Prochlorperazine Increases KCC2 Function and Reduces Spasticity after Spinal Cord Injury
Liabeuf, Sylvie (Aix Marseille Université and Centre National de la Recherche Scientifique (CNRS))
Stuhl-Gourmand, Laetitia (Aix Marseille Université and Centre National de la Recherche Scientifique (CNRS))
Gackière, Florian (Aix Marseille Université and Centre National de la Recherche Scientifique (CNRS))
Mancuso, Renzo (Aix Marseille Université and Centre National de la Recherche Scientifique (CNRS))
Sanchez-Brualla, Irene (Aix Marseille Université and Centre National de la Recherche Scientifique (CNRS))
Marino, Philippe (Aix Marseille Université and Centre National de la Recherche Scientifique (CNRS))
Brocard, Frédéric (Aix Marseille Université and Centre National de la Recherche Scientifique (CNRS))
Vinay, Laurent (Aix Marseille Université and Centre National de la Recherche Scientifique)

Data:	2017
Resum:	In mature neurons, low intracellular chloride level required for inhibition is maintained by the potassium-chloride cotransporter, KCC2. Impairment of Cl- extrusion after KCC2 dysfunction has been involved in many central nervous system 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 post-SCI. The compound alleviates spasticity in chronic adult SCI rats with an efficacy equivalent to the antispastic agent, baclofen, and rescues the SCI-induced downregulation of KCC2 in motoneurons below the lesion. These pre-clinical data support prochlorperazine for a new therapeutic indication in the treatment of spasticity post-SCI and neurological disorders involving a KCC2 dysfunction.
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Llengua:	Anglès
Document:	Article ; recerca ; Versió acceptada per publicar
Matèria:	KCC2 ; Prochloperazine ; Spasticity ; Spinal cord injury
Publicat a:	Journal of neurotrauma, Vol. 34 Núm. 24 (December 2017) , p. 3397-3406, ISSN 1557-9042

DOI: 10.1089/neu.2017.5152
PMID: 28747093

Postprint 32 p, 1.2 MB

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