Oxidant treatment causes a dose-dependent phenotype of apoptosis in cultured motoneurons.
Evidence is growing that reactive oxygen species (ROS), by-products of (normal) cellular aerobic metabolism, are involved in the pathogenesis of neurodegenerative diseases. One of these diseases is amyotrophic lateral sclerosis (ALS), in which motoneurons die, leading to paralysis and death. It remains uncertain whether ROS are the cause of (apoptotic) motoneuron death in ALS. To further understand the role of ROS in motoneuron death, we investigated the effects of ROS on isolated spinal rat motoneurons in culture. ROS were generated with a combination of iron(III) and ascorbate, or with hydrogen peroxide. Both toxic treatments resulted in a dose-dependent motoneuron death. Iron(III)/ascorbate toxicity was completely prevented with the hydrogen peroxide detoxifying enzyme catalase and partially prevented with the antioxidant vitamin E. SOD1, the enzyme that removes superoxide, did not protect against iron(III)/ascorbate toxicity. ROS treatment caused apoptotic motoneuron death: low doses of iron(III)/ ascorbate or hydrogen peroxide resulted in complete apoptosis ending in nuclear fragmentation, while high doses of ROS resulted in incomplete apoptosis (nuclear condensation). Thus, depending on the dose of ROS, the motoneurons complete the apoptotic pathway (low dose) or are stopped somewhere during this route (high dose).
Kaal
E C
EC
Department of Neurology, Utrecht University, The Netherlands.
Veldman
H
H
Sodaar
P
P
Joosten
E A
EA
Dop Bär
P R
PR
D000818:Animals; D000975:Antioxidants / Q000494:pharmacology*; D017209:Apoptosis; D001205:Ascorbic Acid / Q000633:toxicity; D004622:Embryo, Mammalian; D016166:Free Radical Scavengers / Q000633:toxicity; D009046:Motor Neurons / Q000187:drug effects* / Q000502:physiology; D051381:Rats; D017208:Rats, Wistar; D017382:Reactive Oxygen Species; D013127:Spinal Nerves / Q000187:drug effects* / Q000502:physiology
D000975:Antioxidants; D016166:Free Radical Scavengers; D017382:Reactive Oxygen Species; D001205:Ascorbic Acid