title: Neuroprotective Effect of the Novel Compound ITH33/IQM9.21 Against Oxidative Stress and Na(+) and Ca(2+) Overload in Motor Neuron-like NSC-34 Cells.
abstract: Alternatives for the treatment of amyotrophic lateral sclerosis (ALS) are scarce and controversial. The etiology of neuronal vulnerability in ALS is being studied in motor neuron-like NSC-34 cells to determine the underlying mechanisms leading to selective loss of motor neurons. One such mechanism is associated with mitochondrial oxidative stress, Ca(2+) overload, and low expression of Ca(2+)-buffering proteins. Therefore, in order to elicit neuronal death in ALS, NSC-34 cells were exposed to the following cytotoxic agents: (1) a mixture of oligomycin 10 µM and rotenone 30 µM (O/R), or (2) phenylarsine oxide 1 µM (PAO) (to mimic excess free radical production during mitochondrial dysfunction), and (3) veratridine 100 µM (VTD) (to induce overload of Na(+) and Ca(2+) and to alter distribution of Ca(2+)-buffering proteins [parvalbumin and calbindin-D28k]). Thus, the aim of the study was to test the novel neuroprotective compound ITH33/IQM9.21 (ITH33) and to compare it with riluzole on in vitro models of neurotoxicity. Cell viability measured with MTT showed that only ITH33 protected against O/R at 3 μM and PAO at 10 μM, but not riluzole. ITH33 and riluzole were neuroprotective against VTD, blocked the maximum peak and the number of [Ca(2+)]c oscillations per cell, and restored the effect on parvalbumin. However, only riluzole reversed the effect on calbindin-D28k levels. Therefore, ITH33 was neuroprotective against oxidative stress and Na(+)/Ca(2+) overload, both of which are involved in ALS.
authors.affiliation: Instituto Teófilo Hernando,Facultad de Medicina, Universidad Autónoma de Madrid, C/Arzobispo Morcillo, 4, 28029, 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, Universidad Autónoma de Madrid, C/Diego de León 62, 28006, Madrid, Spain.
authors.forename: Ana J
authors.initials: AJ
authors.lastname: Moreno-Ortega
authors.affiliation: Instituto Teófilo Hernando,Facultad de Medicina, Universidad Autónoma de Madrid, C/Arzobispo Morcillo, 4, 28029, Madrid, Spain.|Departamento de Farmacología y Terapéutica, Facultad de Medicina, Universidad Autónoma de Madrid, Madrid, Spain.
authors.forename: Lamiaa Mouhid
authors.initials: LM
authors.lastname: Al-Achbili
authors.affiliation: Instituto Teófilo Hernando,Facultad de Medicina, Universidad Autónoma de Madrid, C/Arzobispo Morcillo, 4, 28029, Madrid, Spain.|Servicio de Farmacología Clínica, Instituto de Investigación Sanitaria, Hospital Universitario de la Princesa, Universidad Autónoma de Madrid, C/Diego de León 62, 28006, Madrid, Spain.
authors.forename: Elba
authors.initials: E
authors.lastname: Alonso
authors.affiliation: Instituto Teófilo Hernando,Facultad de Medicina, Universidad Autónoma de Madrid, C/Arzobispo Morcillo, 4, 28029, Madrid, Spain.|Departamento de Farmacología y Terapéutica, Facultad de Medicina, Universidad Autónoma de Madrid, Madrid, Spain.
authors.forename: Cristóbal
authors.initials: C
authors.lastname: de Los Ríos
authors.affiliation: Instituto Teófilo Hernando,Facultad de Medicina, Universidad Autónoma de Madrid, C/Arzobispo Morcillo, 4, 28029, 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, Universidad Autónoma de Madrid, C/Diego de León 62, 28006, Madrid, Spain.
authors.forename: Antonio G
authors.initials: AG
authors.lastname: García
authors.affiliation: Instituto Teófilo Hernando,Facultad de Medicina, Universidad Autónoma de Madrid, C/Arzobispo Morcillo, 4, 28029, Madrid, Spain. ana.ruiz@uam.es.|Servicio de Farmacología Clínica, Instituto de Investigación Sanitaria, Hospital Universitario de la Princesa, Universidad Autónoma de Madrid, C/Diego de León 62, 28006, Madrid, Spain. ana.ruiz@uam.es.
authors.forename: Ana
authors.initials: A
authors.lastname: Ruiz-Nuño
authors.affiliation: Instituto Teófilo Hernando,Facultad de Medicina, Universidad Autónoma de Madrid, C/Arzobispo Morcillo, 4, 28029, Madrid, Spain. maria.cano@uam.es.|Departamento de Farmacología y Terapéutica, Facultad de Medicina, Universidad Autónoma de Madrid, Madrid, Spain. maria.cano@uam.es.|Servicio de Farmacología Clínica, Instituto de Investigación Sanitaria, Hospital Universitario de la Princesa, Universidad Autónoma de Madrid, C/Diego de León 62, 28006, Madrid, Spain. maria.cano@uam.es.
authors.forename: María F
authors.initials: MF
authors.lastname: Cano-Abad
mesh_terms: D000690:Amyotrophic Lateral Sclerosis / Q000188:drug therapy / Q000378:metabolism / Q000473:pathology; D000818:Animals; D001152:Arsenicals; D001549:Benzamides / Q000494:pharmacology*; D064092:Calbindin 1 / Q000378:metabolism; D002118:Calcium / Q000378:metabolism / Q000633:toxicity; D002470:Cell Survival / Q000187:drug effects / Q000502:physiology; D004353:Drug Evaluation, Preclinical; D005971:Glutamates / Q000494:pharmacology*; D051379:Mice; D008928:Mitochondria / Q000187:drug effects / Q000378:metabolism / Q000473:pathology; D009046:Motor Neurons / Q000187:drug effects* / Q000473:pathology; D018696:Neuroprotective Agents / Q000494:pharmacology*; D009840:Oligomycins / Q000633:toxicity; D018384:Oxidative Stress / Q000187:drug effects* / Q000502:physiology; D010320:Parvalbumins / Q000378:metabolism; D019782:Riluzole / Q000494:pharmacology; D012402:Rotenone / Q000633:toxicity; D012964:Sodium / Q000378:metabolism / Q000633:toxicity; D014701:Veratridine / Q000633:toxicity
chemical_list: D001152:Arsenicals; D001549:Benzamides; D064092:Calbindin 1; D005971:Glutamates; C000621358:ITH33-IQM9.21; D018696:Neuroprotective Agents; D009840:Oligomycins; D010320:Parvalbumins; D012402:Rotenone; C029341:oxophenylarsine; D014701:Veratridine; D019782:Riluzole; D012964:Sodium; D002118:Calcium
keywords: Amyotrophic lateral sclerosis; Ca2+; ITH33/IQ9.21; Mitochondria; NSC-34 cells; Veratridine