Increasing motor neuron excitability to treat weakness in sepsis

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The syndrome of profound weakness following critical illness is termed intensive care unit (ICU) acquired weakness. ICU acquired weakness is a common problem and greatly complicates patient recovery.1 Lack of understanding of mechanisms underlying weakness following critical illness has meant the only reliable therapy available for patients is supportive care. Nonspecific treatments are applied in hopes of promoting long‐term recovery of neuromuscular function, including tight glycemic control4 and physical therapy during critical illness,5 but these therapies have little effect in patients with severe weakness. To develop targeted therapy for ICU acquired weakness, it is necessary to develop an understanding of the cause(s) of weakness.
Until recently, ICU acquired weakness was thought to be due entirely to myopathy and neuropathy.1 However, we identified patients in the early stages of recovery from critical illness in whom neither myopathy nor neuropathy appeared sufficient to account for their severe weakness. These patients had poor recruitment of motor units, despite being alert and cooperative such that it appeared that a defect within the central nervous system was an important contributor to their ICU acquired weakness.6 To explore potential mechanisms underlying reduced motor unit recruitment in patients, we recorded from rat spinal cord in vivo in septic rats and identified a defect in motor neuron excitability.6 The defect in motor neuron excitability was the primary contributor to weakness in rats, as there was little evidence of either myopathy or neuropathy.7 Taken together, our studies in rats and patients raise the possibility that reduced excitability of motor neurons is a significant contributor to ICU acquired weakness.
To develop therapy for ICU acquired weakness, it is necessary to understand the mechanism underlying poor repetitive firing of motor neurons. Passive membrane properties and properties of single action potentials of rat motor neurons were normal, suggesting that the defect in excitability was specific to the currents that generate repetitive firing.6 Persistent inward currents (PICs) have been identified as playing a central role in generation of repetitive firing of neurons.8 PIC in motor neurons is composed of both Na and Ca components, and the NaPIC in particular functions to bring motor neurons to threshold to promote repetitive firing.9 Opposing PICs are subthreshold K currents (Ksthr) that reduce repetitive firing.15
We hypothesized that the defect in motor neuron firing induced by sepsis was due to a defect in the subthreshold currents that govern the approach to action potential threshold. Computer modeling and manipulations of currents in rat motor neurons in vivo supported our hypothesis that a defect in subthreshold currents was an important contributor to weakness. Using identification of this mechanism to guide development of therapy, we identified a drug, U.S. Food and Drug Administration (FDA)‐approved for weight loss, that greatly improved repetitive firing of motor neurons in septic rats. Our findings suggest a surprising approach to development of therapy for ICU acquired weakness.

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