Kelley et al. proposed a hypothesis for an inefficient GABA signaling 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), and PGE2 is an essential mediator for inflammatory pain. However, most of the p38 projects failed to deliver drugs due to CNS toxicity. Are these 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 neuropathic pain. Clomethiazole edisilate is a drug that acts on GABA receptor, which inhibits the p38 MAPK too. This small molecule does not have other p38 inhibitors' structural features, which seems to support 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 RA and pain development will encourage further integration of Immunology in clinical neuroscience. These findings may provide a rational basis for developing subtype-selective GABAergic drugs to treat RA and chronic pain.
