bluuebunny/crossref_metadata_2025_split huggingface dataset:
Neuroprotection of microglial conditioned medium on 6‐hydroxydopamine‐induced neuronal death: role of transforming growth factor beta‐2
Authors: Polazzi Elisabetta , Altamira Luis Emiliano Peña , Eleuteri Simona , Barbaro Raffaella , Casadio Chiara , Contestabile Antonio , Monti Barbara 
Published: April 2009

AbstractMicroglia, the immune cells of the CNS, play essential roles in both physiological and pathological brain states. Here we have used an in vitro model to demonstrate neuroprotection of a 48 h‐microglial conditioned medium (MCM) towards cerebellar granule neurons (CGNs) challenged with the neurotoxin 6‐hydroxydopamine, which induces a Parkinson‐like neurodegeneration, and to identify the protective factor(s). MCM nearly completely protects CGNs from 6‐hydroxydopamine neurotoxicity and at least some of the protective factor(s) are peptidic in nature. While the fraction of the medium containing molecules < 30 kDa completely protects CGNs, fractions containing molecules < 10 kDa or > 10 kDa are not neuroprotective. We further demonstrate that microglia release high amounts of transforming growth factor‐β2 (TGF‐β2) and that its exogenous addition to the fraction of the medium not containing it (< 10 kDa) fully restores the neuroprotective action. Moreover, MCM neuroprotection is significantly counteracted by an inhibitor of TGF‐β2 transduction pathway. Our results identify TGF‐β2 as an essential neuroprotective factor released by microglia in its culture medium that requires to be fully effective the concomitant presence of other factor(s) of low molecular weight.
Mechanism of rhodopsin kinase regulation by recoverin
Authors: Komolov Konstantin E. , Senin Ivan I. , Kovaleva Nadezda A. , Christoph Mathias P. , Churumova Valeriya A. , Grigoriev Ilya I. , Akhtar Muhammad , Philippov Pavel P. , Koch Karl‐Wilhelm 
Published: April 2009

AbstractRecoverin is suggested to inhibit rhodopsin kinase (GRK1) at high [Ca2+] in the dark state of the photoreceptor cell. Decreasing [Ca2+] terminates inhibition and facilitates phosphorylation of illuminated rhodopsin (Rh*). When recoverin formed a complex with GRK1, it did not interfere with the phosphorylation of a C‐terminal peptide of rhodopsin (S338‐A348) by GRK1. Furthermore, while GRK1 competed with transducin on interaction with rhodopsin and thereby suppressed GTPase activity of transducin, recoverin in the complex with GRK1 did not influence this competition. Constructs of GRK1 that encompass its N‐terminal, catalytic or C‐terminal domains were used in pull‐down assays and surface plasmon resonance analysis to monitor interaction. Ca2+‐recoverin bound to the N‐terminus of GRK1, but did not bind to the other constructs. GRK1 interacted with rhodopsin also by its N‐terminus in a light‐dependent manner. No interaction was observed with the C‐terminus. We conclude that inhibition of GRK1 by recoverin is not the result of their direct competition for the same docking site on Rh*, although the interaction sites of GRK1/Rh* and GRK1/recoverin partially overlap. The N‐terminus of GRK1 is recognized by Rh* leading to a conformational change which moves the C‐terminus of Rh* into the catalytic kinase groove. Ca2+‐recoverin interacting with the N‐terminus of GRK1 prevents this conformational change and thus blocks Rh* phosphorylation by GRK1.
The α5(H105R) mutation impairs α5 selective binding properties by altered positioning of the α5 subunit in GABAAreceptors containing two distinct types of α subunits
Authors: Balic Ela , Rudolph Uwe , Fritschy Jean‐Marc , Mohler Hanns , Benke Dietmar 
Published: April 2009

