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Removing Salt from the Wound

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Science Translational Medicine  20 Nov 2013:
Vol. 5, Issue 212, pp. 212ec192
DOI: 10.1126/scitranslmed.3007983

Looks can be deceiving. Take, for example, the nervous system disorders epilepsy, motor spasticity, and chronic neuropathic pain; their symptoms differ dramatically, but the underlying mechanisms of all three may converge on an underfunctioning K+ Cl cotransporter (KCC2), suggesting that KCC2 could be a therapeutic target for these disorders. Now, Gagnon et al. report on a high-throughput screen for drugs that enhance the activity of KCC2.

Binding of the neurotransmitters γ-aminobutyric acid (GABA) and glycine to GABAA and glycine receptors, respectively, on postsynaptic neurons typically results in a flux of chloride ions (Cl) into the cell, membrane hyperpolarization, and neuronal inhibition. The Clinflux is driven by a concentration gradient across the cell membrane, with lower amounts of Cl being present inside versus outside of the cell. KCC2 maintains the gradient by pumping Cl out of the cell. When KCC2 activity is lower than normal, central nervous system disorders arise.

The authors engineered a cell culture assay for high-throughput fluorescent quantitation of Cl efflux via KCC2. After assaying a library of 92,500 compounds, the authors identified 78 positive hits that reduced intracellular Clconcentrations. One of the hits, CL-058, was selected on the basis of its lack of cytotoxic effects, ease of synthesis, and drug-like properties. More than 300 related molecules were then synthesized, and one of these analogs, CLP257, selectively restored impaired Cl transport in neurons (in adult rat spinal cord slices) with reduced KCC2 activity. Furthermore, the authors demonstrated that the Cl extrusion effect by CLP257 alleviated hypersensitivity to neuropathic pain in an animal model. Compared with pregabalin, which is commonly used to treat neuropathic pain in humans, CLP257 was not only equally effective in reducing the pain in the animal model, it also displayed fewer motor side effects.

The new findings are encouraging for three main reasons. First, oral administration of a small molecule was able to enhance KCC2 activity; second, KCC2 can serve as a therapeutic target for effective reduction of neuropathic pain with minor motor side effects; and third, exploration of KCC2 as a treatable target for other neurological disorders may now be feasible.

M. Gagnon et al., Chloride extrusion enhancers as novel therapeutics for neurological diseases. Nat. Med. 19, 1524–1528 (2013). [Full Text]

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