1,720,966 research outputs found
N-acylethanolamine acid amidase (NAAA) inhibition decreases the motivation for alcohol in Marchigian Sardinian alcohol-preferring rats
Full text linkRationale: N-acylethanolamine acid amidase (NAAA) is an intracellular cysteine hydrolase that terminates the biological actions of oleoylethanolamide (OEA) and palmitoylethanolamide (PEA), two endogenous lipid-derived agonists of the nuclear receptor, and peroxisome proliferator–activated receptor-α. OEA and PEA are important regulators of energy balance, pain, and inflammation, but recent evidence suggests that they might also contribute to the control of reward-related behaviors. Objectives and methods: In the present study, we investigated the effects of systemic and intracerebral NAAA inhibition in the two-bottle choice model of voluntary alcohol drinking and on operant alcohol self-administration. Results: Intraperitoneal injections of the systemically active NAAA inhibitor ARN19702 (3 and 10 mg/kg) lowered voluntary alcohol intake in a dose-dependent manner, achieving ≈ 47% reduction at the 10 mg/kg dose (p < 0.001). Water, food, or saccharin consumption was not affected by the inhibitor. Similarly, ARN19702 dose-dependently attenuated alcohol self-administration under both fixed ratio 1 (FR-1) and progressive ratio schedules of reinforcement. Furthermore, microinjection of ARN19702 (1, 3 and 10 μg/μl) or of two chemically different NAAA inhibitors, ARN077 and ARN726 (both at 3 and 10 μg/μl), into the midbrain ventral tegmental area produced dose-dependent decreases in alcohol self-administration under FR-1 schedule. Microinjection of ARN19702 into the nucleus accumbens had no such effect. Conclusion: Collectively, the results point to NAAA as a possible molecular target for the treatment of alcohol use disorder
Antinociceptive profile of ARN19702, (2-ethylsulfonylphenyl)-[(2S)-4-(6-fluoro-1,3-benzothiazol-2-yl)-2-methylpiperazin-1-yl] methanone, a novel orally active N-acylethanolamine acid amidase inhibitor, in animal models
No full textN-Acylethanolamine acid amidase (NAAA) is an N-terminal cysteine hydrolase that stops the physiologic actions of palmitoylethanolamide, an endogenous lipid messenger that activates the transcription factor, peroxisome proliferator-activated receptor-a. We have previously reported that the compound ARN19702 [(2-ethylsulfonylphenyl)-[(2S)-4-(6-fluoro-1,3-ben-zothiazol-2-yl)-2-methylpiperazin-1-yl]methanone] is an orally active, reversible NAAA inhibitor (IC50 on human NAAA = 230 nM) that produces remarkable protective effects against multiple sclerosis in mice. In the present study, we assessed the profile of ARN19702 in mouse and rat models of acute and neuropathic pain. Oral administration in male mice attenuated in a dose-dependent manner the spontaneous nocifensive response elicited by intraplantar formalin injection and the hyper-sensitivity caused by intraplantar carrageenan injection, paw incision, or sciatic nerve ligation. In male rats, ARN19702 reduced nociception associated with paclitaxel-induced neuropathy without development of subacute antinociceptive tolerance. Finally, ARN19702 (30 mg/kg, oral) did not produce place preference or alter exploratory motor behavior in male mice. The findings support the conclusion that NAAA is a suitable molecular target for the discovery of efficacious analgesic drugs devoid of rewarding potential. SIGNIFICANCE STATEMENT This study evaluated the pharmacological profile of the orally bioavailable N-acylethanolamine acid amidase (NAAA) inhibitor (2-ethylsulfonylphenyl)-[(2S)-4-(6-fluoro-1,3-benzothiazol-2-yl)-2-methylpiperazin-1-yl]methanone (ARN19702) in mouse and rat models of neurogenic and inflammatory pain. The compound's potential rewarding and sedative effects were also examined. It is concluded that ARN19702 exhibits a broad analgesic profile that can be generalized across rodent species. The findings point to NAAA as a control node in the processing of neuropathic and inflammatory pain and to ARN19702 as a lead to uncover novel pain therapeutics devoid of addictive potential
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
Activation of peroxisome proliferator-activated receptor γ reduces alcohol drinking and seeking by modulating multiple mesocorticolimbic regions in rats
