Simvastatin therapy in cyclosporine A-induced alveolar bone loss in rats.
OBJECTIVE
Cyclosporine A treatment is important in the therapy of a number of medical conditions; however, alveolar bone loss is an important negative side-effect of this drug. As such, we evaluated whether concomitant administration of simvastatin would minimize cyclosporine A-associated alveolar bone loss in rats subjected, or not, to experimental periodontal disease.


METHODS
Groups of 10 rats each were treated with cyclosporine A (10 mg/kg/day), simvastatin (20 mg/kg/day), cyclosporine A and simvastatin concurrently (cyclosporine A/simvastatin) or vehicle for 30 days. Four other groups of 10 rats each received a cotton ligature around the lower first molar and were treated similarly with cyclosporine A, simvastatin, cyclosporine A/simvastatin or vehicle. Calcium (Ca(2+)), phosphorus and alkaline phosphatase levels were evaluated in serum. Expression levels of interleukin-1beta, prostaglandin E(2) and inducible nitric oxide synthase were evaluated in the gingivomucosal tissues. Bone volume and numbers of osteoblasts and osteoclasts were also analyzed.


RESULTS
Treatment with cyclosporine A in rats, with or without ligature, was associated with bone loss, represented by a lower bone volume and an increase in the number of osteoclasts. Treatment with cyclosporine A was associated with bone resorption, whereas simvastatin treatment improved cyclosporine A-associated alveolar bone loss in all parameters studied. In addition, simvastatin, in the presence of inflammation, can act as an anti-inflammatory agent.


CONCLUSIONS
This study shows that simvastatin therapy leads to a reversal of the cyclosporine A-induced bone loss, which may be mediated by downregulation of interleukin-1beta and prostaglandin E(2) production.
Nassar
P O
PO
Department of Periodontology, Dental School of Araraquara, State University of São Paulo (UNESP), Araraquara, SP, Brazil.
Nassar
C A
CA
Guimarães
M R
MR
Aquino
S G
SG
Andia
D C
DC
Muscara
M N
MN
Spolidorio
D M P
DM
Rossa
C
C
Spolidorio
L C
LC
D000469:Alkaline Phosphatase / Q000097:blood; D016301:Alveolar Bone Loss / Q000139:chemically induced* / Q000503:physiopathology; D000539:Alveolar Process / Q000187:drug effects / Q000473:pathology; D000818:Animals; D000893:Anti-Inflammatory Agents / Q000494:pharmacology; D015519:Bone Density / Q000187:drug effects; D002118:Calcium / Q000097:blood; D002452:Cell Count; D016572:Cyclosporine / Q000009:adverse effects*; D015232:Dinoprostone / Q000032:analysis; D015536:Down-Regulation; D005881:Gingiva / Q000187:drug effects / Q000473:pathology; D019161:Hydroxymethylglutaryl-CoA Reductase Inhibitors / Q000494:pharmacology*; D007166:Immunosuppressive Agents / Q000009:adverse effects*; D053583:Interleukin-1beta / Q000032:analysis; D008297:Male; D009061:Mouth Mucosa / Q000187:drug effects / Q000473:pathology; D052247:Nitric Oxide Synthase Type II / Q000032:analysis; D010006:Osteoblasts / Q000187:drug effects / Q000473:pathology; D010010:Osteoclasts / Q000187:drug effects / Q000473:pathology; D010758:Phosphorus / Q000097:blood; D011897:Random Allocation; D051381:Rats; D017207:Rats, Sprague-Dawley; D019821:Simvastatin / Q000494:pharmacology*
D000893:Anti-Inflammatory Agents; D019161:Hydroxymethylglutaryl-CoA Reductase Inhibitors; D007166:Immunosuppressive Agents; D053583:Interleukin-1beta; D010758:Phosphorus; D016572:Cyclosporine; D019821:Simvastatin; D052247:Nitric Oxide Synthase Type II; C496318:Nos2 protein, rat; D000469:Alkaline Phosphatase; D015232:Dinoprostone; D002118:Calcium