Preconditioning, induced by sub-toxic dose of the neurotoxin L-BMAA, delays ALS progression in mice and prevents Na+/Ca2+exchanger 3 downregulation

Preconditioning (PC) is a phenomenon wherein a mild insult induces resistance to a later, severe injury. Although PChas been extensively studied in several neurological disorders, no studies have been performed in amyotrophic lateralsclerosis (ALS). Here we hypothesize that a sub-toxic acute exposure to the cycad neurotoxin beta-methylamino-L-alanine (L-BMAA) is able to delay ALS progression in SOD1 G93A mice and that NCX3, a membrane transporter able tohandle the deregulation of ionic homeostasis occurring during ALS, takes part to this neuroprotective effect.Preconditioning effect was examined on disease onset and duration, motor functions, and motor neurons in terms offunctional declines and severity of histological damage in male and female mice. Ourfindings demonstrate that a sub-toxic dose of L-BMAA works as preconditioning stimulus and is able to delay ALS onset and to prolong ALS micesurvival. Interestingly, preconditioning prevented NCX3 downregulation in SOD1 G93A mice spinal cord, leading to anincreased number of motor neurons associated to a reduced astrogliosis, and reduced the denervation ofneuromuscular junctions observed in SOD1 G93A mice. These protective effects were mitigated in ncx3+/−mice. Thisstudy established for thefirst time an animal model of preconditioning in ALS and candidates NCX3 as a newtherapeutic target.IntroductionPreconditioning (PC) is a phenomenon wherein a mildinsult induces a cellular and tissue resistance to a latersevere injury1.Over the years numerous stimuli were described aspossible PC inductors. Among these, hypoxic stimuli,bacterial toxins such as LPS, small seizures, volatileanesthetics, hyperthermia, and hypothermia1. Protectiontriggered