Chronic treatment with the glutamate receptor antagonist MK-801 alters periodontal disease susceptibility.
OBJECTIVE
Previous experiments in rats suggest that hypothalamic-pituitary-adrenal (HPA) axis over-responsiveness, which leads to increased secretion of immunoregulatory glucocorticoid hormones, increases periodontal disease susceptibility, whereas HPA axis under-responsiveness is associated with increased resistance to the disease. The present study was designed to investigate whether MK-801 (dizocilipine malate), an antagonist of the glutamate receptor N-methyl-D-aspartate (NMDA) in the brain, which has been found to play an important role in the regulation of the HPA axis, would influence the outcome of experimental ligature-induced periodontal disease in a rat model.


METHODS
Experimental periodontal disease was induced in periodontal disease susceptible and HPA axis high-responding Fischer 344 rats 2 days before chronic treatment with MK-801(1 mg/kg intraperitoneally). The periodontal breakdown was assessed after the ligatures had been in place for 23 days. Following intraperitoneal Gram-negative bacterial lipopolysaccharide stimulation (Escherichia coli, 250 microg/kg), concentrations of glucocorticoid receptors (GRs) in the hippocampus, and levels of the cytokine tumour necrosis factor alpha (TNF-alpha), as well as the HPA axis-derived hormone corticosterone, were measured in serum.


RESULTS
Compared to vehicle-treated controls, MK-801-treated rats had significantly increased periodontal tissue destruction (p < 0.01). MK-801-treated rats also showed significantly increased expression of GRs in the hippocampus (p < 0.05), elevated levels of corticosterone (p < 0.001) and reduced levels of TNF-alpha (p < 0.01) in serum 2 h after lipopolysaccharide stimulation.


CONCLUSIONS
These findings may implicate glutamate receptor-dependent mechanisms in periodontal disease, and support the concept of a bidirectional immune-brain-immune regulatory network with importance for periodontal health and disease.
Breivik
Torbjørn
T
Department of Periodontology, Faculty of Dentistry, University of Oslo, Oslo, Norway. tbreivik@odont.uio.no
Gundersen
Yngvar
Y
Osmundsen
Harald
H
Opstad
Per Kristian
PK
Fonnum
Frode
F
D000818:Animals; D003345:Corticosterone / Q000097:blood; D004198:Disease Susceptibility; D016291:Dizocilpine Maleate / Q000627:therapeutic use*; D004353:Drug Evaluation, Preclinical; D018691:Excitatory Amino Acid Antagonists / Q000627:therapeutic use*; D007030:Hypothalamo-Hypophyseal System / Q000187:drug effects; D008297:Male; D010510:Periodontal Diseases / Q000097:blood / Q000188:drug therapy* / Q000517:prevention & control; D010913:Pituitary-Adrenal System / Q000187:drug effects; D051381:Rats; D011916:Rats, Inbred F344; D011965:Receptors, Glucocorticoid / Q000097:blood; D020133:Reverse Transcriptase Polymerase Chain Reaction; D014409:Tumor Necrosis Factor-alpha / Q000032:analysis
D018691:Excitatory Amino Acid Antagonists; D011965:Receptors, Glucocorticoid; D014409:Tumor Necrosis Factor-alpha; D016291:Dizocilpine Maleate; D003345:Corticosterone