Prolonged NCX activation prevents SOD1 accumulation, reduces neuroinflammation, ameliorates motor behavior and prolongs survival in a ALS mouse model

• Published in: Neurobiology of disease 2021-11, Vol.159, p.105480-105480, Article 105480
• Main Authors: Anzilotti, Serenella, Valsecchi, Valeria, Brancaccio, Paola, Guida, Natascia, Laudati, Giusy, Tedeschi, Valentina, Petrozziello, Tiziana, Frecentese, Francesco, Magli, Elisa, Hassler, Brenda, Cuomo, Ornella, Formisano, Luigi, Secondo, Agnese, Annunziato, Lucio, Pignataro, Giuseppe
• Format: Article
• Language: English
• Subjects: ALS; Amyotrophic Lateral Sclerosis - genetics; Amyotrophic Lateral Sclerosis - metabolism; Amyotrophic Lateral Sclerosis - pathology; Amyotrophic Lateral Sclerosis - physiopathology; Animals; Astrocytes - drug effects; Astrocytes - metabolism; Astrocytes - pathology; Benzodiazepinones - pharmacology; Humans; Mice; Mice, Transgenic; Microglia - drug effects; Microglia - metabolism; Microglia - pathology; Misfolded SOD1; Motor neurons; Motor Neurons - drug effects; Motor Neurons - metabolism; Motor Neurons - pathology; Na+/Ca2+ exchanger; Neuroinflammatory Diseases - metabolism; Neuroinflammatory Diseases - pathology; Neuroinflammatory Diseases - physiopathology; Neuroprotective Agents - pharmacology; Neurounina; Pyrrolidines - pharmacology; SOD1G93A mice; Sodium-Calcium Exchanger - agonists; Spinal Cord - drug effects; Spinal Cord - metabolism; Spinal Cord - pathology; Superoxide Dismutase - genetics; Survival Rate
• ISSN: 0969-9961; 1095-953X
• DOI: 10.1016/j.nbd.2021.105480

Imbalance in cellular ionic homeostasis is a hallmark of several neurodegenerative diseases including Amyotrophic Lateral Sclerosis (ALS). Sodium-calcium exchanger (NCX) is a membrane antiporter that, operating in a bidirectional way, couples the exchange of Ca2+ and Na + ions in neurons and glial cells, thus controlling the intracellular homeostasis of these ions. Among the three NCX genes, NCX1 and NCX2 are widely expressed within the CNS, while NCX3 is present only in skeletal muscles and at lower levels of expression in selected brain regions. ALS mice showed a reduction in the expression and activity of NCX1 and NCX2 consistent with disease progression, therefore we aimed to investigate their role in ALS pathophysiology. Notably, we demonstrated that the pharmacological activation of NCX1 and NCX2 by the prolonged treatment of SOD1G93A mice with the newly synthesized compound neurounina: (1) prevented the reduction in NCX activity observed in spinal cord; (2) preserved motor neurons survival in the ventral spinal horn of SOD1G93A mice; (3) prevented the spinal cord accumulation of misfolded SOD1; (4) reduced astroglia and microglia activation and spared the resident microglia cells in the spinal cord; (5) improved the lifespan and mitigated motor symptoms of ALS mice. The present study highlights the significant role of NCX1 and NCX2 in the pathophysiology of this neurodegenerative disorder and paves the way for the design of a new pharmacological approach for ALS. •The pharmacological activation of NCX1 and NCX2 prevented the reduction in NCX activity observed in spinal cord of ALS mice.•NCX activation preserved motor neurons survival in the ventral spinal horn of SOD1G93A mice.•NCX activation prevented the spinal cord accumulation of misfolded SOD1.•NCX activation reduced astroglia and microglia activation and spared the resident microglia cells in the spinal cord.•NCX activation improved the lifespan and mitigated motor symptoms of ALS mice.