ETD system

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Tesi etd-02212011-181504

Thesis type
Tesi di dottorato di ricerca
Pharmacological modulation of the adenosine system as a novel strategy for the treatment of inflammatory bowel diseases
Settore scientifico disciplinare
Corso di studi
tutor Prof. Da Settimo Passetti, Federico
tutor Prof. Blandizzi, Corrado
Parole chiave
  • rat
  • colitis
  • AMPK
  • adenosine deaminase
  • adenosine
  • A2A receptor
Data inizio appello
Riassunto analitico
Inflammatory bowel diseases (IBDs) are severe chronic pathologies characterized by a wide range of gastrointestinal and extra-digestive symptoms. The identification of novel drugs for treatment of IBDs represents an area of interest and active investigation, since currently available therapeutic options do not ensure adequate improvement/remission of the disease or induce severe adverse reactions in a significant proportion of patients. In this regard, increasing evidence suggests the adenosine system as an attractive target for the development of novel drugs against gut inflammation. Adenosine is thus released in the proximity of immune cells in tissues subjected to various forms of injurious stimuli, including ischemia and inflammation. In the majority of experimental systems, the immunosuppressive effect of adenosine results from the occupancy of its receptors expressed on various immune cell populations (lymphocytes, neutrophils, monocytes, macrophages, and dendritic cells). In addition, it has been showed that the removal of endogenous adenosine signaling exacerbates immune activation, and consequently aggravates tissue dysfunction following acute injurious stimuli.
However, beside the clinical benefits that adenosine may provide on bowel inflammation, the narrow therapeutic index and/or the lack of receptor selectivity of the endogenous nucleoside account for the occurrence of adverse effects on the cardiovascular (tachycardia and hypotension) as well as central nervous system. In this regard, efforts are focusing on the search of new drugs able to increase the endogenous concentration of adenosine at the site of inflammation, either indirectly or directly through the local stimulation of its receptors in order to avoid the systemic side effects associated with the actions of adenosine on the periphery.
In this study the expression of adenosine deaminase in the inflamed colon, the effects of adenosine deaminase inhibitors on established colitis and the recruitment of adenosine receptors by endogenous adenosine following adenosine deaminase blockade were investigated.
Moreover, acadesine (ACA), an activator of AMP-activated protein kinase (AMPK), has been shown to act in a site- and event-specific manner against inflammation, through the local increment of endogenous adenosine levels. The effects of this compound were tested on rats with colitis induced by DNBS. Finally, the effects of PSB0777, a novel and scarcely absorbable A2A receptor agonist, were examined in a rat model of experimental colitis induced by oxazolone.