Acute intermittent hypoxia induced phrenic long-term facilitation despite increased SOD1 expression in a rat model of ALS.
Amyotrophic lateral sclerosis (ALS) is a progressive and fatal neurodegenerative disease characterized by motor neuron death. Since most ALS patients succumb to ventilatory failure from loss of respiratory motor neurons, any effective ALS treatment must preserve and/or restore breathing capacity. In rats over-expressing mutated super-oxide dismutase-1 (SOD1(G93A)), the capacity to increase phrenic motor output is decreased at disease end-stage, suggesting imminent ventilatory failure. Acute intermittent hypoxia (AIH) induces phrenic long-term facilitation (pLTF), a form of spinal respiratory motor plasticity with potential to restore phrenic motor output in clinical disorders that compromise breathing. Since pLTF requires NADPH oxidase activity and reactive oxygen species (ROS) formation, it is blocked by NADPH oxidase inhibition and SOD mimetics in normal rats. Thus, we hypothesized that SOD1(G93A) (mutant; MT) rats do not express AIH-induced pLTF due to over-expression of active mutant superoxide dismutase-1. AIH-induced pLTF and hypoglossal (XII) LTF were assessed in young, pre-symptomatic and end-stage anesthetized MT rats and age-matched wild-type littermates. Contrary to predictions, pLTF and XII LTF were observed in MT rats at all ages; at end-stage, pLTF was actually enhanced. SOD1 levels were elevated in young and pre-symptomatic MT rats, yet superoxide accumulation in putative phrenic motor neurons (assessed with dihydroethidium) was unchanged; however, superoxide accumulation significantly decreased at end-stage. Thus, compensatory mechanisms appear to maintain ROS homoeostasis until late in disease progression, preserving AIH-induced respiratory plasticity. Following intrathecal injections of an NADPH oxidase inhibitor (apocynin; 600 μM; 12 μL), pLTF was abolished in pre-symptomatic, but not end-stage MT rats, demonstrating that pLTF is NADPH oxidase dependent in pre-symptomatic, but NADPH oxidase independent in end-stage MT rats. Mechanisms preserving/enhancing the capacity for pLTF in MT rats are not known.
Department of Comparative Biosciences, University of Wisconsin-Madison, Madison, WI 53706, USA. Electronic address: nicholsn@missouri.edu.
Nicole L
NL
Nichols
Department of Comparative Biosciences, University of Wisconsin-Madison, Madison, WI 53706, USA.
Irawan
I
Satriotomo
Department of Comparative Biosciences, University of Wisconsin-Madison, Madison, WI 53706, USA.
Daniel J
DJ
Harrigan
Department of Comparative Biosciences, University of Wisconsin-Madison, Madison, WI 53706, USA.
Gordon S
GS
Mitchell
D000098:Acetophenones / Q000494:pharmacology; D000367:Age Factors; D000690:Amyotrophic Lateral Sclerosis / Q000235:genetics / Q000378:metabolism* / Q000473:pathology*; D000818:Animals; D000894:Anti-Inflammatory Agents, Non-Steroidal / Q000494:pharmacology; D001784:Blood Gas Analysis; D001831:Body Temperature / Q000187:drug effects; D004195:Disease Models, Animal; D005260:Female; D000860:Hypoxia / Q000503:physiopathology*; D017774:Long-Term Potentiation / Q000235:genetics / Q000502:physiology*; D008297:Male; D009046:Motor Neurons / Q000473:pathology; D010791:Phrenic Nerve / Q000503:physiopathology*; D051381:Rats; D055647:Rats, Transgenic; D017382:Reactive Oxygen Species / Q000378:metabolism; D012131:Respiratory Insufficiency / Q000209:etiology; D013116:Spinal Cord / Q000378:metabolism / Q000473:pathology; D013482:Superoxide Dismutase / Q000235:genetics / Q000378:metabolism; D014628:Vagotomy
D000098:Acetophenones; D000894:Anti-Inflammatory Agents, Non-Steroidal; D017382:Reactive Oxygen Species; C056165:acetovanillone; C109415:SOD1 G93A protein; D013482:Superoxide Dismutase
Motor neuron disease; NADPH oxidase; Phrenic motor neurons; Reactive oxygen species; Respiratory plasticity; Spinal cord; Spinal plasticity; Superoxide