Exploring the Nerve Regenerative Capacity of Compounds with Differing Affinity for PPARγ In Vitro and In Vivo

Abstract

Damage to peripheral nerves can cause debilitating consequences for patients such as lifelong pain and disability. At present, no drug treatments are routinely given in the clinic following a peripheral nerve injury (PNI) to improve regeneration and remyelination of damaged nerves. Appropriately targeted therapeutic agents have the potential to be used at different stages following nerve damage, e.g., to maintain Schwann cell viability, induce and sustain a repair phenotype to support axonal growth, or promote remyelination. The development of therapies to promote nerve regeneration is currently of high interest to researchers, however, translation to the clinic of drug therapies for PNI is still lacking. Studying the effect of PPARγ agonists for treatment of peripheral nerve injures has demonstrated significant benefits. Ibuprofen, a non-steroidal anti-inflammatory drug (NSAID), has reproducibly demonstrated benefits in vitro and in vivo, suggested to be due to its agonist action on PPARγ. Other NSAIDs have demonstrated differing levels of PPARγ activation based upon their affinity. Therefore, it was of interest to determine whether affinity for PPARγ of selected drugs corresponded to an increase in regeneration. A 3D co-culture in vitro model identified some correlation between these two properties. However, when the drug treatments were screened in vivo, in a crush injury model in a rat sciatic nerve, the same correlation was not apparent. Further differences were observed between capacity to increase axon number and improvement in functional recovery. Despite there not being a clear correlation between affinity and size of effect on regeneration, all selected PPARγ agonists improved regeneration, providing a panel of compounds that could be explored for use in the treatment of PNI.