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VALENTINA RUGGIERI

COLLABORATORE DI RICERCA
Dipartimento di Scienze Mediche e Chirurgiche Materno-Infantili e dell'Adulto

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Pubblicazioni

2019 - Respiratory mechanics and diaphragmatic dysfunction in COPD patients who failed non-invasive mechanical ventilation [Articolo su rivista]
Marchioni, Alessandro; Tonelli, Roberto; Fantini, Riccardo; Tabbì, Luca; Castaniere, Ivana; Livrieri, Francesco; Bedogni, Sabrina; Ruggieri, Valentina; Pisani, Lara; Nava, Stefano; Clini, Enrico
abstract

Background. Although non-invasive mechanical ventilation (NIV) is the gold standard treatment for patients with acute exacerbation of COPD (AECOPD) developing respiratory acidosis, failure rates still range from 5% to 40%. Recent studies have shown that the onset of severe diaphragmatic dysfunction (DD) during AECOPD increases risk of NIV failure and mortality in this subset of patients. Although the imbalance between the load and the contractile capacity of inspiratory muscles seems the main cause of AECOPD-induced hypercapnic respiratory failure, data regarding the influence of mechanical derangement on DD in this acute phase are lacking. With this study we investigate the impact of respiratory mechanics on diaphragm function in AECOPD patients experiencing NIV failure. Methods. Twelve AECOPD with respiratory acidosis admitted to the Respiratory ICU of the University Hospital of Modena from 2017-2018 undergoing mechanical ventilation (MV) due to NIV failure were enrolled. Static respiratory mechanics and end expiratory lung volume (EELV) were measured after 30 minutes of volume control mode MV. Subsequently transdiaphragmatic pressure (Pdi) was calculated by means of a sniff maneuver (Pdisniff) after 30 minutes of spontaneous breathing trial. Linear regression analysis and Pearson’s correlation coefficient served to assess associations. Results. Average Pdisniff was 23.3 (standard deviation, SD=29) cmH20 with 3 patients presenting bilateral diaphragm palsy. Pdisniff was directly correlated with static lung elastance (r=0.69, p=0.001) while inverse correlation was found with dynamic intrinsic PEEP (r=-0.73, p=0.007). No significant correlation was found with static intrinsic PEEP (r=-0.55, p=0.06), EELV (r=-0.4, p=0.3), airway resistance (r=-0.2, p=0.54), chest wall and total elastance (r=-0-01, p=0.96 and r=0.3, p=0.36 respectively). Significant linear inverse correlation was found between Pdi/Pdisniff and Pdisniff (r=-0.82, p=0.02). Conclusion. The causes of extreme DD in AECOPD patients who experienced NIV failure might be predominantly mechanical, driven by a severe dynamic hyperinflation that overlaps on an elastic lung substrate favoring volume overload.

2019 - Serial Ultrasound Assessment of Diaphragmatic Function and Clinical Outcome in Patients with Amyotrophic Lateral Sclerosis. [Articolo su rivista]
Fantini, Riccardo; Tonelli, Roberto; Castaniere, Ivana; Tabbì, Luca; Pellegrino, Maria Rosaria; Cerri, Stefania; Livrieri, Francesco; Giaroni, Francesco; Monelli, Marco; Ruggieri, Valentina; Fini, Nicola; Mandrioli, Jessica; Clini, Enrico; Marchioni, Alessandro; Stefania, Cerri
abstract

Background: Ultrasound (US) evaluation of the diaphragm may be a non-volitional useful tool in the clinical management of patients with ALS. Aim of the present study was then to evaluate the impact of serial assessment of ΔTmax index on clinical outcomes during the follow-up in these patients and to correlate non-volitional US indices and other volitional measures with these outcomes. Methods: A cohort of 39 consecutive patients with ALS was followed up to 24 months. At baseline and every 3-month spirometry (forced vital capacity-FVC), sniff inspiratory nasal pressure (SNIP), and US of the diaphragm (ΔTdi and ΔTmax) were recorded. These parameters were correlated with clinical outcomes (hypercapnia, nocturnal hypoventilation, NIV start in the following 6 month, and death within 1 year). Results: The occurrence of ΔTmax >0.75 during follow-up increased the risk for NIV (HR=5.6, p=0.001) and death (HR=3.7, p=0.0001) compared with patients with stable lower values. The evidence of diaphragmatic dysfunction, i.e. ΔTmax >0.75, occurs 3.2 month earlier than the onset of NIV. Moreover, ΔTmax >0.75 correlated with onset of nocturnal hypoventilation, NIV initiation within 6 months, and death within 12 months, similarly to FVC <50% predicted and better than other functional indices. Conclusions: Serial monitoring of diaphragmatic ΔTmax by US may be useful to predict initiation of NIV and death in patients with ALS. The occurrence of an abnormal ΔTmax value in the follow-up precedes the decision for starting NIV.

