Targeting chloride for neurological disease

The activity of the potassium-chloride membrane protein, KCC2, is reduced in many neurological and psychiatric disorders in humans, such as chronic pain, anxiety, and epilepsy. A study published online this week in Nature Medicine reports a newly-developed small molecule that can activate KCC2 and reduce chronic pain in rats. The findings suggest a promising therapeutic approach to treat pain and other conditions in which the KCC2 activity is impaired.

KCC2 is a transmembrane pump that keeps chloride ion concentrations low within neurons, which enables inhibition of nerve impulses. Therefore, Yves De Koninck and colleagues reason that a drug that could activate KCC2 may prove promising in the clinic to restore inhibitory signals and treat neurological diseases. The team screened a small molecule compound library and identify a drug, which they call CLP257. They go on to show that this drug can enhance KCC2 expression and its activity and reduce pain in rats with nerve injury.

They note that a related compound with better pharmacological profiles than CLP257 was as effective in reducing pain in rats as an existing pain treatment called pregabalin, but it lacked the undesirable motor side effects that are often seen with that drug.