期刊
JOURNAL OF NEUROTRAUMA
卷 34, 期 24, 页码 3397-3406出版社
MARY ANN LIEBERT, INC
DOI: 10.1089/neu.2017.5152
关键词
KCC2; prochloperazine; spasticity; spinal cord injury
资金
- Agence National de la Recherche Scientifique [2010-BLAN-1407-01]
- Fondation pour la Recherche Medicale [DEQ20130326540]
- French Institut pour la Recherche sur la Moelle epiniere et l'Encephale
- SATT Sud-Est (Societes d'Acceleration du Transfert de Technologies)
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 (R) 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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