AbstractGABAAreceptors are pentameric ligand‐gated ion channels that are major mediators of fast inhibitory neurotransmission. Clinically relevant GABAAreceptor subtypes are assembled from α5(1‐3, 5), β1‐3 and the γ2 subunit. They exhibit a stoichiometry of two α, two β and one γ subunit, with two GABA binding sites located at the α/β and one benzodiazepine binding site located at the α/γ subunit interface. Introduction of the H105R point mutation into the α5 subunit, to render α5 subunit‐containing receptors insensitive to the clinically important benzodiazepine site agonist diazepam, unexpectedly resulted in a reduced level of α5 subunit protein in α5(H105R) mice. In this study, we show that the α5(H105R) mutation did not affect cell surface expression and targeting of the receptors or their assembly into macromolecular receptor complexes but resulted in a severe reduction of α5‐selective ligand binding. Immunoprecipitation studies suggest that the diminished α5‐selective binding is presumably due to a repositioning of the α5(H105R) subunit in GABAAreceptor complexes containing two different α subunits. These findings imply an important role of histidine 105 in determining the position of the α5 subunit within the receptor complex by determining the affinity for assembly with the γ2 subunit.
The role of ubiquitin linkages on α‐synuclein induced‐toxicity in a Drosophila model of Parkinson’s disease
Authors: Lee Francesca K. M. , Wong Azaria K. Y. , Lee Yuk Wa , Wan Oi Wan , Edwin Chan H. Y. , Chung Kenny K. K. 
Published: April 2009

AbstractParkinson’s disease (PD) is a common movement disorder marked by the loss of dopaminergic (DA) neurons in the brain stem and the presence of intraneuronal inclusions designated as Lewy bodies (LB). The cause of neurodegeneration in PD is not clear, but it has been suggested that protein misfolding and aggregation contribute significantly to the development of the disease. Misfolded and aggregated proteins are cleared by ubiquitin proteasomal system (UPS) and autophagy lysosomal pathway (ALP). Recent studies suggested that different types of ubiquitin linkages can modulate these two pathways in the process of protein degradation. In this study, we found that co‐expression of ubiquitin can rescue neurons from α‐syn‐induced neurotoxicity in a Drosophila model of PD. This neuroprotection is dependent on the formation of lysine 48 polyubiquitin linkage which is known to target protein degradation via the proteasome. Consistent with our results that we observed in vivo, we found that ubiquitin co‐expression in the cell can facilitate cellular protein degradation by the proteasome in a lysine 48 polyubiquitin‐dependent manner. Taken together, these results suggest that facilitation of proteasomal protein degradation can be a potential therapeutic approach for PD.
Receptors for NPY and PACAP differ in expression and activity during adipogenesis in the murine 3T3‐L1 fibroblast cell line
Authors: Gericke Martin T , Kosacka Joanna , Koch Daniela , Nowicki Marcin , Schröder Thomas , Ricken Albert M , Nieber Karen , Spanel‐Borowski Katharina 
Published: April 2009

Background and purpose:  Neuropeptides are involved in the regulation of food intake in the central nervous system, but they might also act on peripheral fat tissue via neuropeptide receptors.Experimental approach:  We investigated the receptor expression and activity of pituitary adenylate cyclase‐activating polypeptide (PACAP) and of neuropeptide Y at the mRNA and protein levels in the 3T3‐L1 fibroblast line during differentiation into adipocytes. Intracellular calcium concentration was measured by calcium imaging.Key results:  The PACAP receptors PAC1 and VPAC2 as well as the neuropeptide Y1 receptor were expressed at the mRNA level in fibroblasts, pre‐adipocytes and adipocytes. The mRNA profile of the PAC1 receptor isoforms showed the HOP sequence, whereas the HIP‐isoform was present in subconfluent 3T3‐L1 fibroblasts only. At the protein level, the mature 3T3‐L1 adipocytes produced the PAC1 and Y1 receptors; only the PAC1 receptor showed carbohydrate residues. Both neuropeptides induced an increase of intracellular calcium in mature adipocytes, which was absent in the precursor cells. These changes in calcium were mediated by Y1 and PAC1 receptors as demonstrated by the effects of specific receptor agonists and antagonists.Conclusions and implications:  As the PAC1‐HOP receptor variant seems to be responsible for PACAP‐mediated calcium influx in many cell types, the HOP sequence might also mediate the increase in intracellular calcium in adipocytes. Because a high intracellular calcium level is associated with lipogenesis, peptidergic innervation of adipose tissue might be involved in stress‐induced obesity. British Journal of Pharmacology (2009) 157, 620–632; doi:10.1111/j.1476‐5381.2009.00164.x; published online 27 April 2009
SB265610 is an allosteric, inverse agonist at the human CXCR2 receptor
Authors: Bradley ME , Bond ME , Manini J , Brown Z , Charlton SJ 
Published: April 2009

