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

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.
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Contributor : Sylvie Liabeuf Connect in order to contact the contributor
Submitted on : Wednesday, August 30, 2017 - 11:32:53 AM
Last modification on : Wednesday, November 3, 2021 - 7:27:02 AM




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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