Activation of the liver x receptors ameliorates diabetic peripheral neuropathy increasing locally neuroactive steroid levels

Neuroactive steroids act in the peripheral nervous system as physiological regulators and as protective agents for acquired or inherited peripheral neuropathy. Recently, it was reported that the modulation of neuroactive steroids levels could be a potential therapeutic approach to protect peripheral nerve sfrom damage caused by diabetes. An innovative approach to restore neuroactive steroid synthesis and level could be represented by the modulation of cholesterol homeostasis. The liver X receptors (LXRs), master regulators of cholesterol homeostasis, would thus represent a key candidate. LXRs are ligand activated transcription factors belonging to the nuclear receptors superfamily. They act as cholesterol sensors leading to prevent excessive intracellular accumulation of cholesterol. In an experimental model of diabetic neuropathy we show that functional LXRα and β isoforms are expressed. Their activation by GW3965, a non-steroid synthetic ligand in streptozotocin induced diabetic rat increases in the sciatic nerve the gene expression of steroidogenic acute regulatory protein, StAR (a molecule involved in the transfer of cholesterol into mitochondrial), of the enzyme P450scc (responsible for conversion of cholesterol into pregnenolone), of 5α-reductase (involved in the generation of neuroactive steroids) and of classical LXRs targets involved in cholesterol efflux, such as ABCA1 and ABCG1. These effects were associated with increased levels of neuroactive steroids (e.g. pregnenolone, progesterone, dihydroprogesterone and 3α-diol) in the sciatic nerve, and with neuroprotective effects on thermal nocipeptive activity, nerve conduction velocity, and Na+, K+ -ATPase activity. Altogether these results suggest that LXR activation may be a promising pharmacological approach to increase local neuroactive steroid to exert neuroprotective effects in diabetic neuropathy.