Adenosine A(2A) Receptor Antagonist Improves Cognitive Impairment by Inhibiting Neuroinflammation and Excitatory Neurotoxicity in Chronic Periodontitis Mice

The adenosine A(2A) receptor antagonist SCH58261 has been reported to have anti-inflammatory effects. However, its role in chronic periodontitis (CP)-induced cognitive impairment, which is associated with Porphyromonas gingivalis lipopolysaccharide (P. gingivalis LPS), remains unclear. This study investigated the role of SCH58261 in mice with CP-induced cognitive impairment. C57BL/6J mice were used to develop CP model by injecting 0.5 mg/kg P. gingivalis LPS into the palatal gingival sulcus of maxillary first molars twice a week for four weeks. The mice were divided into control, P. gingivalis LPS (P-LPS), P-LPS + SCH58261, and SCH58261 groups. The passive avoidance test (PAT) and Morris water maze (MWM) were used to assess cognition in mice. Furthermore, CD73/adenosine, neuroinflammation, glutamate transporters, and glutamate were assessed. Compared with the P-LPS group, 0.1 and 0.5 mg/kg SCH58261 increased latency and decreased error times in PAT, but increased platform crossing number in MWM. SCH58261 inhibited microglial activation, and decreased pro-inflammatory cytokines and glutamate levels, but increased GLT-1 and PSD95 expression in the hippocampus. This was the first report of SCH58261 treatment for CP-induced cognitive impairment, which may be related to its anti-inflammatory activities and anti-glutamate excitatory neurotoxicity. This suggests that SCH58261 can be used as a novel agent to treat cognitive impairment.