Sex dimorphism in an animal model of multiple sclerosis: Focus on pregnenolone synthesis. Issue 199 (May 2020)

• Record Type: Journal Article
• Authors: Giatti, S.; Rigolio, R.; Diviccaro, S.; Falvo, E.; Caruso, D.; Garcia-Segura, L.M.; Cavaletti, G.; Melcangi, R.C.
• Is Part Of: Journal of steroid biochemistry and molecular biology. Issue 199(2020)
• Publication Date: 2020-05
• Subjects: 24OH-C 24-hydroxycholesterol -- 25OH-C 25(S)-hydroxycholesterol -- CNS Central nervous system -- CFA Complete Freund's adjuvant -- P450scc Cytochrome P450 side chain cleavage -- CYP11A1 Cytochrome P450 side chain cleavage (gene symbol) -- dpi Days post induction -- EAE Experimental autoimmune encephalomyelitis -- IFA Incomplete Freund's adjuvant -- LC–MS/MS Liquid chromatography tandem mass spectrometry -- MS Multiple Sclerosis -- PREG Pregnenolone -- StAR Steroidogenic acute regulatory protein; Male -- Female -- Spinal cord -- Multiple sclerosis -- Pregnenolone -- Cholesterol -- Oxysterols; Steroid hormones -- Periodicals; Biochemistry -- Periodicals; Hormones -- Periodicals; Molecular Biology -- Periodicals; Hormones stéroïdes -- Périodiques; Steroid hormones; Periodicals; 572.579
• DOI: 10.1016/j.jsbmb.2020.105596
• Languages: English
• ISSNs: 0960-0760

Abstract

Highlights: Synthesis of PREG in the EAE spinal cord is altered by the pathology in a sex dimorphic way. Synthesis of PREG in the EAE spinal cord is altered depending on the pathological progression. The study of neurosteroidogenic processes could be relevant to better understand the sexual dimorphism of MS. Metabolism of cholesterol and oxysterol may be interconnected with neuroactive steroid production. Abstract: Neuroactive steroids, molecules produced from cholesterol in steroidogenic cells (i.e., peripheral glands and nervous system) are physiological modulators and protective agents of nervous function. A possible role for neuroactive steroids in the sex-dimorphic clinical manifestation, onset and progression of Multiple Sclerosis (MS) has been recently suggested. To explore this possibility, we assessed the synthesis of the first steroidogenic product (pregnenolone; PREG) in the spinal cord of experimental autoimmune encephalomyelitis rats, a MS model. Data obtained indicate that the synthesis of PREG in the spinal cord is altered by the pathology in a sex-dimorphic way and depending on the pathological progression. Indeed, in male spinal cord the synthesis was already decreased at the acute phase of the disease (i.e., 14 days post induction - dpi) and maintained low during the chronic phase (i.e., 45 dpi), while in females this effect was observed only at the chronic phase. Substrate availability had also a role in the sex-dimorphic kinetics. Indeed, at the chronic phase, male animals showed a reduction in the levels of free cholesterol coupled to alteration of cholesterol metabolism into oxysterols; these effects were not observed in female animals. These findings suggest that the comprehension of the neurosteroidogenic processes could be relevant to better understand the sexual dimorphism of MS and to possibly design sex-oriented therapeutic strategies based on neuroactive steroids.