Background and purpose: In several previous studies, the C‐X‐C chemokine receptor (CXCR)2 antagonist 1‐(2‐bromo‐phenyl)‐3‐(7‐cyano‐3H‐benzotriazol‐4‐yl)‐urea (SB265610) has been described as binding competitively with the endogenous agonist. This is in contrast to many other chemokine receptor antagonists, where the mechanism of antagonism has been described as allosteric.Experimental approach: To determine whether it displays a unique mechanism among the chemokine receptor antagonists, the mode of action of SB265610 was investigated at the CXCR2 receptor using radioligand and [35S]‐GTPγS binding approaches in addition to chemotaxis of human neutrophils.Key results: In equilibrium saturation binding studies, SB265610 depressed the maximal binding of [125I]‐interleukin‐8 ([125I]‐IL‐8) without affecting theKd. In contrast, IL‐8 was unable to prevent binding of [3H]‐SB265610. Kinetic binding experiments demonstrated that this was not an artefact of irreversible or slowly reversible binding. In functional experiments, SB265610 caused a rightward shift of the concentration‐response curves to IL‐8 and growth‐related oncogene α, but also a reduction in maximal response elicited by each agonist. Fitting these data to an operational allosteric ternary complex model suggested that, once bound, SB265610 completely blocks receptor activation. SB265610 also inhibited basal [35S]‐GTPγS binding in this preparation.Conclusions and implications: Taken together, these data suggest that SB265610 behaves as an allosteric inverse agonist at the CXCR2 receptor, binding at a region distinct from the agonist binding site to prevent receptor activation, possibly by interfering with G protein coupling.
Effects of NXY‐059 in experimental stroke: an individual animal meta‐analysis
Authors: Bath PMW , Gray LJ , Bath AJG , Buchan A , Miyata T , Green AR 
Published: April 2009

Background and purpose:  Disodium 2,4‐disulphophenyl‐N‐tert‐butylnitrone (NXY‐059) was neuroprotective in experimental stroke models but ineffective in a large clinical trial. This first‐ever individual animal meta‐analysis was used to assess the preclinical studies.Experimental approach:  Studies were obtained from AstraZeneca and PubMed searches. Data for each animal were obtained from the lead author of each study and/or AstraZeneca. Published summary data were used if individual data were not available. Infarct volume and motor impairment were standardized to reflect different species and scales. Standardized mean difference (SMD), coefficients from multilevel models and 95% confidence intervals (95% CI) are presented.Key results:  Fifteen studies (26 conditions, 12 laboratories) involving rats (544), mice (9) and marmosets (32) were identified (NXY‐059: 332, control: 253) with individual data for 442 animals. Four studies were unpublished. Studies variably used randomization (40%), blinding of surgeon (53%) and outcome assessor (67%). NXY‐059 reduced total (SMD −1.17, 95% CI −1.50 to −0.84), cortical (SMD −2.17, 95% CI −2.99 to −1.34) and subcortical (−1.43, 95% CI −2.20 to −0.86) lesion volume; efficacy was seen in transient, permanent and thrombotic ischaemia, up to 180 min post occlusion. NXY‐059 reduced motor impairment (SMD −1.66, 95% CI −2.18 to −1.14) and neglect. Evidence for performance, attrition and publication bias was present.Conclusions and implications:  NXY‐059 was neuroprotective in experimental stroke although bias may have resulted in efficacy being overestimated. Efficacy in young, healthy, male animals is a poor predictor of clinical outcome. We suggest the use of preclinical meta‐analysis before initiation of future clinical trials.
The Piano as Cultural Symbol in Colonial New Zealand
Authors: Moffat Kirstine 
Published: April 2009

