FAAH inhibition as a preventive treatment for migraine: A pre-clinical study

Abstract Background Fatty-acid amide hydrolase (FAAH) is an intracellular serine hydrolase that catalyzes the cleavage of endogenous fatty-acid amides, including the endocannabinoid anandamide (AEA). We previously reported that the peripherally restricted FAAH inhibitor URB937, which selectively increases AEA levels outside the central nervous system, reduces hyperalgesia and c-Fos expression in the trigeminal nucleus caudalis (TNC) and the locus coeruleus in an animal model of migraine based on nitroglycerin (NTG) administration. Aim To further investigate the relevance of FAAH inhibition in the NTG animal model of migraine by testing the effects of the globally active FAAH inhibitor URB597. Methods Our experimental approach involved mapping neuronal c-Fos protein expression, measurement of AEA levels in brain areas and in trigeminal ganglia, evaluation of pain-related behavior and quantification of molecular mediators in rats that received URB597 (2 mg/kg i.p.) either before or after NTG administration (10 mg/kg, i.p.). Results Pre-treatment with URB597 significantly reduced c-Fos immunoreactivity in the TNC and inhibited NTG-induced hyperalgesia in the orofacial formalin test. This behavioral response was associated with a decrease in neuronal nitric oxide synthase, calcitonin gene-related peptide and cytokine gene expression levels in central and peripheral structures. Administration of URB597 after NTG had no such effect. Conclusions The findings suggest that global FAAH inhibition may offer a therapeutic approach to the prevention, but not the abortive treatment, of migraine attacks. Further studies are needed to elucidate the exact cellular and molecular mechanisms underlying the protective effects of FAAH inhibition

Characterization of the peripheral FAAH inhibitor, URB937, in animal models of acute and chronic migraine.

Inhibiting the activity of fatty-acid amide hydrolase (FAAH), the enzyme that deactivates the endocannabinoid anandamide, enhances anandamide-mediated signaling and holds promise as a molecular target for the treatment of human pathologies such as anxiety and pain. We have previously shown that the peripherally restricted FAAH inhibitor, URB937, prevents nitroglycerin-induced hyperalgesia - an animal model of migraine - and attenuates the activation of brain areas that are relevant for migraine pain, e.g. trigeminal nucleus caudalis and locus coeruleus. The current study is aimed at profiling the behavioral and biochemical effects of URB937 in animal models of acute and chronic migraine. We evaluated the effects of URB937 in two rat models that capture aspects of acute and chronic migraine, and are based on single or repeated administration of the vasodilating drug, nitroglycerin (NTG). In addition to nocifensive behavior, in trigeminal ganglia and medulla, we measured mRNA levels of neuropeptides and pro-inflammatory cytokines along with tissue levels of anandamide and palmitoylethanolamide (PEA), an endogenous agonist of peroxisome proliferator-activated receptor type-a (PPAR-a), which is also a FAAH substrate. In the acute migraine model, we also investigated the effect of subtype-selective antagonist for cannabinoid receptors 1 and 2 (AM251 and AM630, respectively) on nocifensive behavior and on levels of neuropeptides and pro-inflammatory cytokines. In the acute migraine paradigm, URB937 significantly reduced hyperalgesia in the orofacial formalin test when administered either before or after NTG. This effect was accompanied by an increase in anandamide and PEA levels in target neural tissue, depended upon CB1 receptor activation, and was associated with a decrease in calcitonin gene-related peptide (CGRP), substance P and cytokines TNF-alpha and IL-6 mRNA. Similar effects were observed in the chronic migraine paradigm, where URB937 counteracted NTG-induced trigeminal hyperalgesia and prevented the increase in neuropeptide and cytokine transcription. The results show that peripheral FAAH inhibition by URB937 effectively reduces both acute and chronic NTG-induced trigeminal hyperalgesia, likely via augmented anandamide-mediated CB1 receptor activation. These effects are associated with inhibition of neuropeptidergic and inflammatory pathways

Spatial scale effects on taxonomic and biological trait diversity of aquatic macroinvertebrates in Mediterranean streams

