supposed to make legislation faster, more efficient and better. To what extent are these expectations justified? In order to assess the likely effects of the reform, this study uses a research design that was recently applied by the Research and Reference Services of the German Bundestag (parliament): we estimate the future effects of the reform by analyzing the impact it would have had on the legislation in the 14th and 15th term of the Bundestag if it had already been been in force at that time. In particular we ask: To what extent would the number of laws requiring the consent of the states' chamber, the Bundesrat, have been reduced? Which type of laws would have been affected by this reduction - the more controversial ones, or the less controversial ones? Which policy sectors would have seen the greatest reduction? How much would the reduction have increased the government's capacity to act effectively? Would the legislative process have been accelerated? -- Die verabschiedete Föderalismusreform soll die Gesetzgebung in Deutschland schneller, effizienter und besser machen. Inwiefern sind diese Erwartungen berechtigt? Zur Abschätzung der Reformfolgen auf die Bundesgesetzgebung folgen wir in dem vorliegenden Working Paper einer Vorgehensweise, die der Wissenschaftliche Dienst des Bundestages kürzlich in einer Studie angewandt hat: Die Auswirkungen der Föderalismusreform insbesondere auf die Zustimmungspflicht werden anhand der Gesetzgebung der 14. und 15. Legislaturperiode untersucht. Wir fragen insbesondere: Wie stark hätte sich der Anteil der Zustimmungsgesetze verringert, wenn die neuen Zustimmungsregeln schon in diesen beiden Legislaturperioden gegolten hätten? Wären eher zwischen Regierung strittige oder unstrittige Gesetze von der Zustimmungspflicht befreit worden? Welche Politikbereiche wären betroffen? Wie sehr hätte sich die politische Handlungsfreiheit der Bundesregierung erhöht? Wäre die Gesetzgebung durch die veränderten Zustimmungsregeln beschleunigt worden?
Idea ofiary u Simone Weil
No full textAutorka omawia ofiarę, jaką z samej siebie złożyła Simone Weil. Głównym celem autorki artykułu jest wykazanie, iż idea ofiary była najważniejszą myślą w życiu francuskiej filozof. W artykule ukazano myśl o ofierze w życiu i pismach intelektualistki, jak również analogie, które rzucają nowe światło na ofiarę Weil. Jako klucz do interpretacji i zrozumienia ofiary Weil, autorka analizuje myśl Emmanuela Levinasa oraz Józefa Tischnera.The author interprets the sacrifice that Simone Weil filed with itself. The main point of the present article is the assumption that the sacrifice Simone Weil was the most important idea of her life. A thought about the victim is portraying the article in the life and letters of the intellectual, as well as is portraying analogies which are shedding new light on the Weil victim. As the key to interpretation and understanding the her victim, the author is analysing the thought of Emmanuel Levinas and Jozef Tischner.Udostępnienie publikacji Wydawnictwa Uniwersytetu Łódzkiego finansowane w ramach projektu „Doskonałość naukowa kluczem do doskonałości kształcenia”. Projekt realizowany jest ze środków Europejskiego Funduszu Społecznego w ramach Programu Operacyjnego Wiedza Edukacja Rozwój; nr umowy: POWER.03.05.00-00-Z092/17-00
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