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Franzese O.,University of Rome Tor Vergata | Tricarico M.,National Research Council Italy | Starace G.,National Research Council Italy | Pepponi R.,Section of Central Nervous System Pharmacology | And 3 more authors.
Journal of Interferon and Cytokine Research | Year: 2013

It is well known that ionizing radiations induce a marked downregulation of antigen-dependent and natural immunity for a prolonged period of time. This is due, at least in part, to radiation-induced apoptosis of different lymphocyte subpopulations, including natural killer (NK) cells. Aim of this study was to investigate the capability of Beta Interferon (β-IFN) and Interleukin-2 (IL2), alone or in combination, to restore the functional activity of the natural immune system. Mononuclear cells (MNCs) obtained from intact or in vitro irradiated human peripheral blood were treated in vitro with β-IFN immediately before or at the end of the 4-day treatment with IL2. Time-course analysis was performed on the NK activity, the total number and the apoptotic fraction of CD16+ and CD56+ cells, the 2 main NK effector cell subpopulations. The results indicate that radiation-induced impairment of natural cytotoxicity of MNC could be successfully antagonized by the β-IFN+IL2 combination, mainly when exposure to β-IFN preceded IL2 treatment. This radioprotective effect is paralleled by lower levels of radiation-induced apoptosis and increased expression of the antiapoptotic Bcl-2 protein. Since natural immunity can play a significant role in antitumor host's resistance, these results could provide the rational basis for a cytokine-based pharmacological strategy able to restore immune responsiveness and to afford possible therapeutic benefits in cancer patients undergoing radiotherapy. © Copyright 2013, Mary Ann Liebert, Inc. 2013. Source


Tebano M.T.,Section of Central Nervous System Pharmacology | Martire A.,Section of Central Nervous System Pharmacology | Popoli P.,Section of Central Nervous System Pharmacology
Brain Research | Year: 2012

The striatum is a subcortical area involved in sensorimotor, cognitive and emotional processes. Adenosine A2A receptors (A2ARs) are highly expressed in the striatum, and their ability to establish functional and molecular interactions with many other receptors attributes to a pivotal role in the modulation and integration of striatal neurotransmission. This review will focus on the interaction between A2ARs and cannabinoid CB1 receptors (CB1Rs), taking it as a paradigmatic example of synaptic integration. Indeed, A2ARs can exert an opposite (permissive vs. inhibitory) influence on CB1-dependent synaptic effect. These apparently irreconcilable functions could depend on a different role of pre- vs. postsynaptic A2ARs, on their interaction with other receptors (namely adenosine A1, metabotropic glutamate 5 and dopamine D2 receptors), and on whether A2ARs form or not heteromers with CB1Rs. Besides providing a good example of the intricate pattern of events taking place in striatal synapses, the A2A/CB1R interaction proves very informative to understand the physiology of the basal ganglia and the mechanisms of related diseases. This article is part of a Special Issue entitled: Brain Integration. © 2012 Elsevier B.V. All rights reserved. Source


Venerosi A.,Section of Neurotoxicology and Neuroendocrinology | Martire A.,Section of Central Nervous System Pharmacology | Rungi A.,Section of Neurotoxicology and Neuroendocrinology | Pieri M.,University of Rome Tor Vergata | And 4 more authors.
Molecular Nutrition and Food Research | Year: 2011

Scope: We hypothesized that chronic supplementation with branched chain amino acids (BCAAs) affects neurobehavioral development in vulnerable gene backgrounds. Methods and results: A murine model of amyotrophic lateral sclerosis (ALS), G93A mice bearing the mutated human superoxide dismutase 1 (SOD1) gene, and control mice received from 4 to 16wk of age dietary supplementation with BCAAs at doses comparable to human usage. Motor coordination, exploratory behaviors, pain threshold, synaptic activity and response to glutamatergic stimulation in primary motor cortex slices were evaluated between the 8th and 16th week. The glial glutamate transporter 1 (GLT-1) and metabotropic glutamate 5 receptor (mGlu5R) were analyzed by immunoblotting in cortex, hippocampus and striatum. BCAAs induced hyperactivity, decreased pain threshold in wild-type mice and exacerbated the motor deficits of G93A mice while counteracting their abnormal pain response. Electrophysiology on G93A brain slices showed impaired synaptic function, reduced toxicity of GLT-1 blocking and increased glutamate toxicity prevented by BCAAs. Immunoblotting indicated down-regulation of GLT-1 and mGlu5R in G93A, both effects counteracted by BCAAs. Conclusion: These results, though not fully confirming a role of BCAAs in ALS-like etiology in the genetic model, clearly indicate that BCAAs' complex effects on central nervous system depend on gene background and raise alert over their spread use. © 2011 WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim. Source


