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Neurosteroidogenesis and progesterone anti‐inflammatory/neuroprotective effects
Author(s) -
De Nicola A. F.,
Garay L. I.,
Meyer M.,
Guennoun R.,
SitrukWare R.,
Schumacher M.,
Gonzalez Deniselle M. C.
Publication year - 2018
Publication title -
journal of neuroendocrinology
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.062
H-Index - 116
eISSN - 1365-2826
pISSN - 0953-8194
DOI - 10.1111/jne.12502
Subject(s) - neuroactive steroid , cholesterol side chain cleavage enzyme , translocator protein , aromatase , endocrinology , medicine , steroidogenic acute regulatory protein , experimental autoimmune encephalomyelitis , neuroprotection , biology , chemistry , messenger rna , neuroinflammation , inflammation , receptor , cytochrome p450 , central nervous system , gabaa receptor , biochemistry , metabolism , cancer , breast cancer , gene
Progesterone shows anti‐inflammatory and promyelinating effects in mice with experimental autoimmune encephalomyelitis ( EAE ), a commonly used model for multiple sclerosis ( MS ). Because neurosteroids have been implicated as protective factors for MS and EAE , we analysed the expression of neurosteroidogenic enzymes in the compromised spinal cord of EAE mice. EAE was induced in female C57Bl6 mice, which were then killed on day 16 after induction. Progesterone was given by pellet implantation 1 week before EAE induction. Untreated EAE mice showed decreased mRNA s for the steroidogenic acute regulatory protein (Star), voltage‐dependent anion channel ( VDAC ), cholesterol side‐chain cleavage (P450scc), 5α‐reductase, 3α‐hydroxysteroid dehydrogenase (3α‐ HSOR ) and aromatase, whereas changes of 3β‐hydroxysteroid dehydrogenase (3β‐ HSD ) were not significant. mRNA translocator protein (18 kDa) ( TSPO ) was elevated, concomitantly with a reactive microgliosis. EAE mice also showed abnormal mitochondrial ultrastructure in axons and neuronal bodies, as well as reduced expression of fission and fusion protein mRNA s. Progesterone pretreatment before EAE induction increased Star, VDAC , P450scc, 5α‐reductase type I, 3α‐ HSOR and aromatase mRNA s and did not modify 3β‐ HSD . TSPO mRNA was decreased, possibly as a result of reversal of microgliosis. Progesterone pretreatment also improved mitochondrial ultrastructure and increased fission/fusion protein mRNA s. These mitochondrial effects may be part of the progesterone recovery of neurosteroidogenesis. The enzymes 3β‐ HSD , 3α‐ HSOR and 5α‐reductase are also responsible for the formation of androgens. Because MS patients and EAE rodents show changes of central androgen levels, it is likely that, together with progestins and oestrogens, neuroandrogens afford neuroprotection for EAE and MS . The data reviewed suggest that enhanced synthesis of neurosteroids contributes in an auto/paracrine manner to reinforce the neuroprotective and anti‐inflammatory effects of exogenous progesterone given to EAE mice.