Trimetazidine, a promising drug for amyotrophic lateral sclerosis, modulates Ca2+ influx in spinal neurons

The metabolic modulator trimetazidine (TMZ) is an antianginal recently found to improve skeletal muscle performance in mice models of sarcopenia and Amyotrophic Lateral Sclerosis (ALS). The mechanism underlying the effect of TMZ on locomotor activity has been proposed to rely on its ability to enhance metabolic efficiency with a consequent improvement of myogenesis and of neuromuscular junction (NMJ) and muscle function. However, although promising and therefore under clinical trials, the mechanism of action of TMZ has not been clearly disclosed; here we hypothesized that it might involve the modulation of neuronal Ca ²⁺ flows. We studied the effect of TMZ on Ca ²⁺ dynamics in vivo , by using the transgenic zebrafish line Tg(neurod1 :GCaMP6f ) in which the neuronal expression of the Ca ²⁺ indicator GCaMP allows to visualize Ca ²⁺ dynamics in neurons of zebrafish larvae. By this elegant tool, we demonstrated, for the first time, that TMZ promotes Ca ²⁺ influx in zebrafish spinal neurons likely enhancing motor neuron firing, which correlates with enhanced motor performance by this drug. Even though elevated intracellular Ca ²⁺ levels have often been associated to neurotoxicity, it is unclear if the neuronal excitability features in ALS are compensatory or pathological. Therefore, TMZ might potentially contribute to counteract neurodegeneration by modulating neuronal Ca ²⁺ fluxes, and transiently and selectively enhancing motor neuron firing, as well as NMJ and locomotor function, without increasing the overall neuronal excitability. This further supports TMZ repurposing for the treatment of ALS and of other conditions characterized by NMJ impairment, such as aging.