Anales de la RANM

85 A N A L E S R A N M R E V I S T A F U N D A D A E N 1 8 7 9 AMYOTROPHIC LATERAL SCLEROSIS IS NOT ONLY A MOTOR NEURON DISEASE Fernández A, et al. An RANM. 2022;139(01): 78 - 87 blue G (BBG) (47); (iii) stimulation of P2X7Rs from microglia of SOD1 G93A mice lead to stimula- tion of NADPH oxidase 2 (NOX2) and kinase ERK1/2, with ROS overproduction (48); (iv) short stimulation of P2X7Rs activated autophagy and increased anti-inflammatory markers in microglia of SOD1 G93A mice, the so-called M2 microglia; in contrast, prolonged stimulation impairs autophagy, indicating a change to inflammatory M1 microglia (49). All these findings have generated the hypoth- esis that the blockade of P2X7Rs could mitigate neuroinflammation and hence, slow down ALS progression. Recently, we tested this hypothesis with the chronic treatment with the potent P2X7R blocker JNJ-47965567, of SOD1 G93A mice. This treatment delayed disease onset, reduced body weight loss, improved motor coordination and phenotypic score only in female mice; treatment did not affect lifespan (50). From the literature and the experiments from our laboratories here reported it seems that the question on why MNs selectively die in ALS, remains unanswered. On the other hand, disease propagation from a CNS area through the CSF is a challenging hypothesis but with few data to support it. However, in spite that ALS is being considered as a MN disease, other cell types are also damaged. This is the case of CCs of the sympathoadrenal axis that in the SOD1 G93A mouse model of ALS, undergo several alterations in the kinetics of the exocytotic release of catecholamines that could be linked to distorted ultrastructural and functional changes of CC mitochondria; of relevance was the observa- tion that several of the changes in mitochondrial structure and function, as well as on exocytosis, were already present at pre-disease stages. During the last few years, the P2X7R blockade as a strategy to slow disease progression, has been explored in various laboratories, including ours; we found that the blocker of P2X7Rs JNJ-47965567, chronically administered to SOD1 G93A mice, delayed disease onset, although this was only observed in females. From a perspective point of view, it should be emphasized that unless disease pathogenesis is clarified, therapeutic targets to combat efficiently the fatal ALS will not be identified. One interesting approach relates to the fact several cell signaling pathways (calcium dyshomeostasis, mitochondrial damage, catecholamine release) seem to be linked to disease pathogenesis. Thus, we propose that drugs acting on three of those pathogenic pathways, if given a in combination to SOD1 G93A mice and/or other mouse models of ALS, should be more effective in delaying disease onset and/or in slowing down disease progres- sion once the symptoms have commenced. Some of those pathways to be targeted with drugs could rely on glutamate excitotoxicity, oxidative stress, mitochondrial bioenergetics, exocytosis and neuroinflammation, among several others. 1. Rowland LP. Riluzole for the treatment of amyo- trophic lateral sclerosis-too soon to tell? N Engl J Med. 1994; 330(9): 636-637. 2. Cruz MP. Edaravone (Radicava): a novel neuro- protective agent for the treatment of amyotro- phic lateral sclerosis. P T. 2018; 43(1): 25-28. 3. Mulder DW, Kurland LT, Offord KP, Beard CM. 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