Chlorion Pharma, Inc.

Existing members of the anti-epileptic drug (AED) class often fail to provide meaningful symptom relief to patients experiencing persistent pain, epilepsy and other neurological disorders, and can evoke substantial adverse events. In an effort to improve treatment options, much attention has turned to novel mechanisms that may represent points of therapeutic intervention. Among these mechanisms are the cation-chloride co-transporters (CCCs), the dysfunction of which has been linked to aberrant chloride homeostasis in neurons of the CNS, and resulting disorders including persistent pain and epilepsy. This review examines the literature linking CCCs to neurological disease, and discusses their considerable potential as the basis for novel therapeutic strategies.

A review.Existing members of the anti-epileptic drug (AED) class often fail to provide meaningful symptom relief to patients experiencing persistent pain, epilepsy and other neurol. disorders, and can evoke substantial adverse events.In an effort to improve treatment options, much attention has turned to novel mechanisms that may represent points of therapeutic intervention.Among these mechanisms are the cation-chloride co-transporters (CCCs), the dysfunction of which has been linked to aberrant chloride homeostasis in neurons of the CNS, and resulting disorders including persistent pain and epilepsy.This review examines the literature linking CCCs to neurol. disease, and discusses their considerable potential as the basis for novel therapeutic strategies.

Spinal disinhibition has been hypothesized to underlie pain hypersensitivity in neuropathic pain. Apparently contradictory mechanisms have been reported, raising questions on the best target to produce analgesia. Here, we show that nerve injury is associated with a reduction in the number of inhibitory synapses in the spinal dorsal horn. Paradoxically, this is accompanied by a BDNF-TrkB-mediated upregulation of synaptic GABAARs and by an α1-to-α2GABAAR subunit switch, providing a mechanistic rationale for the analgesic action of the α2,3GABAAR benzodiazepine-site ligand L838,417 after nerve injury. Yet, we demonstrate that impaired Cl- extrusion underlies the failure of L838,417 to induce analgesia at high doses due to a resulting collapse in Cl- gradient, dramatically limiting the benzodiazepine therapeutic window. In turn, enhancing KCC2 activity not only potentiated L838,417-induced analgesia, it rescued its analgesic potential at high doses, revealing a novel strategy for analgesia in pathological pain, by combined targeting of the appropriate GABAAR-subtypes and restoring Cl- homeostasis.