THE P2X7R ANTAGONIST BRILLIANT BLUE G (BBG) INDUCES THERAPEUTIC EFFECTS IN A PRECLINICAL MODEL OF HUNTINGTON’S DISEASE

Huntington’s disease (HD) is an autosomal dominant neurodegenerative disorder characterized by motor, cognitive and gastrointestinal complications. The purinergic receptor P27XR has been previously implicated in HD pathogenesis, however, its association with gut and brain health is poorly understood. This study aims to test the potential of P2X7R as a therapeutic target in HD, focusing on gut health complications as well as motor, cognitive and other behavioral alterations. Brilliant Blue G (BBG), a P2X7R antagonist, was administered from 6-16 weeks of age at 45.5 mg/kg of body weight intraperitoneally every 48 hours interval in R6/1 HD mice and their WT (wild-type) littermates. A battery of behavioral and gut function assessment tests was performed to evaluate the motor, cognitive and gastrointestinal function. BBG prevented body weight loss in males, improved motor clasping score in both sexes and rotarod performance (motor co-ordination) in females. Additionally, it modulated fear learning and memory in female WT mice, and long-term spatial memory in male WT mice. BBG also increased gut transit time and colon length in males and fecal consistency in females. Moreover, colon weight and length ratio was marginally improved by BBG treatment. This study demonstrated that P2X7R antagonism by BBG confers therapeutic values in HD related phenotypes. To further understand the results, we are exploring the inflammatory profiles of gut by fecal calprotectin analysis and characterizing P2X7R gene expression both in gut and brain samples.