AbstractThe piano was an important cultural symbol in colonial New Zealand, yet although there is a significant body of international scholarship on the social and cultural history of the instrument in Britain, America, Canada, Norway, Spain and India there is a dearth of scholarly criticism relating to New Zealand. Research to redress this absence has revealed that the piano was central to settler culture, demonstrating a migrant desire to replicate the known and familiar but also highlighting settler innovations and an emerging nationalism. International connections between New Zealand, Britain, Western Europe, America and Australia are also apparent in relation to migrant patterns, the importation of instruments and sheet music and networks of musical performance and study. The instrument played a role in the complex dynamic of cultural encounter between Maori and settler, with an initial indigenous negativity and bemusement giving way to an interest in the piano and an appropriation of the instrument into Maori cultural contexts and spaces, including the marae. Prevailing perceptions of gender roles and identity are also challenged by research on the piano. Likewise, an examination of piano and class reveals that the instrument was popular with New Zealanders from all socio‐economic backgrounds.
‘A School Said to Resemble a Luxury Hotel’: Historicizing African Women's Quest for Education before Oprah's School
Authors: Charumbira Ruramisai 
Published: April 2009

AbstractThe public reception of the Oprah Winfrey Leadership Academy for Girls (OWLA) in South Africa and the United States is a recent example of a historical pattern historians have often called the ‘civilizing mission’ on behalf of girls and women in Africa. One of the greatest missed opportunities by founders (and critics) of such schools, past and the present, has been the glaring omission of highlighting contemporary African women's achievements so the girls can see themselves as connected to a long line of female strivers and achievers with varied personal histories. This study utilizes African women's novels and memoirs to historicize African women's quest for (higher) education as well as emphasize the importance of historically grounded international development aid to Africa so as to avoid the pitfalls of neocolonialism that reproduce stereotypes about Africans, and women in particular. Texts highlighted include: Tsitsi Dangarembga'sNervous Conditions, Mariama Bâ'sSo Long a Letter, Mamphela Ramphele'sAcross Boundaries, and Wangari Maathai'sUnbowed.
How Well Do Headache Patients Remember? A Comparison of Self‐Report Measures of Headache Frequency and Severity in Patients with Migraine
Authors: McKenzie Jeff A. , Cutrer F. Michael 
Published: April 2009

Objective.— To compare patient recall of migraine headache frequency and severity over 4 weeks prior to a return visit as reported in an interval questionnaire vs a daily diary.Background.— Many therapeutic decisions in the management of migraine patients are based on patient recall of response to treatment. As consistent completion of a daily headache diary is problematic, we have assessed the reliability of patient recall in a 1‐time questionnaire.Methods.— Headache frequency and average severity (0 to 3‐point scale) were reported in an interval questionnaire by 209 patients who had also maintained a daily diary over the same 4‐week period.Results.— Headache frequency over the previous 4 weeks as reported in interval questionnaires (14.7) was not different from that documented in diaries (15.1), P = .056. However, reported average headache severity on a 0 to 3 scale as reported in the questionnaire (1.84) was worse than that documented in the diaries (1.63), P < .001.Conclusions.— In the management of individual patients, the daily diary is still preferable when available. Aggregate assessment of headache frequency in groups of patients based on recall of the prior 4 weeks is equally as reliable as a diary. Headache severity reported in questionnaires tends to be greater than that documented in daily diaries and may be less reliable.
The antiepileptogenic effect of electrical stimulation at different low frequencies is accompanied with change in adenosine receptors gene expression in rats
Authors: Jahanshahi A. , Mirnajafi‐Zadeh Javad , Javan Mohammad , Mohammad‐Zadeh Mohammad , Rohani Razieh 
Published: April 2009

