Anales RANF

P.48 P2X7 RECEPTOR ANTAGONISM WITH JNJ-47965567 REDUCED BODY WEIGHT LOSS AND DELAYED DISEASE ONSET IN FEMALE AMYOTROPHIC LATERAL SCLEROSIS SOD1 G93A MICE C. Ruiz-Ruiz 1,2 , Ceusters M., A.G. García 1,2,4 1 Instituto Teófilo Hernando, 2 Universidad Autónoma de Madrid, Spain. 3 Janssen Research & Development, Janssen Pharmaceutica NV, Belgium 4 Instituto de Investigación Sanitaria, Hospital Universitario de La Princesa, Madrid, Spain. Neuroinflammation is one of the main physiopathological mechanisms of amyotrophic lateral sclerosis (ALS), a rapidly progressive and devastating neurodegenerative disease caused by the specific loss of motor neurons. The chronic activation of microglia is mainly responsible for this inflammatory process in the central nervous system (CNS), which is triggered by the activation of the ATP-gated P2X7 receptor (P2X7R). The present study aimed to evaluate the effect of the chronic treatment with the P2X7R antagonist JNJ-47965567 in the development and progression of ALS in the SOD1 G93A murine model. SOD1 G93A mice, hemizygote for the mutated human SOD1 gene, were i.p. injected with either 30 mg/kg of JNJ-47965567 or vehicle four times a week, from pre-onset age (60- 80 days of age) until study end-point. Body weight, motor coordination, phenotypic score, disease onset and survival were measured throughout the study and compared between vehicle- and drug-injected groups. Treatment with the P2X7R antagonist JNJ-47965567 delayed disease onset in SOD1 G93A mice of combined sex (119±5 vs. 136±3 days), but had no effect on body weight loss, motor coordination, phenotypic score and survival. However, the treatment significantly reduced body weight loss and delayed disease onset in SOD1 G93A females (128±2 vs. 145±2 days), but not in males. In conclusion, our results suggest a partial, yet important effect of P2X7R in the development and progression of ALS. Moreover, they point out a possible gender effect of the treatment with P2X7R antagonists that could be of high relevance if translated into the clinic and raises new interesting questions about the physiopathology of ALS. This project has received funding from the European Union’s Horizon 2020 research and innovation programme under the Marie Sklodowska-Curie grant agreement No 766124.