Liver X receptors (LXRs) activation ameliorates diabetic peripheral neuropathy increasing locally neuroactive steroid levels

It has been demonstrated that the levels of several neuroactive steroids present in peripheral nerves are impaired by neurodegenerative events. An innovative approach to restore their synthesis and levels could be represented by the modulation of cholesterol homeostasis. Here we report, for the first time, that acting on cholesterol homeostasis through Liver X Receptors (LXRs) activation results in protection of peripheral neuropathy. We observe that rat sciatic nerve express functional LXRα and β isoforms and that, their activation by GW3965 increases the gene expression of steroidogenic enzymes as well as related molecules and of classical targets involved in cholesterol efflux. These effects were associated with an increase of neuroactive steroid levels in the sciatic nerve and with neuroprotective effects on thermal nociceptive activity, nerve conduction velocity and Na+, K+-ATPase. Altogether these results suggest that LXR activation may present an interesting new pharmacological tool able to locally increase neuroactive steroid levels and to exert neuroprotective effects in diabetic neuropathy. This work is supported by “The Giovanni Armenise-Harvard Foundation”