SummaryPurpose:  Previous studies have shown that the anticonvulsant effects of low‐frequency stimulation (LFS) can be affected by activation of adenosine receptors. In the present study, the effect of LFS at different frequencies on kindling rate and adenosine receptors gene expression was investigated.Methods:  Animals were kindled by perforant path stimulation in a rapid kindling manner. LFS (0.5, 1, and 5 Hz) was applied after termination of each kindling stimulation. Seizure severity was measured according to behavioral and electrophysiologic parameters. At the end of the experiments, adenosine A1 and A2A receptor gene expression were measured.Results:  The inhibitory effect of LFS on kindling acquisition was observed at all frequencies. In addition, the inhibitory action of LFS on enhancement of field excitatory postsynaptic potential slope and population spike amplitude during kindling acquisition was not affected by the LFS frequency. However, the effects of LFS on paired‐pulse recordings were greater at frequency of 5 Hz. Application of LFS during kindling acquisition also prevented the kindling induced decrease in the A1 receptor gene expression and attenuated the level of A2A receptor gene expression in the dentate gyrus. These effects were also greater at the frequency of 5 Hz.Discussion:  According to these data, it may be suggested that the antiepileptogenic effects of LFS, developed through inhibition of synaptic transmission in the dentate gyrus, is mediated somehow through preventing the decrease of A1 receptor and through attenuating the A2A receptor gene expression. These effects might be dependent on the frequency of LFS.
Coexistence of symptomatic focal and absence seizures: Video‐EEG and EEG‐fMRI evidence of overlapping but independent epileptogenic networks
Authors: Chassagnon Serge , Hawko Colin S. , Bernasconi Andrea , Gotman Jean , Dubeau François 
Published: April 2009

SummaryThe distinction between typical absences and hypomotor seizures in patients having frontal lesions is difficult. In focal epilepsy, generalized‐like interictal discharges can reflect either a coexistent generalized epileptic trait or a secondary bilateral synchrony. Using combined measures of the EEG and blood oxygenation level dependent (BOLD) activity, we studied a 50‐year‐old patient with both absence‐like and symptomatic focal motor seizures. Focal activity induced activation in the lesional area and deactivation in the contralateral central cortex. Generalized spike‐and‐wave discharges (GSWDs) resulted also in perilesional activation, and multifocal symmetrical cortical and thalamic activations, and deactivation in associative cortical areas. Although the central cortex was involved during both types of epileptic activity, electroencephalography (EEG)–functional magnetic resonance imaging (fMRI) revealed distinct neuronal networks at the time of the focal or generalized discharges, allowing a clear‐cut differentiation of the generators. Whether the patient had distinct epileptic syndromes or distinct electrographic patterns from the lesional trigger remains debatable.
Impaired function of GABABreceptors in tissues from pharmacoresistant epilepsy patients
Authors: Teichgräber Laura A. , Lehmann Thomas‐Nicolas , Meencke Heinz‐Joachim , Weiss Torsten , Nitsch Robert , Deisz Rudolf A. 
Published: April 2009