Full text linkPeroxisome proliferator-activated receptor γ (PPARγ) is an intracellular transcription factor whose signaling activation by the selective agonist pioglitazone reduces alcohol drinking and alcohol-seeking behavior in rats. The present study utilized the two-bottle choice and operant self-administration procedures to investigate neuroanatomical substrates that mediate the effects of PPARγ agonism on alcohol drinking and seeking in msP rats. Bilateral infusions of pioglitazone (0, 5, and 10 μg/μl) in the rostromedial tegmental nucleus (RMTg) decreased voluntary alcohol drinking and alcohol self-administration. Microinjections of pioglitazone in the ventral tegmental area (VTA), central amygdala (CeA), and nucleus accumbens (NAc) shell had no such effect. Notably, water, food, and saccharin consumption was unaltered by either treatment. The yohimbine-induced reinstatement of alcohol seeking was prevented by infusions of pioglitazone (0, 2.5, 5, and 10 μg/μl) in the CeA, VTA, and RMTg but not in the NAc shell. These results emphasize the involvement of mesocorticolimbic circuitries in mediating the effects of PPARγ agonists on alcohol drinking and seeking. These results will facilitate future studies that investigate the pathophysiological role of PPARγ in alcohol use disorder and help clarify the mechanisms by which the activation of this receptor decreases the motivation for drinking
N-Acylethanolamine Acid Amidase (NAAA): Structure, Function, and Inhibition
Full text linkN-Acylethanolamine acid amidase (NAAA) is an N-terminal cysteine hydrolase primarily found in the endosomal-lysosomal compartment of innate and adaptive immune cells. NAAA catalyzes the hydrolytic deactivation of palmitoylethanolamide (PEA), a lipid-derived peroxisome proliferator-activated receptor-α (PPAR-α) agonist that exerts profound anti-inflammatory effects in animal models. Emerging evidence points to NAAA-regulated PEA signaling at PPAR-α as a critical control point for the induction and the resolution of inflammation and to NAAA itself as a target for anti-inflammatory medicines. The present Perspective discusses three key aspects of this hypothesis: the role of NAAA in controlling the signaling activity of PEA; the structural bases for NAAA function and inhibition by covalent and noncovalent agents; and finally, the potential value of NAAA-targeting drugs in the treatment of human inflammatory disorders
Efficacy of a combination of N-palmitoylethanolamide, beta-caryophyllene, carnosic acid, and myrrh extract on chronic neuropathic pain: A preclinical study
Full text linkNeuropathic pain (NP) is a common public health problem that poses a major challenge to basic scientists and health-care providers. NP is a complex problem with an unclear etiology and an often-inadequate response to current medications. Despite the high number of drugs available, their limited pharmacological efficacy and side effects hamper their chronic use. Thus, the search for novel treatments is a priority. In addition to pharmaceuticals, natural extracts and food supplements are often used to help treating patients with NP. One such supplement is Noxiall®, a commercially available combination of N-Palmitoylethanolamide (PEA), beta-caryophyllene; carnosic acid and myrrh. Here, we compare the efficacy of Noxiall® to that of the medications gabapentin and pregabalin in the NP model of chronic constriction injury (CCI) using sciatic nerve ligation in mouse. Following CCI, mice developed a significant increase in mechanical allodynia and thermal hyperalgesia. Results showed that administration of either Noxiall®, pregabalin, or gabapentin significantly attenuated mechanical allodynia. The magnitude of the Noxiall® effect was comparable to that of gabapentin or pregabalin. In addition, co-administration of non-effective doses of pregabalin and Noxiall® resulted in a significant decrease in NP, suggesting an additive efficacy. Noxiall® was efficacious also in reducing CCI-induced thermal hyperalgesia. These findings support the rationale of using natural remedies in conjunction with classical pharmacological agents to treat chronic NP
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
Dispelling the Myths Behind First-author Citation Counts
Full text linkWe conducted a full-scale evaluative citation analysis study of scholars in the XML research field to explore just how different from each other author rankings resulting from different citation counting methods actually are, and to demonstrate the capability of emerging data and tools on the Web in supporting more realistic citation counting methods. Our results contest some common arguments for the continued
use of first-author citation counts in the evaluation of scholars, such as high correlations between author rankings by first-author citation counts and other citation
counting methods, and high costs of using more realistic citation counting methods that are not well-supported by the ISI databases. It is argued that increasingly available digital full text research papers make it possible for citation analysis studies to go beyond what the ISI databases have directly supported and to employ more
sophisticated methods
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