• Journal of neurotrauma · Dec 2017

    PROCHLORPERAZINE INCREASES KCC2 FUNCTION AND REDUCES SPASTICITY AFTER SPINAL CORD INJURY.

    • Sylvie Liabeuf, Laetitia Stuhl-Gourmand, Florian Gackière, Renzo Mancuso, Irene Sanchez Brualla, Philippe Marino, Frédéric Brocard, and Laurent Vinay.
    • Team P3M, Institut de Neurosciences de la Timone, UMR7289, Aix Marseille Université and Centre National de la Recherche Scientifique (CNRS) , Marseille, France .
    • J. Neurotrauma. 2017 Dec 15; 34 (24): 339734063397-3406.

    AbstractIn 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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