Chronic administration of P2X7 receptor antagonist JNJ-47965567 delays disease onset and progression, and improves motor performance in ALS SOD1G93A female mice.

Abstract

Neuroinflammation is one of the main physiopathological mechanisms of amyotrophic lateral sclerosis (ALS), produced by the chronic activation of microglia in the CNS. This process is triggered by the persistent activation of the ATP-gated P2X7 receptor (P2RX7, hereafter referred to as P2X7R). The present study aimed to evaluate the effects of the chronic treatment with the P2X7R antagonist JNJ-47965567 in the development and progression of ALS in the SOD1G93A murine model. SOD1G93A mice were intraperitoneally (i.p.) injected with either 30 mg/kg of JNJ-47965567 or vehicle 4 times per week, from pre-onset age (here, postnatal day 60; P60) until study endpoint. 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, reduced body weight loss and improved motor coordination and phenotypic score in female SOD1G93A mice, although it did not increase lifespan. Interestingly, neither beneficial nor detrimental effects were observed in males in any of the analyzed parameters. Treatment did not affect motor neuron survival or ChAT, Iba-1 and P2X7R protein expression in endpoint individuals of mixed sexes. Overall, chronic administration of JNJ-47965567 for 4 times per week to SOD1G93A mice from pre-onset stage altered disease progression in female individuals while it did not have any effect in males. Our results suggest a partial, yet important, effect of P2X7R in the development and progression of ALS.

• Authors: Cristina Ruiz-Ruiz, Nuria García-Magro, Pilar Negredo, Carlos Avendaño, Anindya Bhattacharya, Marc Ceusters, Antonio G García
• Journal: Disease models & mechanisms (Dis Model Mech) Vol. 13 Issue 10 (10 30 2020) ISSN: 1754-8411 [Electronic] England
• PMID: 33174532 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)
• Copyright: © 2020. Published by The Company of Biologists Ltd.

Chemical References

• JNJ-47965567
• Piperazines
• Purinergic P2X Receptor Antagonists
• Receptors, Purinergic P2X7
• Niacinamide

Topics

• Amyotrophic Lateral Sclerosis (drug therapy, physiopathology)
• Animals
• Cell Survival (drug effects)
• Disease Progression
• Endpoint Determination
• Female
• Humans
• Mice, Inbred C57BL
• Mice, Transgenic
• Motor Activity (drug effects)
• Motor Neurons (drug effects, pathology)
• Niacinamide (administration & dosage, analogs & derivatives, chemistry, pharmacology, therapeutic use)
• Piperazines (administration & dosage, chemistry, pharmacology, therapeutic use)
• Purinergic P2X Receptor Antagonists (administration & dosage, chemistry, pharmacology, therapeutic use)
• Receptors, Purinergic P2X7 (metabolism)
• Rotarod Performance Test
• Survival Analysis
• Weight Loss (drug effects)