Peroxisome Proliferator Activated Receptor‐δ Agonist GW0742 Prevents the Development of Paclitaxel‐induced Peripheral Neuropathy in Mice

Abstract

Peroxisome proliferator activated receptor (PPAR)‐δ is found in all the areas of origin of the spinoreticulothalamic and spinothalamic tracts, but also in the terminal fields. PPAR‐δ could be implicated both in the regulation of pain sensation and in pain transmission acting as immediate early gene controlling the transcription of genes encoding protein implicated in the facilitated spinal transmission and the central sensitization, such as COX‐2 or iNOS. Painful neuropathy was induced in male mice by administration of paclitaxel (2 mg/kg, i.p.) on 4 alternate days. Paclitaxel‐treated animals received PPAR‐δ agonist (GW0742; 0.3mg/kg, i.p.) daily for 14 days (days −1 to 13). Both the activation of glial cells at day 29 and the time course of proinflammatory cytokine release within the spinal cord were also determined. Repeated administration of GW0742 prevented the development of thermal hyperalgesia and mechanical allodynia in paclitaxel‐treated mice. GW0742 treatment prevented spinal microglial and astrocytic activation evoked by paclitaxel at day 29 and attenuated the early production of spinal proinflammatory cytokines IL‐1β, IL‐6 and TNF‐α. Our results confirm changes in the reactivity of glial cells during the development of peripheral neuropathy induced by paclitaxel and support a preventive effect of GW0742, probably via glial cells reactivity reduction, on the development of this neuropathy.