The atp-gated P2X7 rceptor as a movel therapeutic target for amyotrophic lateral sclerosis

Resumen

Amyotrophic lateral sclerosis (ALS) is a devastating neurodegenerative disease characterized by the rapid and specific loss of upper and lower motor neurons. The aetiology of ALS is not completely understood, but different factors such as chronic neuroinflammation are known to play an important role in the development of the disease. The inflammatory process starts with the activation of microglia as a response to various stimuli such as high ATP concentration in the extracellular media liberated by damaged neurons. Extracellular ATP promotes microglial activation through the ionotropic purinergic receptor P2X7 (P2X7R). In this study we hypothesised that the ATP-gated P2X7R is playing a detrimental role in ALS progression by promoting microglial activation and neuroinflammation, and that blocking the receptor could be a new therapeutic strategy for ALS patients. To test our hypothesis, we treated SOD1G93A mice, model of ALS, with two different P2X7R antagonists: JNJ-47965567 and JNJ-55308942. Both compounds are blood-brain barrier-penetrant and have the ability to block P2X7R with very high potency and specificity. The difference between the two antagonists relies on their residence time in the central nervous system, which is significantly higher for JNJ-55308942. The chronic treatment with JNJ-47965567 delayed disease onset and improved disease progression in female mice but had no effect in males. On the contrary, a 30 days-treatment with JNJ-55308942 did not modify disease progression in SOD1G93A mice. The treatment neither improved motor neuron viability nor diminished neuroinflammatory markers in SOD1G93A male and female mice. The discrepancies encountered between our studies led us to the assessment of P2X7R expression and distribution along the disease with in vivo PET imaging. We showed that P2X7R expression was lower in spinal cord of SOD1G93A female mice compared to their WT counterparts at endpoint disease stages, while there were not differences between males. Moreover, P2X7R diminished in the spinal cord of female SOD1G93A mice between presymptomatic and endpoint disease stages. Similar results were obtained for the distribution of TSPO, another commonly used marker of neuroinflammation in PET studies. TSPO was reduced in brain and spinal cord of SOD1G93A male and female mice compared to WT mice and diminished between presymptomatic and endpoint disease stages. These results indicate that the reliability of P2X7R and TSPO as markers of neuroinflammation in ALS needs to be further evaluated. In summary, our results show the implication of P2X7R in ALS progression, at least in female mice. However, the use of receptor antagonists as new therapeutics for the disease needs to be further studied and optimised before being translated into the clinic.