Editors' ChoiceNeuromuscular Disease

A diet pill for critical illness weakness?

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Science Translational Medicine  13 Dec 2017:
Vol. 9, Issue 420, eaar4432
DOI: 10.1126/scitranslmed.aar4432


The serotoninergic drug Lorcaserin rescued motor neuron electrophysiological abnormalities in an animal model of critical illness–induced weakness.

After recovering from critical illness, patients are often debilitated from muscular weakness known as intensive care unit (ICU)–acquired weakness. The lack of knowledge of the mechanism responsible for this syndrome has hindered the development of targeted therapies. In previous work in rats, the authors have found that the traditional notions of neuropathy and myopathy do not adequately explain the profound weakness. Instead, a central nervous system deficiency in recruiting motor neurons is a major contributing factor for sepsis-related weakness in rodents. In this study, Nardelli et al. tested the hypothesis that a reduced excitability of motor neurons due to a defect in subthreshold currents contributes to ICU-acquired weakness.

Using computer simulations and in vivo electrophysiology, they found that a reduction in the ratio of the persistent sodium (PIC) to the low threshold Kv1-type potassium (K) currents in motor neurons could explain the motor neuron abnormalities observed in rodent with sepsis-induced weakness. Additionally, an increase in the PIC/K current ratio in motor neurons from septic rodents reversed the sepsis-induced defect.

Activation of the serotonin receptor has been shown previously to increase excitatory subthreshold PIC in motor neurons. Treatment with Lorcaserin, a U.S. Food and Drug Administration–approved serotoninergic medication for weight loss, restored repetitive firing in septic rats.

The study introduces a novel mechanism that might be associated with ICU-acquired weakness and a potential treatment candidate. Future studies investigating the contribution of this mechanism to clinical weakness in human disease and the potential clinical utility of Lorcaserin are required.

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