2019 - Three-year hospitalization and mortality in elderly smokers with COPD or CHF. [Articolo su rivista]
Beghé, B; Fabbri, Lm; Garofalo, M; Schito, M; Verduri, A; Bortolotti, M; Stendardo, M; Ruggieri, V; Fucili, A; Sverzellati, N; Della Casa, G; Maietti, E; Clini, E; Boschetto, P.
abstract

Background: In elderly smokers, COPD and CHF usually present with dyspnoea. COPD and CHF are associated almost invariably with concomitant chronic diseases which contribute to severity and prognosis. Objectives: We investigated similarities and differences in the clinical presentation, concomitant chronic diseases and risk factors for mortality and hospitalization at 3-year follow-up in elderly smokers/ex-smokers with a primary diagnosis of COPD or CHF recruited and followed in specialized centers. Methods: We examined 144 patients with COPD and 96 with CHF, ≥ 65 yrs, ≥20 pack/years, and measured CAT score, mMRC, NYHA, and Charlson Index, routine blood test, eGFR, HRCTscan, 6MWT. In addition, in each patient we actively searched for CHF, COPD, peripheral vascular disease, and metabolic syndrome. Results: COPD and CHF patients had mild to moderate disease, but the majority was symptomatic. Comorbidities were highly prevalent and often unrecognized in both groups. COPD and CHF patients had a similar risk of hospitalization and death at 3 years. Lower glomerular filtration rate, shorter 6MWT and ascending aorta calcification score ≥2 were independent predictors of mortality in COPD, whereas previous 12 month hospitalizations, renal disease and heart diameter were in CHF patients. Lower glomerular filtration rate value, higher CAT score and lower FEV1/FVC ratio were associated with hospitalization in COPD, whilst age, lower FEV1 % predicted and peripheral vascular disease were in CHF. Conclusions: There are relevant similarities and differences between patients with COPD and CHF even when admitted to specialized outpatient centers, suggesting that these patients should be manage in multidisciplinary units.

2018 - Breathlessness, but not cough, suggests chronic obstructive pulmonary disease in elderly smokers with stable heart failure. [Articolo su rivista]
Roversi, S; Boschetto, P; Beghè, B; Schito, M; Garofalo, M; Stendardo, M; Ruggieri, V; Tonelli, R; Fucili, A; D'Amico, R; Banchelli, F; Fabbri, Lm; Clini, E.
abstract

Chronic obstructive pulmonary disease (COPD) is a common comorbidity of heart failure (HF), but remains often undiagnosed, and we aimed to identify symptoms predicting COPD in HF. As part of an observational, prospective study, we investigated stable smokers with a confirmed diagnosis of HF, using the 8-item COPD-Assessment-Test (CAT) questionnaire to assess symptoms. All the items were correlated with the presence of COPD, and logistic regression models were used to identify independent predictors. 96 HF patients were included, aged 74, 33% with COPD. Patients with HF and COPD were more symptomatic, but only breathlessness when walking up a hill was an independent predictor of COPD (odds ratio=1.33, p=0.0484). Interestingly, COPD-specific symptoms such as cough and phlegm were not significant. Thus, in elderly smokers with stable HF, significant breathlessness when walking up a hill is most indicative of associated COPD, and may indicate the need for further lung function evaluation.

2018 - In vitro and in vivo characterization of the bifunctional μ and δ opioid receptor ligand UFP-505 [Articolo su rivista]
Dietis, N.; Niwa, H.; Tose, R.; Mcdonald, J.; Ruggieri, V.; Filaferro, M.; Vitale, G.; Micheli, L.; Ghelardini, C.; Salvadori, S.; Calo', Giovanni Fabrizio; Guerrini, Remo; Rowbotham, D. J.; Lambert, D. G.
abstract

Background and Purpose: Targeting more than one opioid receptor type simultaneously may have analgesic advantages in reducing side-effects. We have evaluated the mixed μ opioid receptor agonist/ δ opioid receptor antagonist UFP-505 in vitro and in vivo. Experimental Approach: We measured receptor density and function in single μ, δ and μ /δ receptor double expression systems. GTPγ35S binding, cAMP formation and arrestin recruitment were measured. Antinociceptive activity was measured in vivo using tail withdrawal and paw pressure tests following acute and chronic treatment. In some experiments, we collected tissues to measure receptor densities. Key Results: UFP-505 bound to μ receptors with full agonist activity and to δ receptors as a low efficacy partial agonist At μ, but not δ receptors, UFP-505 binding recruited arrestin. Unlike morphine, UFP-505 treatment internalized μ receptors and there was some evidence for internalization of δ receptors. Similar data were obtained in a μ /δ receptor double expression system. In rats, acute UFP-505 or morphine, injected intrathecally, was antinociceptive. In tissues harvested from these experiments, μ and δ receptor density was decreased after UFP-505 but not morphine treatment, in agreement with in vitro data. Both morphine and UFP-505 induced significant tolerance. Conclusions and Implications: In this study, UFP-505 behaved as a full agonist at μ receptors with variable activity at δ receptors. This bifunctional compound was antinociceptive in rats after intrathecal administration. In this model, dual targeting provided no advantages in terms of tolerance liability. Linked Articles: This article is part of a themed section on Emerging Areas of Opioid Pharmacology. To view the other articles in this section visit http://onlinelibrary.wiley.com/doi/10.1111/bph.v175.14/issuetoc.

