Excitotoxic motoneuron degeneration induced by glutamate receptor agonists and mitochondrial toxins in organotypic cultures of chick embryo spinal cord.
Glutamate receptor-mediated excitotoxicity and mitochondrial dysfunction appear to play an important role in motoneuron (MN) degeneration in amyotrophic lateral sclerosis (ALS). In the present study we used an organotypic slice culture of chick embryo spinal cord to explore the responsiveness of mature MNs to different excitotoxic stimuli and mitrochondrial inhibition. We found that, in this system, MNs are highly vulnerable to excitotoxins such as glutamate, N-methyl-D-aspartate (NMDA), and kainate (KA), and that the neuroprotective drug riluzole rescues MNs from KA-mediated excitotoxic death. MNs are also sensitive to chronic mitochondrial inhibition induced by malonate and 3-nitropropionic acid (3-NP) in a dose-dependent manner. MN degeneration induced by treatment with mitochondrial toxins displays structural changes similar to those seen following excitotoxicity and can be prevented by applying either the antiexcitotoxic drug 6-cyano-7-nitroquinoxaline-2,3-dione disodium (CNQX) or riluzole. Excitotoxicity results in an increased frequency of normal spontaneous Ca2+ oscillations in MNs, which is followed by a sustained deregulation of intracellular Ca2+. Tolerance to excitotoxic MN death resulting from chronic exposure to excitotoxins correlates with a reduced excitotoxin-induced increase in intracellular Ca2+ and increased thapsigargin-sensitive Ca2+ stores.
Brunet
Núria
N
Unitat de Neurobiologia Cel.lular, Departament de Medicina Experimental, Facultat de Medicina, Universitat de Lleida and Institut de Recerca Biomèdica de Lleida (IRBLLEIDA), 25008 Lleida, Catalonia, Spain.
Tarabal
Olga
O
Esquerda
Josep E
JE
Calderó
Jordi
J
D000818:Animals; D020013:Calcium Signaling / Q000187:drug effects; D002642:Chick Embryo; D004195:Disease Models, Animal; D004305:Dose-Response Relationship, Drug; D018690:Excitatory Amino Acid Agonists / Q000633:toxicity*; D018698:Glutamic Acid / Q000633:toxicity; D007608:Kainic Acid / Q000633:toxicity; D008314:Malonates / Q000633:toxicity; D008928:Mitochondria / Q000187:drug effects; D016472:Motor Neuron Disease / Q000473:pathology*; D009046:Motor Neurons / Q000187:drug effects / Q000473:pathology*; D016202:N-Methylaspartate / Q000633:toxicity; D009410:Nerve Degeneration / Q000139:chemically induced* / Q000473:pathology; D018696:Neuroprotective Agents / Q000494:pharmacology; D009498:Neurotoxins / Q000633:toxicity; D009574:Nitro Compounds / Q000633:toxicity; D009924:Organ Culture Techniques; D011422:Propionates / Q000633:toxicity; D019782:Riluzole / Q000494:pharmacology; D013116:Spinal Cord / Q000187:drug effects / Q000473:pathology*
D018690:Excitatory Amino Acid Agonists; D008314:Malonates; D018696:Neuroprotective Agents; D009498:Neurotoxins; D009574:Nitro Compounds; D011422:Propionates; D018698:Glutamic Acid; D016202:N-Methylaspartate; D019782:Riluzole; C030290:malonic acid; C015392:3-nitropropionic acid; D007608:Kainic Acid