We examined the effect of spatial scale on aquatic macroinvertebrate communities in Mediterranean streams from six basins distributed across southern Europe, including Spain, France, Italy, and Greece. We classified the studied streams according to their long-term aquatic regime into the three following types: (i) permanent (P), (ii) intermittent with summer pools (I-P), and (iii) intermittent with summer dry channels (I-D). For each stream type, we analyzed taxonomic and trait diversity, as well as the composition of the macroinvertebrate community, following a spatially nested design at three spatial scales of analysis: microhabitat (substratum patches), mesohabitat (pools vs. riffles), and macrohabitat (streams). In order to assess intrinsic seasonal variability in streams from the Mediterranean region, 20 Surber samples were taken from each stream according to meso- and microhabitat frequency in the wet and the dry season during 2010. Given the need for adaptation to specific hydrological conditions and the fact that microhabitats should encompass the niche requirements of particular taxa, we hypothesized that this spatial scale would have a greater influence on macroinvertebrate taxa composition and biological traits than the other two larger spatial scales in intermittent streams. We observed that patterns in the relative importance of variance components across hierarchical spatial scales changed with time because low flow or droughts altered both mesohabitat preva - lence and microhabitat composition. Our results confirm the importance of the microhabitat scale in I-P streams in the wet season but not in the dry one, when a loss of microhabitat diversity occurred. Stream-to-stream variability was more important in P and I-D streams. Our study also explored the relationships between traits and aquatic regimes. We found that aquatic macroinvertebrates inhabiting permanent streams exhibited traits related to the longer duration of life cycles in these rivers (e.g. large size of adult stages) and adaptations to flowing conditions (e.g. modes of aquatic dispersal), whereas aquatic macroinvertebrates inhabiting intermittent streams with summer pools had traits adapted to depositional conditions and ecological preferences for confined habitats (i.e. disconnected pools without flow). Finally, aquatic macroinvertebrates from intermittent streams with summer dry channels had adaptations conferring ability to survive periods with no water (e.g. modes of aerial dispersal, resistant stages). These results indicate that microhabitat conditions should not be neglected as they can play an important role in certain situations

A biological tool to assess flow connectivity in reference temporary streams from the Mediterranean Basin

Many streams in the Mediterranean Basin have temporary flow regimes. While timing for seasonal drought is predictable, they undergo strong inter-annual variability in flow intensity. This high hydrological variability and associated ecological responses challenge the ecological status assessment of temporary streams, particularly when setting reference conditions. This study examined the effects of flow connectivity in aquatic macroinvertebrates from seven reference temporary streams across the Mediterranean Basin where hydrological variability and flow conditions are well studied. We tested for the effect of flow cessation on two streamflow indices and on community composition, and, by performing random forest and classification tree analyses we identified important biological predictors for classifying the aquatic state either as flowing or disconnected pools. Flow cessation was critical for one of the streamflow indices studied and for community composition. Macroinvertebrate families found to be important for classifying the aquatic state were Hydrophilidae, Simuliidae, Hydropsychidae, Planorbiidae, Heptageniidae and Gerridae. For biological traits, trait categories associated to feeding habits, food, locomotion and substrate relation were the most important and provided more accurate predictions compared to taxonomy. A combination of selected metrics and associated thresholds based on the most important biological predictors (i.e. Bio-AS Tool) were proposed in order to assess the aquatic state in reference temporary streams, especially in the absence of hydrological data. Although further development is needed, the tool can be of particular interest for monitoring, restoration, and conservation purposes, representing an important step towards an adequate management of temporary rivers not only in the Mediterranean Basin but also in other regions vulnerable to the effects of climate change

"Writing as a Professional Resource in Southern Switzerland": Quantitative and Qualitative Aspects of Bachelor’s Theses at the University of Applied Sciences and Arts of Southern Switzerland

