title: Activation of the liver X receptor increases neuroactive steroid levels and protects from diabetes-induced peripheral neuropathy.
abstract: Neuroactive steroids act in the peripheral nervous system as physiological regulators and as protective agents for acquired or inherited peripheral neuropathy. In recent years, modulation of neuroactive steroids levels has been studied as a potential therapeutic approach to protect peripheral nerves from damage induced by diabetes. Nuclear receptors of the liver X receptor (LXR) family regulate adrenal steroidogenesis via their ability to control cholesterol homeostasis. Here we show that rat sciatic nerve expresses both LRXα and β isoforms and that these receptors are functional. Activation of liver X receptors using a synthetic ligand results in increased levels of neurosteroids and protection of the sciatic nerve from neuropathy induced by diabetes. LXR ligand treatment of streptozotocin-treated rats increases expression in the sciatic nerve of steroidogenic acute regulatory protein (a molecule involved in the transfer of cholesterol into mitochondria), of the enzyme P450scc (responsible for conversion of cholesterol into pregnenolone), of 5α-reductase (an enzyme involved in the generation of neuroactive steroids) and of classical LXR 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 nociceptive activity, nerve conduction velocity, and Na(+), K(+)-ATPase activity. These results suggest that LXR activation may represent a new pharmacological avenue to increase local neuroactive steroid levels that exert neuroprotective effects in diabetic neuropathy.
authors.affiliation: Department of Pharmacological Sciences, Giovanni Armenise-Harvard Foundation Laboratory, Università degli Studi di Milano, Milano, Italy.
authors.forename: Gaia
authors.initials: G
authors.lastname: Cermenati
authors.forename: Silvia
authors.initials: S
authors.lastname: Giatti
authors.forename: Guido
authors.initials: G
authors.lastname: Cavaletti
authors.forename: Roberto
authors.initials: R
authors.lastname: Bianchi
authors.forename: Omar
authors.initials: O
authors.lastname: Maschi
authors.forename: Marzia
authors.initials: M
authors.lastname: Pesaresi
authors.forename: Federico
authors.initials: F
authors.lastname: Abbiati
authors.forename: Alessandro
authors.initials: A
authors.lastname: Volonterio
authors.forename: Enrique
authors.initials: E
authors.lastname: Saez
authors.forename: Donatella
authors.initials: D
authors.lastname: Caruso
authors.forename: Roberto Cosimo
authors.initials: RC
authors.lastname: Melcangi
authors.forename: Nico
authors.initials: N
authors.lastname: Mitro
mesh_terms: D000704:Analysis of Variance; D000818:Animals; D001565:Benzoates / Q000494:pharmacology; D001596:Benzylamines / Q000494:pharmacology; D001835:Body Weight / Q000187:drug effects; D002853:Chromatography, Liquid / Q000379:methods; D003921:Diabetes Mellitus, Experimental / Q000150:complications; D003929:Diabetic Neuropathies / Q000378:metabolism* / Q000503:physiopathology / Q000517:prevention & control*; D004195:Disease Models, Animal; D005786:Gene Expression Regulation / Q000187:drug effects; D006930:Hyperalgesia / Q000209:etiology; D008024:Ligands; D000071518:Liver X Receptors; D008297:Male; D009185:Myelin Proteins / Q000235:genetics / Q000378:metabolism; D009431:Neural Conduction / Q000502:physiology; D057093:Orphan Nuclear Receptors / Q000378:metabolism*; D017288:Pain Threshold; D051381:Rats; D017207:Rats, Sprague-Dawley; D012584:Sciatic Nerve / Q000378:metabolism / Q000382:microbiology / Q000473:pathology / Q000503:physiopathology; D000254:Sodium-Potassium-Exchanging ATPase / Q000378:metabolism; D013256:Steroids / Q000378:metabolism* / Q000627:therapeutic use*; D053719:Tandem Mass Spectrometry / Q000379:methods
chemical_list: D001565:Benzoates; D001596:Benzylamines; C473027:GW 3965; D008024:Ligands; D000071518:Liver X Receptors; D009185:Myelin Proteins; D057093:Orphan Nuclear Receptors; D013256:Steroids; D000254:Sodium-Potassium-Exchanging ATPase
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