2018 - Ultrasound assessed Diaphragm Impairment is a Predictor of Outcomes in Acute Exacerbation of Chronic Obstructive Pulmonary Disease undergoing Non-Invasive Ventilation. [Articolo su rivista]
Marchioni, Alessandro; Castaniere, Ivana; Tonelli, Roberto; Fantini, Riccardo; Fontana, Matteo; Luca, Tabbi; Andrea, Viani; Francesco, Giaroni; Ruggieri, Valentina; Cerri, Stefania; Clini, Enrico
abstract

Background. Ultrasound (US) evaluation of diaphragm dysfunction (DD) has proved to be a reliable technique in critical care. In this single center prospective study we investigated the impact of US assessed DD on Non Invasive Ventilation (NIV) failure in AECOPD patients and its correlation with the trans-diaphragmatic pressure assessed through invasive sniff maneuver (Pdi sniff). Methods. A population of 75 consecutive AECOPD with hypercapnic acidosis admitted in our Respiratory Intensive Care Unit (RICU) were enrolled. Change of the diaphragm thickness (ΔTdi) < 20% during tidal volume was the pre-definite cut off to identify DD+/-. Correlations between ΔTdi <20% NIV failure and other clinical outcomes was investigated. Correlation between ΔTdi and Pdi sniff values was analyzed in a subset of 10 patients. Results. DD+ had higher risk for NIV failure as compared with DD- (RR= 4.4, p<0.001) and was significantly associated with greater RICU, in-hospital and 90-day mortality rate, MV duration, tracheostomy rate, and RICU stay. A huge increase in NIV failure (HR=6.2, p< 0.0001) and 90-day mortality (HR=4.7, p=0.008) in DD+ was reported at the Kaplan-Meyer analysis. ΔTdi highly correlated with Pdi sniff (r Pearson = 0.81, p= 0.004). ΔTdi< 20% showed better accuracy in predicting NIV failure when compared to baseline pH value and early change of both arterial blood pH and pCO2 following NIV start (AUC=0.84, 0.51, 0.56, 0.54 respectively, p<0.0001). Conclusion. Early and non-invasive US assessment of DD during severe AECOPD is reliable and accurate in identifying patients at major risk for NIV failure and worse prognosis.

2017 - Effects of [Nphe1, Arg14, Lys15] N/OFQ-NH2 (UFP-101), a potent NOP receptor antagonist, on molecular, cellular and behavioural alterations associated with chronic mild stress. [Articolo su rivista]
Vitale, Giovanni; Filaferro, Monica; Micioni Di Bonaventura, Maria Vittoria; Ruggieri, Valentina; Cifani, Carlo; Guerrini, Remo; Simonato, Michele; Zucchini, Silvia
abstract

The present study investigated the effect of [Nphe1] Arg14, Lys15-N/OFQ-NH2 (UFP-101), a selective NOP receptor antagonist, in chronic mild stress (CMS) in male Wistar rats. NOP receptor antagonists were reported to elicit antidepressant-like effects in rodents. Our aim was to investigate UFP-101 effects on CMS-induced anhedonia and impairment of hippocampal neurogenesis. UFP-101 (10 nmol/rat intracerebroventricularly) did not influence sucrose intake in non-stressed animals, but reinstated basal sucrose consumption in stressed animals from the second week of treatment. UFP-101 also reversed stress effects in forced swimming test and in open field. Fluoxetine (10 mg/kg intraperitoneally) produced similar effects. Moreover, we investigated whether UFP-101 could affect CMS-induced impairment in hippocampal cell proliferation and neurogenesis, and in fibroblast growth factor (FGF-2) expression. Our data confirm that CMS reduced neural stem cell proliferation and neurogenesis in adult rat hippocampus. Chronic UFP-101 treatment did not affect the reduced proliferation (bromodeoxyuridine-positive cells) observed in stressed animals. However, UFP-101 increased the number of doublecortin-positive cells, restoring neurogenesis. Finally, UFP-101 significantly increased FGF-2 expression, reduced by CMS. These findings support the view that blockade of NOP receptors produces antidepressant-like effects in CMS associated with positive effects on neurogenesis and FGF-2 expression. Therefore, NOP receptors may represent a target for innovative antidepressant drugs.

