Chapter 7 - The amyotrophic lateral sclerosis SOD1G93A mouse model and applications: Studies into the P2X7 receptor

Abstract

Amyotrophic lateral sclerosis (ALS) is a progressively incapacitating, adult onset neurodegenerative disease. It is essentially a motor neuron disease with progressive paralysis and death 3–5years after diagnosis. The only available medications are riluzole and edaravone, but they do not affect disease progression. Several gene mutations found in ALS patients have been modeled in mice; the mutations of superoxide dismutase 1 (SOD1) were first identified and modeled in mice. The SOD1G93A mouse model best reproduced the ALS hallmarks, and hence, it has been the most widely used model to establish the proof of concept of new drugs with potential therapeutic actions in ALS. Several drug targets have been identified in drug development programs. Recently, increasing interest has been manifested for the purinergic receptor P2X7 (P2X7R) that is tightly implicated in neuroinflammation, a relevant pathway in disease pathogenesis. We describe in detail the generation of the SOD1G93A mice colony, the protocol for chronic drug and placebo administration to these mice, the experimental groups, the phenotypic variables being tested along the period of drug treatment to observe disease progression, and the tissue biomarkers evaluated at the end of the experimental protocol. Six reports using three different P2X7R blockers have been published so far. We comment on the protocol and the outcomes that have been quite variable. We next analyze the possible causes for this variability and suggest new protocols to establish the proof of concept of new compounds in the SOD1G93A mouse model of ALS.