Martire A.,Section of Central Nervous System Pharmacology | Tebano M.T.,Section of Central Nervous System Pharmacology | Chiodi V.,Section of Central Nervous System Pharmacology | Ferreira S.G.,University of Coimbra | And 3 more authors.
Journal of Neurochemistry | Year: 2011

An interaction between adenosine A2A receptors (A 2ARs) and cannabinoid CB1 receptors (CB1Rs) has been consistently reported to occur in the striatum, although the precise mechanisms are not completely understood. As both receptors control striatal glutamatergic transmission, we now probed the putative interaction between pre-synaptic CB1R and A2AR in the striatum. In extracellular field potentials recordings in corticostriatal slices from Wistar rats, A2AR activation by CGS21680 inhibited CB1R-mediated effects (depression of synaptic response and increase in paired-pulse facilitation). Moreover, in superfused rat striatal nerve terminals, A 2AR activation prevented, while A2AR inhibition facilitated, the CB1R-mediated inhibition of 4-aminopyridine-evoked glutamate release. In summary, the present study provides converging neurochemical and electrophysiological support for the occurrence of a tight control of CB1R function by A2ARs in glutamatergic terminals of the striatum. In view of the key role of glutamate to trigger the recruitment of striatal circuits, this pre-synaptic interaction between CB 1R and A2AR may be of relevance for the pathogenesis and the treatment of neuropsychiatric disorders affecting the basal ganglia. © 2010 The Authors. Journal of Neurochemistry © 2010 International Society for Neurochemistry. Source


Martire A.,Section of Central Nervous System Pharmacology | Pepponi R.,Section of Central Nervous System Pharmacology | Domenici M.R.,Section of Central Nervous System Pharmacology | Ferrante A.,Section of Central Nervous System Pharmacology | And 2 more authors.
Journal of Neurochemistry | Year: 2013

NMDA receptor-mediated excitotoxicity is thought to play a pivotal role in the pathogenesis of Huntington's disease (HD). The neurotrophin brain-derived neurotrophic factor (BDNF), which is also highly involved in HD and whose effects are modulated by adenosine A2ARs, influences the activity and expression of striatal NMDA receptors. In electrophysiology experiments, we investigated the role of BDNF toward NMDA-induced effects in HD models, and the possible involvement of A2ARs. In corticostriatal slices from wild-type mice and age-matched symptomatic R6/2 mice (a model of HD), NMDA application (75 μM) induced a transient or a permanent (i.e., toxic) reduction of field potential amplitude, respectively. BDNF (10 ng/mL) potentiated NMDA effects in wild-type, while it protected from NMDA toxicity in R6/2 mice. Both effects of BDNF were prevented by A2AR blockade. The protective effect of BDNF against NMDA-induced toxicity was reproduced in a cellular model of HD. These findings may have very important implications for the neuroprotective potential of BDNF and A2 AR ligands in HD. BDNF prevents NMDA-induced toxicity in models of Huntington's disease: the effects are genotype specific and adenosine A 2A receptor is involved We observed that BDNF, similar to adenosine A2A receptors' (A2ARs) stimulation, reduces NMDA-induced toxicity in Huntington's disease (HD) models, whereas increases it in wild-type preparations. In both genotypes, BDNF actions are prevented by A2AR blockade, confirming that A2ARs, directly and by activating TrkBRs, profoundly affect NMDAR functioning. These findings may have very important implications for the neuroprotective potential of both BDNF and A2AR ligands in HD. © 2013 International Society for Neurochemistry. Source

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