Neuroactive steroids in periphery and cerebrospinal fluid

Area of Science:

• Neuroendocrinology
• Neurochemistry
• Steroid Metabolism

Background:

• Peripheral steroids can penetrate the blood-brain barrier (BBB), contributing to the central nervous system (CNS) steroid metabolome.
• Cerebrospinal fluid (CSF) steroid concentrations are significantly lower than peripheral levels, yet peripheral steroid profiles may predict CNS steroid status.
• Neurosteroids can be synthesized de novo in the CNS or derived from peripheral precursors transported across the BBB.

Purpose of the Study:

• To investigate the relationship between peripheral and CNS steroid levels, specifically pregnenolone and dehydroepiandrosterone (DHEA).
• To determine the influence of peripheral pregnenolone sulfate and DHEA on their respective concentrations within the CNS.
• To elucidate the contribution of peripheral steroids versus CNS synthesis to the brain's neurosteroid pool.

Main Methods:

• Analysis of pregnenolone and DHEA levels in both serum and CSF.
• Correlation analysis between peripheral (serum) and central (CSF) steroid concentrations.
• Review of existing data on steroid transport across the BBB and CNS steroidogenesis.

Main Results:

• Serum pregnenolone sulfate showed a borderline correlation with CSF pregnenolone, suggesting its potential role in CNS pregnenolone levels.
• CSF pregnenolone levels did not significantly correlate with serum free pregnenolone.
• CSF DHEA (both free and conjugated) correlated with serum DHEA and its sulfate, indicating peripheral influence on CNS DHEA.

Conclusions:

• Circulating pregnenolone sulfate may be a key determinant of CNS pregnenolone levels in humans.
• Peripheral DHEA and its sulfate significantly influence CNS DHEA concentrations, potentially due to limited endogenous CNS synthesis.
• Brain steroids originate from both peripheral sources and local synthesis, with peripheral steroids reflecting systemic physiological and pathological conditions.