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

Serenella Anzilotti, Paola Brancaccio, Giuseppe Simeone, Valeria Valsecchi, Antonio Vinciguerra, Agnese Secondo, Tiziana Petrozziello, Natascia Guida, Rossana Sirabella, Ornella Cuomo, Pasquale Cepparulo, Andrè Herchuelz, Salvatore Amoroso, Gianfranco DI Renzo, Lucio Annunziato, Giuseppe Pignataro

Research output: Contribution to journalArticle

4 Citations (Scopus)

Abstract

Preconditioning (PC) is a phenomenon wherein a mild insult induces resistance to a later, severe injury. Although PC has been extensively studied in several neurological disorders, no studies have been performed in amyotrophic lateral sclerosis (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 to handle 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 of functional declines and severity of histological damage in male and female mice. Our findings demonstrate that a sub-toxic dose of L-BMAA works as preconditioning stimulus and is able to delay ALS onset and to prolong ALS mice survival. Interestingly, preconditioning prevented NCX3 downregulation in SOD1 G93A mice spinal cord, leading to an increased number of motor neurons associated to a reduced astrogliosis, and reduced the denervation of neuromuscular junctions observed in SOD1 G93A mice. These protective effects were mitigated in ncx3+/-mice. This study established for the first time an animal model of preconditioning in ALS and candidates NCX3 as a new therapeutic target.

Original languageEnglish
Article number206
JournalCell Death and Disease
Volume9
Issue number2
DOIs
Publication statusPublished - Feb 1 2018

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Poisons
Neurotoxins
Amyotrophic Lateral Sclerosis
Down-Regulation
Motor Neurons
Membrane Transport Proteins
Neuromuscular Junction
Neuroprotective Agents
Denervation
Nervous System Diseases
beta-N-methylamino-L-alanine
Spinal Cord
Homeostasis
Animal Models
Wounds and Injuries

ASJC Scopus subject areas

  • Immunology
  • Cellular and Molecular Neuroscience
  • Cell Biology
  • Cancer Research

Cite this

Preconditioning, induced by sub-toxic dose of the neurotoxin L-BMAA, delays ALS progression in mice and prevents Na+/Ca2+ exchanger 3 downregulation. / Anzilotti, Serenella; Brancaccio, Paola; Simeone, Giuseppe; Valsecchi, Valeria; Vinciguerra, Antonio; Secondo, Agnese; Petrozziello, Tiziana; Guida, Natascia; Sirabella, Rossana; Cuomo, Ornella; Cepparulo, Pasquale; Herchuelz, Andrè; Amoroso, Salvatore; DI Renzo, Gianfranco; Annunziato, Lucio; Pignataro, Giuseppe.

In: Cell Death and Disease, Vol. 9, No. 2, 206, 01.02.2018.

Research output: Contribution to journalArticle

Anzilotti, S, Brancaccio, P, Simeone, G, Valsecchi, V, Vinciguerra, A, Secondo, A, Petrozziello, T, Guida, N, Sirabella, R, Cuomo, O, Cepparulo, P, Herchuelz, A, Amoroso, S, DI Renzo, G, Annunziato, L & Pignataro, G 2018, 'Preconditioning, induced by sub-toxic dose of the neurotoxin L-BMAA, delays ALS progression in mice and prevents Na+/Ca2+ exchanger 3 downregulation', Cell Death and Disease, vol. 9, no. 2, 206. https://doi.org/10.1038/s41419-017-0227-9
Anzilotti, Serenella ; Brancaccio, Paola ; Simeone, Giuseppe ; Valsecchi, Valeria ; Vinciguerra, Antonio ; Secondo, Agnese ; Petrozziello, Tiziana ; Guida, Natascia ; Sirabella, Rossana ; Cuomo, Ornella ; Cepparulo, Pasquale ; Herchuelz, Andrè ; Amoroso, Salvatore ; DI Renzo, Gianfranco ; Annunziato, Lucio ; Pignataro, Giuseppe. / Preconditioning, induced by sub-toxic dose of the neurotoxin L-BMAA, delays ALS progression in mice and prevents Na+/Ca2+ exchanger 3 downregulation. In: Cell Death and Disease. 2018 ; Vol. 9, No. 2.
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