title: Neuroactive steroid treatment modulates myelin lipid profile in diabetic peripheral neuropathy.
abstract: Diabetic peripheral neuropathy causes a decrease in the levels of dihydroprogesterone and 5α-androstane-3α,17β-diol (3α-diol) in the peripheral nerves. These two neuroactive steroids exert protective effects, by mechanisms that still remain elusive. We have previously shown that the activation of Liver X Receptors improves the peripheral neuropathic phenotype in diabetic rats. This protective effect is accompanied by the restoration to control values of the levels of dihydroprogesterone and 3α-diol in peripheral nerves. In addition, activation of these receptors decreases peripheral myelin abnormalities by improving the lipid desaturation capacity, which is strongly blunted by diabetes, and ultimately restores the myelin lipid profile to non-diabetic values. On this basis, we here investigate whether dihydroprogesterone or 3α-diol may exert their protective effects by modulating the myelin lipid profile. We report that both neuroactive steroids act on the lipogenic gene expression profile in the sciatic nerve of diabetic rats, reducing the accumulation of myelin saturated fatty acids and promoting desaturation. These changes were associated with a reduction in myelin structural alterations. These findings provide evidence that dihydroprogesterone and 3α-diol are protective agents against diabetic peripheral neuropathy by regulating the de novo lipogenesis pathway, which positively influences myelin lipid profile.
authors.affiliation: Department of Pharmacological and Biomolecular Sciences, Università degli Studi di Milano, via Balzaretti 9, 20133 Milan, Italy.
authors.forename: Nico
authors.initials: N
authors.lastname: Mitro
authors.affiliation: Department of Pharmacological and Biomolecular Sciences, Università degli Studi di Milano, via Balzaretti 9, 20133 Milan, Italy.
authors.forename: Gaia
authors.initials: G
authors.lastname: Cermenati
authors.affiliation: Department of Pharmacological and Biomolecular Sciences, Università degli Studi di Milano, via Balzaretti 9, 20133 Milan, Italy.
authors.forename: Elisabetta
authors.initials: E
authors.lastname: Brioschi
authors.affiliation: Department of Pharmacological and Biomolecular Sciences, Università degli Studi di Milano, via Balzaretti 9, 20133 Milan, Italy.
authors.forename: Federico
authors.initials: F
authors.lastname: Abbiati
authors.affiliation: Department of Pharmacological and Biomolecular Sciences, Università degli Studi di Milano, via Balzaretti 9, 20133 Milan, Italy.
authors.forename: Matteo
authors.initials: M
authors.lastname: Audano
authors.affiliation: Department of Pharmacological and Biomolecular Sciences, Università degli Studi di Milano, via Balzaretti 9, 20133 Milan, Italy.
authors.forename: Silvia
authors.initials: S
authors.lastname: Giatti
authors.affiliation: Department of Pharmacological and Biomolecular Sciences, Università degli Studi di Milano, via Balzaretti 9, 20133 Milan, Italy.
authors.forename: Maurizio
authors.initials: M
authors.lastname: Crestani
authors.affiliation: Department of Pharmacological and Biomolecular Sciences, Università degli Studi di Milano, via Balzaretti 9, 20133 Milan, Italy.
authors.forename: Emma
authors.initials: E
authors.lastname: De Fabiani
authors.affiliation: Departamento de Biología Celular, Facultad de Biología, Universidad Complutense de Madrid, E-28040 Madrid, Spain.
authors.forename: Inigo
authors.initials: I
authors.lastname: Azcoitia
authors.affiliation: Instituto Cajal, C.S.I.C., E-28002 Madrid, Spain.
authors.forename: Luis Miguel
authors.initials: LM
authors.lastname: Garcia-Segura
authors.affiliation: Department of Pharmacological and Biomolecular Sciences, Università degli Studi di Milano, via Balzaretti 9, 20133 Milan, Italy. Electronic address: donatella.caruso@unimi.it.
authors.forename: Donatella
authors.initials: D
authors.lastname: Caruso
authors.affiliation: Department of Pharmacological and Biomolecular Sciences, Università degli Studi di Milano, via Balzaretti 9, 20133 Milan, Italy. Electronic address: roberto.melcangi@unimi.it.
authors.forename: Roberto Cosimo
authors.initials: RC
authors.lastname: Melcangi
mesh_terms: D004092:20-alpha-Dihydroprogesterone / Q000494:pharmacology*; D045930:Anabolic Agents / Q000494:pharmacology; D015113:Androstane-3,17-diol / Q000494:pharmacology*; D000818:Animals; D015415:Biomarkers / Q000032:analysis; D002853:Chromatography, Liquid; D003921:Diabetes Mellitus, Experimental / Q000150:complications; D003929:Diabetic Neuropathies / Q000188:drug therapy / Q000209:etiology / Q000378:metabolism*; D008055:Lipids / Q000032:analysis*; D008297:Male; D009186:Myelin Sheath / Q000187:drug effects / Q000378:metabolism*; D010523:Peripheral Nervous System Diseases / Q000188:drug therapy / Q000209:etiology / Q000378:metabolism*; D011372:Progestins / Q000494:pharmacology; D012333:RNA, Messenger / Q000235:genetics; D051381:Rats; D017207:Rats, Sprague-Dawley; D060888:Real-Time Polymerase Chain Reaction; D020133:Reverse Transcriptase Polymerase Chain Reaction; D012584:Sciatic Nerve / Q000187:drug effects / Q000378:metabolism*; D053719:Tandem Mass Spectrometry
chemical_list: D045930:Anabolic Agents; D015415:Biomarkers; D008055:Lipids; D011372:Progestins; D012333:RNA, Messenger; D004092:20-alpha-Dihydroprogesterone; D015113:Androstane-3,17-diol
keywords: Metabolites; Peripheral nerve; Progesterone; Streptozotocin; Testosterone