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

NEUROBIOLOGY OF DISEASE

卷:159

Article

Anzilotti, Serenella¹  Valsecchi, Valeria²  Brancaccio, Paola²  Guida, Natascia¹  Laudati, Giusy²  Tedeschi, Valentina²  Petrozziello, Tiziana²  Frecentese, Francesco³  Magli, Elisa³  Hassler, Brenda²  Cuomo, Ornella²  Formisano, Luigi²  Secondo, Agnese²  Annunziato, Lucio¹  Pignataro, Giuseppe² 

[1] IRCCS SDN, Naples, Italy

[2] Univ Naples Federico II, Sch Med, Dept Neurosci Reprod & Dent Sci, Div Pharmacol, I-80131 Naples, Italy

[3] Univ Naples Federico II, Sch Med, Dept Pharm, I-80131 Naples, Italy

关键词: ALS;    Na+/Ca2+exchanger;    SOD1(G93A) mice;    Motor neurons;    Neurounina;    Misfolded SOD1;   

DOI  :  10.1016/j.nbd.2021.105480

来源: Elsevier

【 摘 要 】

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 SOD1(G93A) 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 SOD1(G93A) 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.