112,469 research outputs found
SYNTHESIS AND BIOLOGICAL EVALUATION OF NOVEL A1 ADENOSINE RECEPTOR AGONISTS
No full textA1 adenosine receptor (A1AR) is the best characterized subtype of the four known adenosine receptors.1 Selective A1AR agonists show neuro- and cardio-protective effects, reduce intraocular pressure in glaucoma, and have anticonvulsivant activity. The majority of A1AR agonists are adenosine derivatives and even though many efforts have been carried out, only few drugs in advanced clinical studies are A1AR agonists. The main
problem is represented by the significant cardiovascular side effects (bradicardia and hypotension).1 In our previous studies we found that the replacement of the 5’-hydroxy-group by a chlorine atom in N6-substituted adenosine derivatives, improved both the A1AR affinity and selectivity. 5’-Chloro-5’-deoxy-N6-(±)-endo-
norbornyl-adenosine (5’Cl5’d-(±)-ENBA) resulted a potent and highly selective A1AR2 agonist showing
analgesic effects in a mice model of neuropathic pain.3 Interestingly, at analgesic doses it did not lower blood pressure and locomotor activity in mice.3 Moreover, it reduced dyskinesia evoked by L-DOPA in a mice model of Parkinson disease.4
Based on these interesting findings, a novel series of 5’-modified N6-substitued adenosine derivatives was synthesized and tested in human A1, A2A, A2B, and A3 adenosine receptors binding assay. The most potent and

selective compounds of the series were also assayed in a formalin test in mice. The results of this work will be discussed.
1Fredholm, B.B.; IJzerman, A.P.; Jacobson, K.A.; Linden, J.; Muller, C.E. Pharmacol. Rev. 2011, 63, 1-34.
2Franchetti, P.; Cappellacci, L.; Vita, P.; Petrelli, R.; Lavecchia, A.; Kachler, S.; Klotz, K.-N.; Marabese, I.; Luongo, L.; Maione, S.;
Grifantini, M. J. Med. Chem. 2009, 52, 2393−2406.
3(a) Luongo, L.; Petrelli, R.; Gatta, L.; Giordano, C.; Guida, F.; Vita, P.; Franchetti, P.; Grifantini, M.; De Novellis, V.; Cappellacci, L.; Maione, S. Molecules 2012, 17, 13712−13726. (b) Luongo, L.; Guida, F.; Imperatore, R.; Napolitano, F.; Gatta, L.; Cristino, L.; Giordano, C.; Siniscalco, D.; Di Marzo, V.; Bellini, G.; Petrelli, R.; Cappellacci, L.; Usiello, A.; de Novellis, V.; Rossi, F.; Maione, S. Glia 2014, 62, 122−132.
4Mango, D.; Bonito-Oliva, A.; Ledonne, A.; Cappellacci, L.; Petrelli, R.; Nisticò, R.; Berretta, N.; Fisone, G.; Mercuri, N.B. Exp. Neurol. 2014, 261, 733−743
One year follow up of spinal cord injury patients using a reciprocating gait orthosis: Preliminary results
No full textOne year follow up of spinal cord injury patients using a reciprocating gait orthosis: preliminary report.
Scivoletto G, Petrelli A, Lucente LD, Giannantoni A, Fuoco U, D'Ambrosio F, Filippini V.
Source
Spinal Cord Unit, I.R.C.C.S., S. Lucia, via Ardeatina 306, 00179 - Rome, Italy.
Abstract
OBJECTIVE:
To examine the influence of social, physical and psychological factors in determining the usage/non usage of reciprocating gait orthosis (RGO) in spinal cord injury (SCI) patients.
DESIGN:
Prospective clinical trial.
SETTING:
A large rehabilitation hospital in Rome, Italy.
PARTICIPANTS:
Twenty four SCI patients of traumatic aetiology (all fulfilling the criteria to prescribe the device). Methods: Social, physical and neurological examination according to ASIA standards; psychological enquiry by means of the Eysenck Personality Questionnaire (EPQ) and the scale for self rating anxiety and depression of the Cognitive Behavioural Assessment.
RESULTS:
After 1 year follow up 11 (46%) of our patients no longer used the RGO. There was no statistically significant difference between patients who used the RGO and those who rejected the orthosis with regard to social and physical data. There was a significant difference (P=0.005 at the end of training and P=0.003 at 1 year follow up) with regard to functional ambulation level. With regard to psychological enquiry RGO-non users showed a higher frequency of values over the mean in the E scale (extroversion) of the EPQ than RGO-users (P=0.05).