2015 - Antibiotic treatment of severe exacerbations of chronic obstructive pulmonary disease with procalcitonin: A randomized noninferiority trial [Articolo su rivista]
Verduri, Alessia; Luppi, Fabrizio; D'Amico, Roberto; Balduzzi, Sara; Vicini, Roberto; Liverani, Anna; Ruggieri, Valentina; Plebani, Mario; Barbaro Foschino, Maria Pia; Spanevello, Antonio; Canonica, Giorgio Walter; Papi, Alberto; Fabbri, Leonardo; Beghe', Bianca
abstract

The duration of antibiotic treatment of exacerbations of COPD (ECOPD) is controversial. Serum procalcitonin (PCT) is a biomarker of bacterial infection used to identify the cause of ECOPD. METHODS AND FINDINGS: We investigated whether a PCT-guided plan would allow a shorter duration of antibiotic treatment in patients with severe ECOPD. For this multicenter, randomized, non-inferiority trial, we enrolled 184 patients hospitalized with ECOPD from 18 hospitals in Italy. Patients were assigned to receive antibiotics for 10 days (standard group) or for either 3 or 10 days (PCT group). The primary outcome was the rate of ECOPD at 6 months. Having planned to recruit 400 patients, we randomized only 183: 93 in the PCT group and 90 in the standard group. Thus, the completed study was underpowered. The ECOPD rate at 6 months between PCT-guided and standard antibiotic treatment was not significant (% difference, 4.04; 90% confidence interval [CI], -7.23 to 15.31), but the CI included the non-inferiority margin of 15. In the PCT-guided group, about 50% of patients were treated for 3 days, and there was no difference in primary or secondary outcomes compared to patients treated for 10 days. CONCLUSIONS: Although the primary and secondary clinical outcomes were no different for patients treated for 3 or 10 days in the PCT group, the conclusion that antibiotics can be safely stopped after 3 days in patients with low serum PCT cannot be substantiated statistically. Thus, the results of this study are inconclusive regarding the noninferiority of the PCT-guided plan compared to the standard antibiotic treatment. The study was funded by Agenzia Italiana del Farmaco (AIFA-FARM58J2XH). Clinical trial registered with www.clinicaltrials.gov (NCT01125098). TRIAL REGISTRATION: ClinicalTrials.gov NCT01125098.

2014 - Functional antagonism between nociceptin/orphanin FQ and corticotropin-releasing factor in rat anxiety-related behaviors: involvement of the serotonergic system [Articolo su rivista]
Filaferro, Monica; Ruggieri, Valentina; Novi, C; Calò, G; Cifani, C; Micioni Di Bonaventura, M. V; Sandrini, Maurizio; Vitale, Giovanni
abstract

Nociceptin/orphanin FQ (N/OFQ) acts as an anxiolytic-like agent in the rat and behaves as a functional antagonist of corticotropin-releasing factor (CRF) due to its ability to oppose CRF biological actions. In response to stress, CRF triggers changes in neurotransmitter systems including serotonin (5-HT). The role of 5-HT1A receptor in anxiety has been supported by preclinical and clinical studies. The present study investigated the possible functional antagonism between N/OFQ (1nmol/rat) and CRF (0.2nmol/rat) in anxiety-related conditions in rats, using elevated plus maze and defensive burying tests, in order to confirm previous literature results. Moreover, possible changes in the serotonergic system were studied in areas rich of serotonergic neurons: frontal cortex and pons. In both tests N/OFQ showed anxiolytic-like effects while CRF displayed anxiogenic-like effects. N/OFQ before CRF treatment counteracted the anxiogenic-like effects evoked by CRF. In frontal cortex, N/OFQ significantly decreased 5-HT levels but did not modify the hydroxyindoleacetic acid (5-HIAA) ones; CRF modified neither 5-HT nor 5-HIAA content but counteracted changes induced by N/OFQ alone. In pons, N/OFQ induced no change in serotonergic activity while CRF significantly decreased 5-HT levels and increased 5-HIAA content. The two peptides' combination reinstated serotonergic parameters to controls. In frontal cortex, N/OFQ increased the 5HT1A receptor density but reduced its affinity, while CRF alone did not induce any change. In pons, CRF decreased 5HT1ABmax and KD whereas N/OFQ was ineffective. All biochemical modifications were reverted by N/OFQ plus CRF treatment. The present study confirms that N/OFQ counteracts CRF anxiogenic-like effects in the behavioral tests evaluated. These effects may involve central serotonergic mechanisms since N/OFQ plus CRF induces a reversion of serotonergic changes provoked by single peptide. Our data support the hypothesis that N/OFQ may behave as functional CRF antagonist, this action being of interest for the treatment of anxiety disorders.

