Furosemide unmasks inhibitory dysfunction following spinal cord injury in humans: Implication for spasticity

Abstract

Potassium chloride co-transporter KCC2 plays a key role in chloride homeostasis and inhibitory functions in mature neurons. Animal studies have demonstrated a down-regulation of KCC2 function following spinal cord transection. This reverses the inhibitory effect of gamma aminobutyric acid and glycine to an excitatory effect, resulting in reduced inhibition. We have previously demonstrated in healthy subjects that furosemide, a potent KCC2 antagonist, can be readily used to assess inhibitory synapse efficiency in humans. We have shown that furosemide reduces both presynaptic and postsynaptic inhibitions without altering monosynaptic excitatory transmission [1] thus suggesting that furosemide can be used as a probe to study the function of inhibitory synapses in humans. The aim of this presentation is to explore if in paraplegic patients a down regulation of KCC2 may contribute to the reflex hyperexcitability following spinal cord injury. In the present study, we used a similar experimental design to that developed in healthy subjects: the study of the effects of 40 mg of furosemide intake per os onto soleus H reflexes conditioned by inhibitory percutaneous stimulations were explored during 60 minutes following furosemide intake. Furosemide fails to modulate both pre- and postsynaptic inhibitions relayed to soleus spinal motoneurons in spinal cord injured patients. The reduced inhibitory effect of furosemide in spinal cord injury patients suggests a KCC2 dysfunction in human spinal neurons, resulting in a regression to immature inhibitory synapses, similarly to animal models. The reversal from inhibitory to excitatory synapses may be an important contributor to hyperreflexia in spinal cord injury and may lead to novel therapeutic strategies centred on chloride homeostasis.