CONCLUSIONS:
None of the identified parameters were useful to predict the use/rejection of the orthosis. Although they need to be confirmed, our psychological data suggest that extensive psychological testing could be useful to sharpen the ability to predict
Novel N6/5’-Disubstituted Adenosine Derivatives As A1 Adenosine Receptor Agonists: Synthesis, Binding Assay And Antinociceptive Activity
No full textAdenosine is a regulatory nucleoside that can be generated in response to cellular stress and tissue damage as well as during episodes of tissue hypoxia or inflammation. It acts on specific G-protein coupled receptors that have been classified into four subtypes (A1, A2A, A2B and A3) on the basis of their structures and signal transduction systems.
Selective A1 adenosine receptor (A1AR) agonists have antinociceptive, antiarrhythmic and neuro- and cardioprotective effects. There is a large body of evidence to suggest that A1AR agonists produce antinociception at spinal cord level as well as at supraspinal level. Our previous work showed that replacement of the 5′ -hydroxy-group by a chlorine atom in N6-substituted adenosine derivatives increased selectivity for A1AR [1]. 5′-Chloro-5′-deoxy-N6-(±)-(endo-norborn-2-yl)-adenosine (5′Cl5′d-(±)- ENBA) displayed high A1AR affinity and selectivity. It was shown to reduce both mechanical allodynia and thermal hyperalgesia in a mice model of neuropathic pain without affecting motor and cardiovascular functions [2]. Moreover, it reduced dyskinesia evoked by L-DOPA in a mice model of Parkinson’s disease [3].
In this work, novel N6/5’-disubstituted adenosine derivatives were synthesized and evaluated for analgesic activity in a formalin test in mice. The most potent compound of the series was found to inhibit the second phase of the nocifensive response induced by intrapaw injection of formalin at a dose of 2 mg/kg i.p. [2] Franchetti, P.; Cappellacci, L.; Vita, P.; Petrelli, R.; Lavecchia, A.; Kachler, S.; Klotz, K.-N.; Marabese, I.; Luongo, L.; Maione, S.; Grifantini, M. J. Med. Chem. 2009, 52, 2393−2406.
[3] (a) Luongo, L.; Petrelli, R.; Gatta, L.; Giordano, C.; Guida, F.; Vita, P.; Franchetti, P.; Grifantini, M.; De Novellis, V.; Cappellacci, L.; Maione, S. Molecules 2012, 17, 13712−13726. (b) Luongo, L.; Guida, F.; Imperatore, R.; Napolitano, F.; Gatta, L.; Cristino, L.; Giordano, C.; Siniscalco, D.; Di Marzo, V.; Bellini, G.; Petrelli, R.; Cappellacci, L.; Usiello, A.; de Novellis, V.; Rossi, F.; Maione, S. Glia 2014, 62, 122−132.
[4] Mango, D.; Bonito-Oliva, A.; Ledonne, A.; Cappellacci, L.; Petrelli, R.; Nisticò, R.; Berretta, N.; Fisone, G.; Mercuri, N.B. Exp. Neurol. 2014, 261, 733−743
A southern mode of the imagination: spazio e mito nella narrativa di Cormac McCarthy
No full textOggetto di questo studio è l’analisi del ruolo dello spazio nei romanzi appalachiani di Cormac McCarthy. Attraverso una geografia ibrida, tanto realistica quanto espressionistica, l’autore evoca lo spazio mitico per eccellenza del sud statunitense: il giardino prelapsario delle rappresentazioni pastorali. Critici come Jay Ellis e Georg Guillemin hanno individuato la predominanza del setting sui personaggi e le trame dei romanzi di McCarthy, aprendo la via a una lettura di tipo geocritico/ geopoetico, essendo la rappresentazione dello spazio il luogo testuale ove indubbiamente la poetica dell’autore si realizza appieno. In virtù del suo ibridismo, la geografia di McCarthy è una matrice, un terzospazio fluido che, se di frequente risponde ai canoni della pastorale, più spesso mostra quello che Lewis P. Simpson ha definito come il suo opposto estetico e simbolico: il gotico. Il genere pastorale è tipicamente espressione di un ordine divino e, nel caso del Sud, di uno sguardo retrospettivo e malinconico che interpreta il presente sul modello di un passato idealizzato. Lo spazio gotico (nella definizione di Ruth D. Weston), al contrario, è irrazionale, caotico e imprevedibile. Se la critica ha generalmente posizionato l’autore in osservanza o trasgressione delle strutture mitiche tradizionali, è mia opinione che un approccio efficace debba contemplare una compresenza di questi paradigmi. L’opera di McCarthy è dedicata agli uomini nello spazio, ed è caratterizzata da un’erraticità di fondo che è un continuo tentativo di orientamento ideologico. Il vagabondaggio continuo dei personaggi diviene espressione di un’alienazione dal territorio che, storicamente, è stato per il Sud luogo di definizione identitaria e culturale, racchiusa nel concetto ubiquo e sfuggente di sense of place. La pastorale come mito e mappa, e il gotico come anti-mito e labirinto, forniscono dunque gli strumenti ermeneutici fondamentali per comprendere la dialettica tra spazio e personaggi in McCarthy, e, di conseguenza, l’evoluzione del tradizionale sense of place nella narrativa del Sud contemporaneo
5'-CHLORO-5'-DEOXY-N6-(±)-endo-NORBORNYLADENOSINE, A POTENT AND HIGHLY SELECTIVE HUMAN A1 ADENOSINE RECEPTOR AGONIST, PREVENTS HYPERALGESIA/ALLODYNIA AND EARLY OVER-EXPRESSION OF PRO-APOPTOTIC AND PRO-INFLAMMATORY GENES IN A MICE MODEL OF NEUROPATHIC PAIN
No full textA1 adenosine receptor (A1AR) is a promising drug target for neuropathic pain treatment. Some N6-substituted adenosine derivatives as A1AR agonists have shown to modulate nociception in vivo. Recently, we reported 5'-chloro-5'-deoxy-N6-(±)-endo-norbornyladenosine (5'Cl5'd-(±)-ENBA) as a very potent and highly selective human A1AR agonist with antinociceptive effects in mice.1 In this study we used mice with sciatic nerve injury (spared nerve injury, SNI) and combined behavioural, molecular and morphological approaches to assess the involvement of A1AR in neuropathic pain-associated hyperalgesia and allodynia and spinal cord gliosis and neuro-inflammation.
Mechanical allodynia and thermal hyperalgesia developed 2-3 days after surgery. Morphological changes in the ipsilateral L4-L6 laminae I-II consisted of: i) increased TUNEL-positive profiles, ii) increased microglia activity, and iii) astrogliosis. Molecular expression data showed: 1) increased expression of pro-apoptotic and pro-inflammatory genes (bax, 325 ± 12%; caspase 7, 109 ± 17%; caspase 8, 133 ± 17%), 7 days after SNI. The selective A1AR agonist 5'Cl5'd-(±)-ENBA (1 mg/Kg i.p. once daily), reduced the development of thermal hyperalgesia and mechanical allodynia. This treatment in part normalized the spinal cord expression of bax, bcl-2 and caspases in SNI mice, and proved to be cytoprotective at 7 days post-SNI. This study shows that: a) allodynia and hyperalgesia developed with spinal cord glia activation, b) over-expression of pro-apoptotic or pro-inflammatory genes may be critical for maintaining gliosis in the spinal cord, and c) adenosine A1 receptor stimulation was capable to protect neuropathic mice from the observed biomolecular and morphological modifications.
(1) Franchetti, P.; Cappellacci, L.; Vita, P.; Petrelli, R.; Lavecchia, A.; Kachler, S.; Klotz, K.-N.; Marabese, I.; Luongo, L.; Maione, S.; Grifantini, M. J. Med. Chem. 2009, 52, 2393-2406
SYNTHESIS AND PHARMACOLOGICAL CHARACTERIZATION OF RIBOSE-MODIFIED ADENOSINE DERIVATIVES AS P1 RECEPTOR LIGANDS
No full textAdenosine, the natural ligand of P1 receptors, is implicated in the control of many physiological and pathological conditions such as inflammation, pain, cardiovascular and central nervous system (CNS) diseases.1
P1 receptors belong to the large family of GPCR receptors and are divided in four subtypes: A1, A2A, A2B and A3 adenosine receptors (ARs). Even though a large number of P1 ligands have been synthesized and characterized byin vitro and in vivo pharmacological studies, only very few of them are commercially available.