2013 - Neuropeptide S stimulates human monocyte chemotaxis via NPS receptor activation. [Articolo su rivista]
Filaferro, Monica; Novi, Chiara; Ruggieri, Valentina; Genedani, Susanna; Alboni, Silvia; Malagoli, Davide; Caló, G; Guerrini, R; Vitale, Giovanni
abstract

Neuropeptide S (NPS) produces several biological actions by activating a formerly orphan GPCR, now named NPS receptor (NPSR). It has been previously demonstrated that NPS stimulates murine leukocyte chemotaxis in vitro. In the present study we investigated the ability of NPS, in comparison with the proinflammatory peptide formyl-Met-Leu-Phe (fMLP), to stimulate human monocyte chemotaxis. At a concentration of 10(-8)M fMLP significantly stimulated chemotaxis. NPS produced a concentration dependent chemotactic action over the concentration range 10(-12) to 10(-5)M. The NPSR antagonists [D-Cys((t)Bu)(5)]NPS, [(t)Bu-D-Gly(5)]NPS and SHA 68 were used to pharmacologically characterize NPS action. Monocyte chemoattractant effect of NPS, but not fMLP, was completely blocked by either peptide antagonists or SHA with the nonpeptide molecule being more potent. None of the NPSR antagonists modified per se random cell migration. Thus, the present study demonstrated that NPS is able to stimulate human monocyte chemotaxis and that this effect is entirely due to selective NPSR activation.

2012 - [tBu-D-Gly5]NPS, a pure and potent antagonist of the neuropeptide S receptor: in vitro and in vivo studies. [Articolo su rivista]
Ruzza, C; Rizzi, A; Camarda, V; Pulga, A; Marzola, G; Filaferro, Monica; Novi, Chiara; Ruggieri, Valentina; Marzola, E; Vitale, Giovanni; Salvadori, S; Guerrini, R; Calo', G.
abstract

Neuropeptide S (NPS) regulates various biological functions by selectively activating the NPS receptor (NPSR). Recently, the NPSR ligand [(t)Bu-D-Gly(5)]NPS was generated and in vitro characterized as a pure antagonist at the mouse NPSR. In the present study the pharmacological profile of [(t)Bu-D-Gly(5)]NPS has been investigated. [(t)Bu-D-Gly(5)]NPS activity was evaluated in vitro in the calcium mobilization assay at the rat NPSR and in vivo in the locomotor activity and righting reflex tests in mice and in the elevated plus maze and defensive burying assays in rats. In vitro, [(t)Bu-D-Gly(5)]NPS was inactive per se while it inhibited the calcium mobilization induced by 30 nM NPS (pK(B) 7.42). In Schild analysis experiments [(t)Bu-D-Gly(5)]NPS (0.1-10 μM) produced a concentration-dependent rightward shift of the concentration-response curve to NPS, showing a pA(2) value of 7.17. In mouse locomotor activity experiments, supraspinal injection of [(t)Bu-D-Gly(5)]NPS (1-10 nmol) dose dependently counteracted NPS (0.1 nmol) stimulant effects. In the mouse righting reflex assay [(t)Bu-D-Gly(5)]NPS (0.1-10 nmol) fully prevented the arousal-promoting action of the natural peptide (0.1 nmol). Finally, [(t)Bu-D-Gly(5)]NPS (3-30 nmol) was able to completely block NPS (1 nmol) anxiolytic-like actions in rat elevated plus maze and defensive burying assays. Collectively, the present results demonstrated that [(t)Bu-D-Gly(5)]NPS behaves both in vitro and in vivo as a pure and potent NPSR antagonist. This compound represents a novel and useful tool for investigating the pharmacology and neurobiology of the NPS/NPSR system.

2010 - Effect of salidroside, active principle of Rhodiola rosea extract, on binge eating. [Articolo su rivista]
Cifani, C; Micioni Di B., Mv; Vitale, Giovanni; Ruggieri, Valentina; Ciccocioppo, R; Massi, M.
abstract

Stress is a key determinant of binge eating (BE). Since Rhodiola rosea is known to modulate stress responses, its effect in a model of BE was investigated. BE for highly palatable food (HPF) was evoked in female rats by three 8-day cycles of food restriction/re-feeding (for 4days 66% of the usual chow intake; for 4days food ad libitum) and acute stress on the test day (day 25). R. rosea dry extract (3% rosavin, 3.12% salidroside) or its active principles were given by gavage 1h before access to HPF. Only rats exposed to both food restrictions and stress exhibited BE in the first 15-60min after the stressful procedure. R. rosea extract 10mg/kg significantly reduced and 20mg/kg abolished the BE episode. R. rosea extract 20mg/kg abolished also stress-induced increase in serum corticosterone levels. The R. rosea active principle salidroside, but not rosavin, at doses present in the extract, dose-dependently reduced or abolished BE for the period in which it was elicited. In conclusion results indicate that R. rosea extracts may have therapeutic properties in bingeing-related eating disorders and that salidroside is the active principle responsible for this effect.

