Prochlorperazine Increases KCC2 Function and Reduces Spasticity after Spinal Cord Injury. - Aix-Marseille Université Accéder directement au contenu
Article Dans Une Revue Journal of Neurotrauma Année : 2017

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

Résumé

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.

Domaines

Neurobiologie
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Dates et versions

hal-01579014 , version 1 (30-08-2017)

Identifiants

Citer

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, 2017, ⟨10.1089/neu.2017.5152⟩. ⟨hal-01579014⟩
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