In questo contributo viene introdotto il progetto Scrivere Come Risorsa Professionale nella Svizzera italiana (SCRiPSIt), promosso dal Dipartimento formazione e apprendimento (DFA) della Scuola Universitaria Professionale della Svizzera Italiana (SUPSI). Il progetto si propone di identificare le difficoltà e gli errori più ricorrenti nella scrittura delle tesi di laurea in lingua italiana degli studenti di tre dipartimenti della SUPSI (Dipartimento Formazione e Apprendimento, Dipartimento Tecnologie Innovative, Dipartimento Economia Aziendale, Sanità e Sociale) e di una scuola affiliata (Accademia Teatro Dimitri), con l’obiettivo di migliorarne la qualità linguistica e formale. Dopo una descrizione degli obiettivi e dello stato attuale di realizzazione del corpus, ci si sofferma sull’illustrazione dei software impiegati per l’analisi automatica, sui primi esiti dell’analisi relativa al lessico e sulle potenzialità dell’impiego della pipeline Tint. I risultati del progetto consentiranno di attivare corsi specifici dedicati alla scrittura delle tesi di laurea e più in generale alla scrittura di tipo funzionale e professionale, con applicazione potenzialmente estesa a tutti i dipartimenti della SUPSI e alle scuole affiliate.This paper describes the highlights of Project SCRiPSIt (Writing as a Professional Resource in Southern Switzerland), led by the Department of Teaching and Learning of the University of Applied Sciences and Arts of Southern Switzerland (SUPSI). Located in the largest Italian-speaking population centre outside of Italy, SUPSI is a heterogeneous higher-learning institution with a strong emphasis on professional development. Project SCRiPSIt investigates a relatively large corpus of SUPSI bachelor’s theses by bringing together a heterogeneous research team featuring a combination of qualitative and quantitative research expertise in linguistics as well as in automated text processing. After a description of the key project objectives, we present an overview of the current state of the corpus and of the text-processing pipeline, along with some preliminary results

Endocannabinoid system and migraine pain: An update

The trigeminovascular system (TS) activation and the vasoactive release from trigeminal endings, in proximity of the meningeal vessels, are considered two of the main effector mechanisms of migraine attacks. Several other structures and mediators are involved, however, both upstream and alongside the TS. Among these, the endocannabinoid system (ES) has recently attracted considerable attention. Experimental and clinical data suggest indeed a link between dysregulation of this signaling complex and migraine headache. Clinical observations, in particular, show that the levels of anandamide (AEA)-one of the two primary endocannabinoid lipids-are reduced in cerebrospinal fluid and plasma of patients with chronic migraine (CM), and that this reduction is associated with pain facilitation in the spinal cord. AEA is produced on demand during inflammatory conditions and exerts most of its effects by acting on cannabinoid (CB) receptors. AEA is rapidly degraded by fatty acid amide hydrolase (FAAH) enzyme and its levels can be modulated in the peripheral and central nervous system (CNS) by FAAH inhibitors. Inhibition of AEA degradation via FAAH is a promising therapeutic target for migraine pain, since it is presumably associated to an increased availability of the endocannabinoid, specifically at the site where its formation is stimulated (e.g., trigeminal ganglion and/or meninges), thus prolonging its action

A theoretical four-compartment model to evaluate separate kidney technetium-99m-MAG3 kinetics in humans

A theoretical four-compartment model to evaluate separate kidney technetium-99m-MAG3 kinetics in humans.BackgroundPharmacokinetic modeling based on compartmentalization has provided a valuable tool to assess the clearance patterns of various glomerular and tubular agents. However, no models have been proposed thus far that combine vascular data and imaging data in order to gain a deeper knowledge on renal pathophysiology, and to obtain more diagnostic information of clinical relevance. To this aim, we propose a four-pool model for the evaluation of separate renal function.MethodsIn a group of ten normal volunteers and twenty patients with various renal diseases, we tested the four-pool model based on the identification of the two kidneys as two distinct pools. This approach made it possible to integrate the separate kidney contributions deriving from in vivo imaging data, and allows the researcher to quantitate many parameters specific to each kidney.ResultsThe parameters TERR, TERL, MRTR, MRTL, νR, νL, k3R-1, k3L-1 permit the normal from abnormal states of renal function to be differentiated, as well as monolateral from bilateral renal disease to be separated within the abnormal function group.ConclusionsThe proposed approach combines the advantages of plasma clearance methods with those derived by gamma-camera imaging, and makes it possible to quantitate the differential renal function. This feature may be clinically relevant in renal transplant donors, where full knowledge of renal pathophysiology could guide the procedure