2010 - Further studies on the pharmacological profile of the neuropeptide S receptor antagonist SHA 68. [Articolo su rivista]
Ruzza, C; Rizzi, A; Trapella, C; Pela', M; Camarda, V; Ruggieri, Valentina; Filaferro, Monica; Cifani, C; Reinscheid, Rk; Vitale, Giovanni; Ciccocioppo, R; Salvadori, S; Guerrini, R; Calo', G.
abstract

Neuropeptide S (NPS) regulates various biological functions by selectively activating the NPS receptor (NPSR). Previous studies demonstrated that the non-peptide molecule SHA 68 acts as a selective NPSR antagonist. In the present study the pharmacological profile of SHA 68 has been further investigated in vitro and in vivo. In cells expressing the mouse NPSR SHA 68 was inactive per se up to 10 μM while it antagonized NPS-stimulated calcium mobilization in a competitive manner showing a pA2 value of 8.06. In the 10–50 mg/kg range of doses, SHA 68 counteracted the stimulant effects elicited by NPS, but not those of caffeine, in mouse locomotor activity experiments. In the mouse righting reflex assay SHA 68 fully prevented the arousal-promoting action of the peptide. The anxiolytic-like effects of NPS were slightly reduced by SHA 68 in the mouse open field, fully prevented in the rat elevated plus maze and partially antagonized in the rat defensive burying paradigm. Finally, SHA 68 was found poorly active in antagonizing the NPS inhibitory effect on palatable food intake in rats. In all assays SHA 68 did not produce any effect per se. In conclusion, the present study demonstrated that SHA 68 behaves as a selective NPSR antagonist that can be used to characterize the in vivo actions of NPS. However the usefulness of this research tool is limited by its poor pharmacokinetic properties.

2010 - Glutamate-mediated astrocyte-to-neuron signaling in the rat dorsal horn [Articolo su rivista]
Bardoni, Rita; Ghirri, Alessia; Micaela, Zonta; Betelli, Chiara; Vitale, Giovanni; Ruggieri, Valentina; Sandrini, Maurizio; Giorgio, Carmignoto
abstract

By releasing neuroactive agents, including proinflammatory cytokines, prostaglandinsand neurotrophins, microglia and astrocytes are proposed to be involved in nociceptivetransmission, especially in conditions of persistent, pathological pain. The specificaction on dorsal horn neurons of agents released from astrocytes, such as glutamate, hasbeen, however, poorly investigated. By using patch-clamp and confocal microscopecalcium imaging techniques in rat spinal cord slices, we monitored the activity of dorsalhorn lamina II neurons following astrocyte activation. Results obtained revealed thatstimuli that triggered Ca2+ elevations in astrocytes, such as the purinergic receptoragonist BzATP and low extracellular Ca2+, induce in lamina II neurons slow inwardcurrents (SICs). Similarly to SICs triggered by astrocytic glutamate in neurons fromother central nervous system regions, these currents: i) are insensitive to TTX, ii) areblocked by the NMDA receptor antagonist D-AP5, iii) lack an AMPA component, andiv) have slow rise and decay times. Ca2+ imaging also revealed that astrocytic glutamateevokes NMDAR-mediated episodes of synchronous activity in groups of substantiagelatinosa neurons. Importantly, in a model of peripheral inflammation, thedevelopment of thermal hyperalgesia and mechanical allodynia was accompanied by a significant increase of spontaneous SICs in dorsal horn neurons. The NMDARmediatedastrocyte-to-neuron signaling thus represents a novel pathway that maycontribute to the control of central sensitization in pathological pai

2010 - The antinociceptive effect of acetylsalicylic acid is differently affected by a CB1 agonist or antagonist and involves the serotonergic system in rats [Articolo su rivista]
Ruggieri, Valentina; Vitale, Giovanni; Filaferro, Monica; Frigeri, Claudio; Pini, Luigi Alberto; Sandrini, Maurizio
abstract

Combinations of non steroidal anti-inflammatory drugs (NSAIDs) and cannabinoids are promising because of their potential synergistic effects in analgesia, resulting in a reduction in dosage and minimizing adverse reactions. The analgesic effect of Acetylsalicylic acid (ASA), probably due to a central mechanism, also implicates changes in the central monoaminergic system. Therefore, we decided to evaluate the antinociceptive interaction between the CB1 receptor agonist, HU210, and ASA in tests involving central pain in rats as well as the implication of the central serotonergic system thereon.