SummaryPurpose: Effects of pre‐ and postsynaptic γ‐aminobutyric acid B (GABAB) receptor activation were characterized in human tissue from epilepsy surgery.Methods: Slices of human cortical tissue were investigated in a submerged‐type chamber with intracellular recordings in layers II/III. Parallel experiments were performed in rat neocortical slices with identical methods. Synaptic responses were elicited with single or paired stimulations of incrementing intervals.Results: Neurons in human epileptogenic tissue exhibited usually small inhibitory postsynaptic potentials (IPSP) mediated by GABABreceptor, verified by the sensitivity to the selective antagonist CGP 55845A. The IPSPBconductance averaged 5.8 nS in neurons from epileptogenic tissues and 15.9 nS in neurons from nonepileptogenic tissues (p < 0.0001). Application of baclofen caused small conductance increases in human neurons, which were linearly related to IPSPBconductances. Paired‐pulse stimulation revealed constant synaptic responses in human temporal lobe epilepsy (TLE) slices at all interstimulus intervals (ISIs). Pharmacologically isolated IPSPAin the human tissue exhibited a small paired‐pulse depression (average 10% at 500 ms ISI). Bicuculline‐induced paroxysmal depolarization shifts (PDSs) were transiently depressed by 24% in human TLE tissue; and by 74% in rat neocortical slices (200 ms ISI; p = 0.015). The depressions of bicuculline‐induced PDSs were antagonized by CGP 55845A in both species. Staining for GABABreceptors revealed significantly smaller numbers of immunopositive dots in human epileptogenic neurons versus human control neurons.Discussion: The small IPSPB, baclofen‐conductances, and paired‐pulse depression of PDSs and IPSPs in human TLE tissue indicate a reduced density of post‐ and presynaptic GABABreceptors. The reduced efficacy of presynaptic GABABreceptors facilitates the occurrence of repetitive synaptic activity.
The effects of intracerebroventricular AM‐251, a CB1‐receptor antagonist, and ACEA, a CB1‐receptor agonist, on penicillin‐induced epileptiform activity in rats
Authors: Kozan Ramazan , Ayyildiz Mustafa , Agar Erdal 
Published: April 2009

SummaryPurpose: Several results support the conclusion that the cannabinoid system has a role in generation and cessation of epileptic seizures. The aim of this study was to evaluate the effects of intracerebroventricular AM‐251 [N‐(piperidin‐1‐yl)‐5‐(4‐iodophenyl)‐1‐(2,4‐dichlorophenyl)‐4‐methyl‐1H‐pyrazole‐3‐carboxamide], a CB1‐receptor antagonist, and ACEA (arachidonyl‐2‐chloroethylamide), a CB1‐receptor agonist, on penicillin‐induced epileptiform activity in rats.Methods: In the first set of experiments, 30 min after penicillin injection, AM‐251, at doses of 0.125, 0.25, 0.5, and 1 μg, was administered intracerebroventricularly (i.c.v.). In the second set of experiments, 30 min after penicillin injection, ACEA, at doses of 2.5, 5, 7.5, and 15 μg (i.c.v.), was administered. In the third set of experiments, AM‐251, at doses of 0.125 and 0.25 μg (i.c.v.), was administered 10 min before ACEA (7.5 μg, i.c.v.) injection.Results: ACEA, at a dose of 7.5 μg, significantly decreased the frequency of penicillin‐induced epileptiform activity without changing the amplitude. ACEA, at doses of 2.5, 5, and 15 μg, had no impact on either frequency or amplitude of epileptiform activity. AM‐251, at doses of 0.25 and 0.50 μg, significantly increased the frequency of epileptiform activity. AM‐251, at a dose of 0.25 μg (i.c.v.), was the most effective in changing the frequency of penicillin‐induced epileptiform activity, and it also caused status epilepticus–like activity. AM‐251, at doses of 0.125 and 0.25 μg, 10 min before ACEA (7.5 μg), reversed the anticonvulsant action of ACEA.Discussion: The results of the present study provide electrophysiologic evidence for the role of CB1 receptors in regulating the frequency of epileptiform activity in the model of penicillin‐induced epilepsy. To elucidate the precise mechanism of cannabinoid action in the brain during seizure, more advanced electrophysiologic and neurochemical studies are required.