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.

Prolonged NCX activation prevents SOD1 accumulation, reduces neuroinflammation, ameliorates motor behavior and prolongs survival in a ALS mouse model / Anzilotti, S.; Valsecchi, V.; Brancaccio, P.; Guida, N.; Laudati, G.; Tedeschi, V.; Petrozziello, T.; Frecentese, F.; Magli, E.; Hassler, B.; Cuomo, O.; Formisano, L.; Secondo, A.; Annunziato, L.; Pignataro, G.. - In: NEUROBIOLOGY OF DISEASE. - ISSN 0969-9961. - 159:(2021), p. 105480. [10.1016/j.nbd.2021.105480]

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

Anzilotti S.
Primo
;
Valsecchi V.
Secondo
;
Brancaccio P.;Guida N.;Laudati G.;Tedeschi V.;Petrozziello T.;Frecentese F.;Magli E.;Cuomo O.;Formisano L.;Secondo A.;Annunziato L.
Penultimo
;
Pignataro G.
Ultimo
2021

Abstract

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.
2021
Prolonged NCX activation prevents SOD1 accumulation, reduces neuroinflammation, ameliorates motor behavior and prolongs survival in a ALS mouse model / Anzilotti, S.; Valsecchi, V.; Brancaccio, P.; Guida, N.; Laudati, G.; Tedeschi, V.; Petrozziello, T.; Frecentese, F.; Magli, E.; Hassler, B.; Cuomo, O.; Formisano, L.; Secondo, A.; Annunziato, L.; Pignataro, G.. - In: NEUROBIOLOGY OF DISEASE. - ISSN 0969-9961. - 159:(2021), p. 105480. [10.1016/j.nbd.2021.105480]
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Utilizza questo identificativo per citare o creare un link a questo documento: https://hdl.handle.net/11588/858122
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