Prochlorperazine Increases KCC2 Function and Reduces Spasticity after Spinal Cord Injury

Area of Science:

• Neuroscience
• Pharmacology

Background:

• Mature neurons rely on the potassium-chloride cotransporter (KCC2) to maintain low intracellular chloride levels essential for neuronal inhibition.
• Dysfunctional KCC2 impairs chloride extrusion, contributing to central nervous system disorders like seizures, neuropathic pain, and spasticity following spinal cord injury (SCI).

Purpose of the Study:

• To identify KCC2 activity enhancers for therapeutic applications.
• To investigate the potential of identified compounds in treating SCI-induced spasticity and related neurological disorders.

Main Methods:

• Screening of the Prestwick Chemical Library® to identify KCC2 enhancers.
• Testing identified compounds, specifically phenothiazine derivatives like prochlorperazine, in neonatal rat motoneurons and adult chronic SCI rat models.
• Assessing prochlorperazine's effects on chloride equilibrium potential, reciprocal inhibition, spasticity, and KCC2 expression post-SCI.

Main Results:

• Phenothiazine derivatives were identified as KCC2 activity enhancers.
• Prochlorperazine effectively hyperpolarized the chloride equilibrium potential in neonatal rat motoneurons.
• Prochlorperazine alleviated spasticity in chronic adult SCI rats, showing efficacy comparable to baclofen, and reversed SCI-induced KCC2 downregulation.

Conclusions:

• Prochlorperazine demonstrates significant therapeutic potential for treating spasticity post-SCI.
• The findings support prochlorperazine as a candidate for neurological disorders associated with KCC2 dysfunction.
• This study highlights KCC2 as a viable drug target for restoring neuronal inhibition and treating CNS disorders.