The K+-Cl- cotransporter2 (KCC2) is responsible for maintaining low Cl- concentration in neurons of the central nervous system (CNS), which is essential for postsynaptic inhibition through GABAA and glycine receptors. Loss of activity of this transporter has emerged as a key mechanism underlying several neurological and psychiatric disorders, including epilepsy, motor spasticity, stress, anxiety, schizophrenia, morphine-induced hyperalgesia (MIH) and chronic pain[1]. CLP290, a CLP257 prodrug, is an orally available activator of the neuron-specific K+-Cl- cotransporter KCC2, displays potential for treatment of a wide range of neurological and psychiatric indications[1]. In vivo co-treatment with morphine and oral CLP290 prevented membrane KCC2 downregulation in superficial dorsal horn (SDH) neurons. Concurrently, co-treatment with CLP290 significantly mitigated MIH and acute administration of CLP257 in established MIH restored normal nociceptive behavior[2]. Treatment with CLP290 significantly lowered blood arginine-vasopressin (AVP) and glucose levels in STZ rats[3].
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