Intermittent hypoxia and stem cell implants preserve breathing capacity in a rodent model of amyotrophic lateral sclerosis.

Nichols NL, Gowing G, Satriotomo I, Nashold LJ, Dale EA, Suzuki M, Avalos P, Mulcrone PL, McHugh J, Svendsen CN, Mitchell GS
Am J Respir Crit Care Med. 2013 187 (5): 535-42

PMID: 23220913 · PMCID: PMC3733409 · DOI:10.1164/rccm.201206-1072OC

RATIONALE - Amyotrophic lateral sclerosis (ALS) is a devastating motor neuron disease causing paralysis and death from respiratory failure. Strategies to preserve and/or restore respiratory function are critical for successful treatment. Although breathing capacity is maintained until late in disease progression in rodent models of familial ALS (SOD1(G93A) rats and mice), reduced numbers of phrenic motor neurons and decreased phrenic nerve activity are observed. Decreased phrenic motor output suggests imminent respiratory failure.

OBJECTIVES - To preserve or restore phrenic nerve activity in SOD1(G93A) rats at disease end stage.

METHODS - SOD1(G93A) rats were injected with human neural progenitor cells (hNPCs) bracketing the phrenic motor nucleus before disease onset, or exposed to acute intermittent hypoxia (AIH) at disease end stage.

MEASUREMENTS AND MAIN RESULTS - The capacity to generate phrenic motor output in anesthetized rats at disease end stage was: (1) transiently restored by a single presentation of AIH; and (2) preserved ipsilateral to hNPC transplants made before disease onset. hNPC transplants improved ipsilateral phrenic motor neuron survival.

CONCLUSIONS - AIH-induced respiratory plasticity and stem cell therapy have complementary translational potential to treat breathing deficits in patients with ALS.

MeSH Terms (16)

Amyotrophic Lateral Sclerosis Animals Brain-Derived Neurotrophic Factor Glial Cell Line-Derived Neurotrophic Factor Hypoxia Inspiratory Capacity Male Motor Neurons Phrenic Nerve Rats Rats, Sprague-Dawley Rats, Transgenic Respiratory Insufficiency Respiratory Therapy Stem Cell Transplantation Superoxide Dismutase

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