Kelley et al proposed a hypothesis for an inefficient GABA signalling system that resulted in unchecked pro-inflammatory cytokine production via the p38 MAP kinase pathway. p38 is a kinase target that regulates the production of inflammatory cytokines TNF, IL-1, IL-6 and PGE2.
TNF, IL-1 and IL-6 are well-validated cytokines for controlling inflammation in rheumatoid arthritis (RA). PGE2 is the important mediator for inflammatory pain. But most of the p38 projects failed to deliver drugs due to CNS toxicity, Is this CNS side effects linked to GABA?
The research team led by Ulrich Zeilhofer used genetically altered mice in experiments to target the GABA receptors that control spinal pain relay, they showed that the non-sedative benzodiazepine ligand L- 838417 (a GABA receptor ligand) is highly effective against inflammatory and neuoapathic pain.
Clomethiazole edisilate is a drug that act on GABA receptor, which inhibits the p38 MAPK too. The small molecule doesn’t have the structural features of the other p38 inhibitors have, seems to provide the support for this hypothesis. The task is to find which subtype of GABA responsible for the chronic pain.
However no direct link has been reported between GABA and p38 MAPK.
The role of GABA in the development of RA and pain will encourage the further integration of Immunology in to clinical neuroscience. These finding may provide a rational basis for the development of subtype selective GABAergic drugs for the treatment of RA and chronic pain.