2009 - Chronic treatment with the selective NOP receptor antagonist [Nphe1,Arg14,Lys15]N/OFQ-NH2 (UFP-101) reverses the behavioural and biochemical effects of unpredictable chronic mild stress in rats [Articolo su rivista]
Vitale, Giovanni; Ruggieri, Valentina; Filaferro, Monica; Frigeri, Claudio; Alboni, Silvia; Tascedda, Fabio; Brunello, Nicoletta; Guerrini, R; Cifani, C; Massi, M.
abstract

Introduction The present study was designed to assess the antidepressant effects of UFP-101, a selective nociceptin/orphanin FQ peptide (NOP) receptor antagonist, in a validated animal model of depression: the chronic mild stress (CMS). Materials and methods and Results UFP-101 (5, 10 and 20 nmol/rat; i.c.v., once a day for 21 days) dose- and time-dependently reinstated sucrose consumption in stressed animals without affecting the same parameter in non-stressed ones. In the forced swimming test, UFP-101 reduced immobility of stressed rats from day 8 of treatment. After a 3-week treatment, rats were killed for biochemical evaluations. UFP-101 abolished increase in serum corticosterone induced by CMS and reverted changes in central 5-HT/5-HIAA ratio. The behavioural and biochemical effects of UFP-101 mimicked those of imipramine, the reference antidepressant drug, administered at the dose of 15 mg/kg (i.p.). Co-administration of nociceptin/orphanin FQ (5 nmol/rat, from day 12 to 21) prevented the effects of UFP-101. Brain-derived neurotrophic factor mRNA and protein in hippocampus were not reduced by CMS nor did UFP-101 modify these parameters. Discussion and Conclusion This study demonstrated that chronic treatment with UFP-101 produces antidepressant-like effects in rats subjected to CMS supporting the proposal that NOP receptors represent a candidate target for the development of innovative antidepressant drugs.

2008 - ANXIOLYTIC LIKE EFFECT OF NEUROPEPTIDE S IN THE RAT DEFENSIVE BURYING. [Articolo su rivista]
Vitale, Giovanni; Filaferro, Monica; Ruggieri, Valentina; S., Pennella; Frigeri, Claudio; A., Rizzi; R., Guerrini; G., Calò
abstract

Neuropeptide S (NPS) has been recently identified as the endogenous ligand of a previously orphan G-protein-coupled receptor now named NPSR. Both NPS and its receptor are expressed in the brain, where they modulate different functions. In particular, it has been demonstrated that intracerebroventricular (i.c.v.) injection of NPS in rodents increases wakefulness and promotes anxiolytic-like effects. In the present study we used the defensive burying (DB) test in rats to further investigate the action of human NPS (0.1–10 nmol, i.c.v.) on anxiety-related behaviors. Diazepam (1.5 mg/kg, i.p.) and caffeine (20 mg/kg, i.p.) were used in parallel experiments as standard anxiolytic and anxiogenic drugs, respectively. None of the tested drugs produced statistical differences in the latency to contact the probe, burying behavior latency, number of shocks received or immobility/freezing duration. Caffeine increased cumulative burying behavior and the buried bedding height in a statistically significant manner thus promoting anxiogenic like effects. Opposite results were obtained with diazepam that significantly reduced these behavioral parameters. The anxiolytic-like action of diazepam was mimicked by NPS that reduced cumulative burying behavior in a dose dependent manner. Collectively, robust anxiolytic-like effects were recorded in response to NPS in the DB test. These results are of particular interest since the outcome of this assay is marginally influenced by drug effects on locomotor activity. In conclusion, we provide further evidence that NPS evokes genuine anxiolytic-like effects in the rat; therefore NPSR selective agonists are worthy of development as innovative drugs for the treatment of anxiety disorders.

2008 - Differential involvement of opioidergic and serotoninergic systems in the antinociceptive activity of N-arachidonoyl-phenolamine (AM404) in the rat: comparison with paracetamol [Articolo su rivista]
Ruggieri, Valentina; Vitale, Giovanni; Pini, Luigi Alberto; Sandrini, Maurizio
abstract

It is recognized that paracetamol undergoes ametabolic transformation to N-arachydonylphenolamine(AM404), a CB1 receptor ligand and anandamide uptakeinhibitor. Using hot-plate and paw pressure tests, wedecided to establish whether AM404 may act throughopioidergic and serotonergic mechanisms. Thus, we pretreatedrats with opioid μ1 (naloxonazine) and κ (MR2266)or 5-HT1A (NAN-190), 5-HT2 (ketanserin), and 5-HT3(ondansetron) receptor antagonists. We investigated thepossible changes in 5-hydroxyindoleacetic acid/serotoninratio in the frontal cortex and pons. The antinociceptiveeffect of AM404 (10 mg/kg, intrapertoneally) or paracetamol(400 mg/kg, intrapertoneally) in either test wasabolished by naloxonazine or MR2266. Ondansetronprevented AM404 activity; NAN-190 and ketanserin wereineffective. Ketanserin antagonized paracetamol activity;NAN-190 and ondansetron were inactive. AM404 did notchange serotonergic activity, while paracetamol decreasedserotonin turnover. The diverse antinociceptive potency ofthe compounds might be explained by the differentinfluence on the serotonergic system, despite a similarinvolvement of opioidergic one.

