Ameliorative Effect of Cdk5 Inhibitor TP5 on Ligation-Induced Periodontitis

Objectives: Periodontitis is a chronic oral inflammatory disease that leads to alveolar bone loss and may exert an adverse impact on systemic health. Currently, the disease affects 64.7 million adult Americans. The severity of periodontitis can vary from patient to patient with over 30% of these adults having moderate to severe periodontitis. Although this disease is prevalent, there are little to no adequate treatments available that can efficiently alleviate the disease. Thus, our specific aim was to test the efficacy of Cdk5 inhibitor TP5 in a mouse model of ligation-induced periodontitis.
Methods: C57BL/6J female mice were randomly divided into control, ligation and ligation plus TP5 groups. TP5 was administered intraperitoneally 1 or 5 days after the ligation. During the surgery, tight ligature was placed around the left second molar. Development of the disease was monitored in time and evaluated by qPCR, Western blot, immunohistochemistry and in vitro kinase assay.
Results: qPCR analysis revealed significantly increased trigeminal and brainstem mRNA levels of p35 at 1 day, and at 5 days after the ligation that was accompanied by similar increase in immunostaining. This increase was also followed with a significant increase in expression of excitatory markers such as N- Methyl-D-Aspartate receptors and decrease in inhibitory markers such as GABA. In vitro kinase assay showed upregulated Cdk5 activity as early as 1 day after the ligation, with the maximum of its activity at day 5 after the surgery. Furthermore in vitro culture of trigeminal ganglia confirmed increased expression of p35, an activator of Cdk5 accompanied by elevated Cdk5 activity that was downregulated after TP5 treatment.
Conclusions: Since administration of TP5 effectively inhibited increased activity of Cdk5 and elevated levels of pro-inflammatory mediators after ligation-induced periodontitis, TP5 may have potential ameliorative effects on the experimentally induced periodontitis.