PURINE NUCLEOSIDE PHOSPHORYLASE INHIBITION BLOCKS BONE RESORPTION IN A RAT MODEL OF INDUCED PERIODONTAL DISEASE

Candida Deves (INCT-TB); Maria Martha Campos (INCT-TB); Luiz Augusto Basso (INCT-TB); Diógenes Santiago Santos (INCT-TB); Eraldo Luiz Batista Junior (INCT-TB)

Purine Nucleoside Phosphorylase (PNP) is an important component of the purine salvage pathway that catalyzes the reversible phosphorolysis of purine nucleosides. T-CD4 lymphocytes, which play a key role in the pathogenesis of periodontal disease, heavily rely on PNP to avoid intracellular accumulation of dGTP and inhibition of ribonucleotide reductase, which, in turn, enables proliferation. Inactivation of PNP produces an accumulation of dGTP that causes an imbalance in the dNTP pools and DNA fragmentation leading to apoptosis of T-cells. PNP has recently become a potential target of drug development since analogs of the PNP transition state have been synthesized and tested with promising results. The present investigation sought to determine whether the pharmacological blockage of PNP activity can arrest pathogen-mediated periodontal bone loss in a ligature-induced animal model. To assess the effects of a pharmacological inhibitor of PNP (BCX-1777) in a model of chronic periodontal disease, Wistar male rats (n=4) received BCX-1777 intraperitoneally and had silk ligatures tied around the right and left first molars. Additional doses were administered every two days until sacrifice (7th day). Control animals received the same volume of sterile saline. A third group that comprised animals that did not receive any treatment was used as a reference for the normal position of the bone and histomorphometric parameters were recorded (non-challenged control). The mandibles were processed for direct quantification of alveolar bone loss, histomorphometric analysis and osteoclast counting. A marked loss of alveolar bone in the group treated with saline only was observed (60%). Animals treated with BCX-1777, on the other hand, presented abrogation of the bone loss induced by the ligatures, with no significant differences relative to non-challenged animals. The analysis also depicted clear effects over osteoclast numbers and inflammatory/immune cell subpopulations present in the periodontal tissues.