ITH33/IQM9.21 provides neuroprotection in a novel ALS model based on TDP-43 and Na+/Ca2+overload induced by VTD.
Therapeutic options for amyotrophic lateral sclerosis (ALS) are scarce and controversial. Although the aetiology of neuronal vulnerability is unknown, growing evidence supports a complex network in which multiple toxicity pathways, rather than a single mechanism, are involved in the pathogenesis of ALS. However, most cellular models only explain single pathogenic mechanisms. The present study proposes the two main cytotoxic mechanisms: (1) veratridine (VTD), which induced Na+and Ca2+overload; and (2) the TARD DNA-binding protein 43 (TDP-43) in NSC-34 cell line as an in vitro model of ALS. The study was carried out by MTT as an indirect measurement of cell viability and by flow cytometry to determine cell death stages. The impact of Ca2+overload combined with TDP-43 overexpression increased early apoptosis of NSC-34 cells. Furthermore, we found that ITH33/IQM9.21 (ITH33) exerted a neuroprotective effect in this model by reducing activation of the apoptotic pathway. Therefore, treatment with VTD in TDP-43 overexpressing NSC-34 cells is a good in vitro ALS model that makes it possible to test new neuroprotective compounds such as ITH33.
Instituto-Fundación Teófilo Hernando, Facultad de Medicina, Universidad Autónoma de Madrid, Madrid, Spain; Departamento de Farmacología y Terapéutica, Facultad de Medicina, Universidad Autónoma de Madrid, Madrid, Spain.
Lamia
L
Mouhid Al-Achbili
Instituto-Fundación Teófilo Hernando, Facultad de Medicina, Universidad Autónoma de Madrid, Madrid, Spain; Departamento de Farmacología y Terapéutica, Facultad de Medicina, Universidad Autónoma de Madrid, Madrid, Spain; Servicio de Farmacología Clínica, Instituto de Investigación Sanitaria, Hospital Universitario de la Princesa, Madrid, Universidad Autónoma de Madrid, Madrid, Spain.
Ana J
AJ
Moreno-Ortega
Servicio de Neurología, Hospital Clínico San Carlos, Universidad Complutense de Madrid, Madrid, Spain; Instituto de Neurociencias, Hospital Clínico San Carlos, Universidad Complutense de Madrid, Madrid, Spain.
Jorge
J
Matías-Guiu
Instituto-Fundación Teófilo Hernando, Facultad de Medicina, Universidad Autónoma de Madrid, Madrid, Spain; Departamento de Farmacología y Terapéutica, Facultad de Medicina, Universidad Autónoma de Madrid, Madrid, Spain; Servicio de Farmacología Clínica, Instituto de Investigación Sanitaria, Hospital Universitario de la Princesa, Madrid, Universidad Autónoma de Madrid, Madrid, Spain. Electronic address: maria.cano@uam.es.
María F
MF
Cano-Abad
Instituto-Fundación Teófilo Hernando, Facultad de Medicina, Universidad Autónoma de Madrid, Madrid, Spain; Servicio de Farmacología Clínica, Instituto de Investigación Sanitaria, Hospital Universitario de la Princesa, Madrid, Universidad Autónoma de Madrid, Madrid, Spain. Electronic address: anaruiznuno@yahoo.es.
Ana
A
Ruiz-Nuño
D000690:Amyotrophic Lateral Sclerosis / Q000188:drug therapy*; D000818:Animals; D017209:Apoptosis; D001549:Benzamides / Q000494:pharmacology*; D002118:Calcium / Q000378:metabolism*; D002413:Cations, Divalent; D002414:Cations, Monovalent; D002460:Cell Line; D002470:Cell Survival; D004268:DNA-Binding Proteins / Q000378:metabolism*; D005971:Glutamates / Q000494:pharmacology*; D006801:Humans; D051379:Mice; D009046:Motor Neurons / Q000187:drug effects / Q000378:metabolism / Q000473:pathology; D018696:Neuroprotective Agents / Q000494:pharmacology*; D012964:Sodium / Q000378:metabolism*; D014701:Veratridine / Q000633:toxicity*
D001549:Benzamides; D002413:Cations, Divalent; D002414:Cations, Monovalent; D004268:DNA-Binding Proteins; D005971:Glutamates; C000621358:ITH33-IQM9.21; D018696:Neuroprotective Agents; C000598624:TARDBP protein, human; D014701:Veratridine; D012964:Sodium; D002118:Calcium
Amyotrophic lateral sclerosis; Apoptosis; Ca(2+); NSC-34 cells; TDP-43; Veratridine