Modifications at the ribose moiety and substitution at the N6-position of adenosine, lead to adenosine derivatives endowed with increased potency at A1 or A3AR. Our previous SAR studies showed that the replacement of OH at 5’-position of the ribose moiety of N6-substituted adenosine derivatives by a chlorine improved A1AR potency and selectivity versus A3AR, with 5′-chloro-5′-deoxy-N6-(±)-(endo- norborn-2-yl)-adenosine (5′Cl5′d-(±)-ENBA) as one of the most potent and selective A1AR agonists,2 while a 5’-C-ethyl-tetrazolyl moiety maintained the A1AR potency, but restored high A3AR affinity, leading to very potent dual A1AR and A3AR ligands.3 Interestingly, both modifications at 5’-position of adenosine derivatives brought to human A3AR antagonism.
In order to further explore the structural determinants of this class of P1 ligands, a new series of ribose- modified N6-substituted adenosine derivatives was synthesized and their pharmacological profile was assayed. The results of this study will be discussed.References
1. Jacobson KA, Muller CE, Neuropharmacology 2015, doi: 10.1016/J.neuropharm.2015.12.001.
2. (a) Franchetti, P.; Cappellacci, L.; Vita, P.; Petrelli, R.; Lavecchia, A.; Kachler, S.; Klotz, K.-N.; Marabese, I.; Luongo, L.; Maione, S.; Grifantini, M. J. Med. Chem. 2009, 52, 2393−2406. (b) Luongo, L.; Petrelli, R.; Gatta, L.; Giordano, C.; Guida, F.; Vita, P.; Franchetti, P.; Grifantini, M.; De Novellis, V.; Cappellacci, L.; Maione, S. Molecules 2012, 17, 13712−13726. (c) Luongo, L.; Guida, F.; Imperatore, R.; Napolitano, F.; Gatta, L.; Cristino, L.; Giordano, C.; Siniscalco, D.; Di Marzo, V.; Bellini, G.; Petrelli, R.; Cappellacci, L.; Usiello, A.; de Novellis, V.; Rossi, F.; Maione, S. Glia 2014, 62, 122−132.
3. Petrelli, R.; Torquati, I.; Kachler, S.; Luongo, L.; Maione, S.; Franchetti, P.; Grifantini, M.; Novellino, E.; Lavecchia, A.; Klotz, K.-N-; Cappellacci, L. J. Med. Chem. 2015, 58, 2560-2566
Nick Cave. Preghiere di fuoco e ballate assassine
No full textEsplosioni di rabbia disarticolata e afflati lirici da poeta romantico; capace di passaredal linguaggio sboccato del teppista di strada all’inglese barocco di un maestro del modernismo nordamericano come William Faulkner, Cave è un cantautore dal sapere letterario vasto e caotico. La sua musica esplora il lato più buio della vita, insistendo sul male insito in ognuno di noi, sulla pervasività del peccato e sulla ricerca spesso vana della redenzione.John Milton, Flannery O’ Connor, John Berryman, Leonard Cohen, l’Antico testamento, Cormac McCarthy, Michael Ondaatje, murder ballads e Robert Burton lo accompagnano attraverso un paesaggio ora infernale e ora edenico, dove si raccontano i destini tragici, cruenti e surreali di un’umanità perduta ma ancora capace di trovare una bellezza terribile nella fragilità dell’esistenza
Stato e regioni nel governo dell'agricoltura
No full textLe modifiche che hanno interessato il Titolo V della Carta costituzionale hanno indotto a rivisitare lo studio della distribuzione delle competenze tra Stato e Regioni nel settore agricolo, anche se la portata dell'innovazione è tale da impedire di porre un punto fermo sullo stato della materia. Se da un lato il nuovo articolo 117 Cost. sembra ampliare a dismisura le competenze regionali, dall'altro restano prive di interpretazione autentica le competenze riservate allo Stato, mentre giacciono in un limbo ancora non bene determinato, quelle materie oggetto di competenza concorrente che interessano sempre più l'agricoltura.
Il tema del decentramento delle competenze tra Stato e Regioni nella materia agricoltura e foreste viene svolto attraverso un' essenziale analisi sistematica della materia stessa che non può prescindere dallo studio del sistema italo-comunitario delle fonti
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