Abstract
ABSTRACTNeuroinflammation 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.
Highlights
Amyotrophic lateral sclerosis (ALS) is an adult-onset and heterogeneous neurodegenerative disorder characterized by gradual loss of muscle function, spasticity and weakness, cramps and muscle wasting, speech and swallowing impairment, compromised respiration, progressive paralysis and death within 3-5 years after diagnosis (Calvo et al, 2014; Hardiman et al, 2017)
Treatment with JNJ-47965567 delays disease onset in female SOD1G93A mice To assess whether JNJ-47965567 treatment can delay disease onset in SOD1G93A mice, 24 males and 26 females were i.p. injected from pre-symptomatic stage (P60) until the humane endpoint was reached
In this study, we analyzed the effects that chronic administration of the selective, potent and brain-penetrant P2X7R antagonist JNJ47965567 has on the SOD1G93A mouse model of ALS
Summary
Amyotrophic lateral sclerosis (ALS) is an adult-onset and heterogeneous neurodegenerative disorder characterized by gradual loss of muscle function, spasticity and weakness, cramps and muscle wasting, speech and swallowing impairment, compromised respiration, progressive paralysis and death within 3-5 years after diagnosis (Calvo et al, 2014; Hardiman et al, 2017). Stimulation of P2X7R with ATP or 3′-O-(4Benzoyl)benzoyl ATP (BzATP) triggers a neurotoxic phenotype in astrocytes, inducing motor neuron death which is prevented by the P2X7R antagonist Brilliant Blue G (BBG) (Gandelman et al, 2010). These in vitro experiments point out to a role of the P2X7R receptor in ALS disease. Short stimulation of P2X7R causes the activation of autophagy and upregulation of anti-inflammatory markers in microglia of SOD1G93A mice (M2 microglia), whereas persistent stimulation impairs the autophagic flux that might correspond to the change to a pro-inflammatory phenotype (M1 microglia), suggesting a dual functional role of the receptor in the pathway (Fabbrizio et al, 2017). Receptor blockade with antagonists has been proposed as a new therapeutic approach to treat the disease
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