2007 - Effect of acute and repeated administration of paracetamol on opioidergic and serotonergic systems in rats. [Articolo su rivista]
Sandrini, Maurizio; Vitale, Giovanni; Ruggieri, Valentina; Pini, Luigi Alberto
abstract

Objective and design: We investigated the antinociceptiveeffect of paracetamol or morphine after repeatedadministration and the changes in the characteristics of centralμ-, κ- and 5-HT2 receptors.Treatment: Male rats were injected twice a day for sevendays with paracetamol (400 mg/kg, i. p.) or morphine (5 mg/kg, s. c.).Methods: The antinociceptive effect was evaluated 30 minafter single and multiple doses of paracetamol and morphinethrough the hot-plate test. Binding techniques were used toevaluate the receptor characteristics in the frontal cortex.Results: Both paracetamol and morphine induced an antinociceptiveeffect on day 1 but only paracetamol maintainedthis effect for seven days while morphine did not.The number of μ-opioid receptors decreased on days 1, 3,and 7 by a similar percentage after paracetamol administration(by 29, 31 and 34 %, respectively), while morphineproduced a progressive decrease in comparison with controls(by 37, 49 and 60 %, respectively) and κ-opioid receptorswere unaffected. Both drugs similarly decreased the 5-HT2receptor number on all days of treatment (by about 30 %).Conclusions: The opioidergic and serotonergic systems areinvolved in different ways in the induction and maintenanceof antinociception after paracetamol or morphine treatment.

2006 - Anxiolytic-like effects of nociceptin/orphanin FQ in the elevated plus maze and in the conditioned defensive burying test in rats [Articolo su rivista]
Vitale, Giovanni; Arletti, Rossana; Ruggieri, Valentina; Cifani, C; Massi, M.
abstract

Different reports suggest that nociceptin/orphanin FQ (N/OFQ) may have either anxiolytic- or anxiogenic-like effect in rodents. Since N/OFQ elicits hypolocomotion, which undergoes rapid tolerance, and hypolocomotion may be associated to emotional consequences, the present study was designed to investigate the effect of N/OFQ on anxiety after development of tolerance to its hypolocomotor effect. The effect of single or double intracerebroventricular (i.c.v.) injection of N/OFQ was evaluated on anxiety-related behaviors in rats, in the elevated plus maze (EPM) and conditioned defensive burying (CDB) tests. After single administration, N/OFQ displayed an anxiogenic-like pattern of response on the elevated plus maze but hypolocomotion was also observed. Conversely, in the CDB test, N/OFQ induced a clear-cut anxiolytic pattern. To produce tolerance to N/OFQ-induced hypolocomotion the peptide was administered by two i.c.v. injections separated by 120 min; in these conditions it decreased the expression of anxiety-related behaviors in both tests without affecting locomotor activity. The nociceptin/orphanin FQ peptide (NOP) receptor antagonist UFP-101 significantly reduced the effects of N/OFQ to control values in either tests. Corticosterone levels were significantly increased after a single N/OFQ administration (not in a dose-dependent manner) but this increase did not reach significance after double administration (1 nmol/rat). Our results support the idea that N/OFQ may act as an anxiolytic-like agent in the rat; the apparent anxiogenic-like effect observed following its single administration in the EPM may be consequent to its, effect on locomotion. (c) 2006 Elsevier Inc. All rights reserved.

2006 - Switching from HPLC/UV to MEIA for whole blood sirolimus quantitation: Comparison of methods [Articolo su rivista]
Pini, Luigi Alberto; Gallesi, Daniela; Brovia, Daria; Bertolini, Alfio; Pinetti, Diego; Ruggieri, Valentina; Pisa, S; Poppi, B; Castellana, Cn
abstract

Sirolimus is a immunosuppressive agent for renal transplant recipients. Monitoring of whole blood sirolimus concentration is necessary in order to improve clinical outcomes. An increasing number of clinical laboratories (4-14% during 2005) are using microparticle enzyme immunoassay (MEIA) for sirolimus quantitation but previous reports indicated a high variability, with a mean difference of 17% for MEIA method vs. high-performance liquid chromatography/ultraviolet (HPLC/UV). This study was aimed at comparing the reliability of MEIA with the HPLC/UV method. Blood samples from transplant patients were processed using both HPLC/UV and MEIA assays. Comparison and Bland-Altman plots, as well as regression analysis and paired t-test were used to compare results of the assays. Concentrations were stratified into three groups and used to investigate whether any observed difference between methods could be influenced by sirolimus concentration. Regression analysis yielded a coefficient of correlation R of 0.9756, the line of best fit being y = 0.9832x + 0.1976. The statistical analysis showed no difference between the two sets of experimental data. The average percentage difference between the two methods was found to be -0.2 +/- 19.2%. On the basis of our present results, the tested MEIA assay is able to quantify sirolimus concentration with a clinically acceptable imprecision, similar to that of HPLC/UV method.