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Prochlorperazine Increases KCC2 Function and Reduces Spasticity after Spinal Cord Injury.

Sylvie Liabeuf 1 Laetitia Stuhl-Gourmand 1 Florian Gackière 1 Renzo Mancuso 1 Irene Sanchez-Brualla 1 Phlippe Marino 1 Frederic Brocard 1 Laurent Vinay 1
1 INT - Institut de Neurosciences de la Timone
Abstract : In mature neurons, low intracellular chloride level required for inhibition is maintained by the potassium-chloride co-transporter KCC2. Impairment of Cl- extrusion following KCC2 dysfunction has been involved in many CNS disorders such as seizures, neuropathic pain or spasticity after a spinal cord injury (SCI). This makes KCC2 an appealing drug target for restoring Cl-homeostasis and inhibition in pathological conditions. In the present study, we screen the Prestwick Chemical Library® and identify conventional antipsychotics phenothiazine derivatives as enhancers of KCC2 activity. Among them, prochlorperazine hyperpolarizes the Cl- equilibrium potential in motoneurons of neonatal rats and restores the reciprocal inhibition after SCI. The compound alleviates spasticity in chronic adult SCI rats with an efficacy equivalent to the anti-spastic agent baclofen, and rescues the SCI-induced downregulation of KCC2 in motoneurons below the lesion. These preclinical data support prochlorperazine for a new therapeutic indication in the treatment of spasticity after SCI and neurological disorders involving a KCC2 dysfunction.
Keywords : spinal cord injury spasticity prochloperazine KCC2
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Journal articles
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https://hal-amu.archives-ouvertes.fr/hal-01579014
Contributor : Sylvie Liabeuf <>
Submitted on : Wednesday, August 30, 2017 - 11:32:53 AM
Last modification on : Thursday, December 19, 2019 - 12:18:02 PM

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UNIV-AMU | CNRS | INT

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Sylvie Liabeuf, Laetitia Stuhl-Gourmand, Florian Gackière, Renzo Mancuso, Irene Sanchez-Brualla, et al.. Prochlorperazine Increases KCC2 Function and Reduces Spasticity after Spinal Cord Injury.. Journal of Neurotrauma, Mary Ann Liebert, 2017, ⟨10.1089/neu.2017.5152⟩. ⟨hal-01579014⟩

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