Neurosteroidogenesis and progesterone anti-inflammatory/neuroprotective effects

Area of Science:

• Neuroscience
• Immunology
• Endocrinology

Background:

• Multiple sclerosis (MS) is a demyelinating disease where neurosteroids may play a protective role.
• Experimental autoimmune encephalomyelitis (EAE) in mice is a model for MS, exhibiting reduced neurosteroidogenic enzyme expression.
• Progesterone demonstrates anti-inflammatory and promyelinating effects in EAE.

Purpose of the Study:

• To analyze neurosteroidogenic enzyme expression in the spinal cord of EAE mice.
• To investigate the effects of progesterone pretreatment on neurosteroidogenesis and mitochondrial function in EAE.
• To explore the potential neuroprotective roles of neurosteroids, including androgens, in EAE and MS.

Main Methods:

• EAE was induced in female C57Bl6 mice.
• Progesterone was administered via pellet implantation one week before EAE induction.
• Messenger RNA (mRNA) expression of key steroidogenic enzymes and mitochondrial proteins was quantified using quantitative real-time PCR (qRT-PCR) on day 16 post-induction.
• Mitochondrial ultrastructure was examined using electron microscopy.

Main Results:

• Untreated EAE mice exhibited decreased mRNA levels for steroidogenic acute regulatory protein (Star), voltage-dependent anion channel (VDAC), cholesterol side-chain cleavage (P450scc), 5α-reductase, 3α-hydroxysteroid dehydrogenase (3α-HSOR), and aromatase.
• Translocator protein (18 kDa) (TSPO) mRNA was elevated in EAE mice, correlating with reactive microgliosis and abnormal mitochondrial ultrastructure.
• Progesterone pretreatment normalized or increased the expression of Star, VDAC, P450scc, 5α-reductase type I, 3α-HSOR, and aromatase mRNAs, while decreasing TSPO mRNA.
• Progesterone also improved mitochondrial ultrastructure and increased the expression of mitochondrial fission and fusion protein mRNAs.

Conclusions:

• Progesterone pretreatment reverses the decrease in neurosteroidogenic enzyme expression and improves mitochondrial function in EAE mice.
• Enhanced neurosteroid synthesis, potentially including neuroandrogens, may contribute to the neuroprotective and anti-inflammatory effects of progesterone in EAE and MS.
• The findings suggest that targeting neurosteroidogenesis could be a therapeutic strategy for MS.