title: Chronic mitochondrial inhibition induces selective motoneuron death in vitro: a new model for amyotrophic lateral sclerosis.
abstract: Evidence is increasing that mitochondrial dysfunction is involved in amyotrophic lateral sclerosis, a neurodegenerative disease characterized by selective motoneuron death. To study the role of mitochondrial dysfunction in the pathways leading to motoneuron death, we developed an in vitro model of chronic motoneuron toxicity, based on malonate-induced inhibition of complex II in the mitochondrial electron transport chain. Treatment with malonate resulted in a dose-dependent decrease in cellular ATP levels. We observed that motoneurons were significantly more vulnerable to mitochondrial inhibition than control neurons in the dorsal horn. We could reproduce this dose-dependent phenomenon with the complex IV inhibitor sodium azide. The free radical scavenger alpha-phenyl-N-tert-butylnitrone, the AMPA/kainate receptor blocker 6-cyano-7-nitroquinoxaline-2,3-dione, and riluzole, a drug that is currently used for the treatment of amyotrophic lateral sclerosis, were protective against malonate-induced motoneuron death. Furthermore, the caspase inhibitors N-benzyloxycarbonyl-Val-Ala-Asp-fluoromethyl ketone and z-Asp-Glu-Val-Asp-fluoromethyl ketone were both protective against malonate toxicity. Our model shows that chronic mitochondrial inhibition leads to selective motoneuron death, which is most likely apoptotic.
authors.affiliation: Laboratory for Experimental Neurology, University Medical Center Utrecht, The Netherlands.
authors.forename: E C
authors.initials: EC
authors.lastname: Kaal
authors.forename: A S
authors.initials: AS
authors.lastname: Vlug
authors.forename: M W
authors.initials: MW
authors.lastname: Versleijen
authors.forename: M
authors.initials: M
authors.lastname: Kuilman
authors.forename: E A
authors.initials: EA
authors.lastname: Joosten
authors.forename: P R
authors.initials: PR
authors.lastname: Bär
mesh_terms: D000255:Adenosine Triphosphate / Q000378:metabolism; D000690:Amyotrophic Lateral Sclerosis / Q000209:etiology; D000818:Animals; D002470:Cell Survival / Q000187:drug effects / Q000502:physiology; D002478:Cells, Cultured; D004195:Disease Models, Animal; D004791:Enzyme Inhibitors / Q000506:poisoning; D066298:In Vitro Techniques; D008314:Malonates / Q000506:poisoning; D008928:Mitochondria / Q000187:drug effects / Q000502:physiology*; D009046:Motor Neurons / Q000187:drug effects / Q000502:physiology*; D009474:Neurons / Q000187:drug effects / Q000502:physiology; D018696:Neuroprotective Agents / Q000494:pharmacology; D051381:Rats; D019810:Sodium Azide / Q000494:pharmacology; D013116:Spinal Cord / Q000166:cytology; D013997:Time Factors
chemical_list: D004791:Enzyme Inhibitors; D008314:Malonates; D018696:Neuroprotective Agents; D000255:Adenosine Triphosphate; D019810:Sodium Azide; C030290:malonic acid