SUN-036 - Neurohormones: Steroid Phosphoryl Diesters (Spds) in the Brain

Steroid phosphoryl diesters (SPDs) differ from other steroids in two fundamental ways: SPDs are not synthesized from cholesterol and SPDs don’t have nuclear receptors. Until now, the known steroid hormones in the brain (neurohormones) have been limited to androgens and progestogens. We now describe SPDs in brain extracts from goats and rabbits.
In brain extracts, there were 3 major steroid phosphoryl choline diesters (SPCDs) (designated as C313, C339, and C385) and trace amounts of C341. C313 is formed by sidechain cleavage of 7-dehydrocholesterol but can’t be formed from desmosterol; C313 seems to be the precursor of the other SPDs; C339 and C341 have a γ-lactone ring; C385 is a carboxylic acid. For comparison, goat and rabbit serum contained 4 major SPCDs – C313, C341, C385 and lessor amounts of C339. The difference in relative concentrations of C341 and C339 suggests that C341, like cholesterol, does not cross the blood brain barrier but that C339 does cross. The trace amounts of C341 found in brain extracts, may have originated from blood. The SPCDs could not have originated in the brain by methylation of the corresponding steroid phosphoryl ethanolamine diester (SPED) because those SPEDs were not in the brain extract and no SPED has been detected in serum.
In brain extracts, in addition to the SPCDs, there were 6 SPEDs, designated E327, E343, E351, E367, E379, and E395. As C329, C353, C369, and C381 are present in serum and in other tissues, the brain must not have the enzyme (DCHR7) necessary to reduce Δ7-8 alkenes. Trial-and-error analysis allowed us to propose molecular formulas for each of the novel SPEDs. Four of the SPEDs have a γ-lactone ring and one of these could be an endogenous ligand for NaK-ATPase.
The approximate concentration of SPEDs in the brain is 1 mg/kg or 2 µM. The binding affinity of testosterone to the androgen receptor is less than 10 nM. If there were a receptor for an SPD with a similar affinity for its ligand, the receptor would always have a ligand. Thus, in the absence of a nuclear receptor, SPDs must function by different mechanisms. Spironolactone, a synthetic γ-lactone, can bind to NaK-ATPase; DMHCA, a synthetic sterol carboxylic acid derivative, binds to epithelial sodium channels (ENaC). In the brain, specific SPEDs may be ligands for these two proteins for which endogenous receptors have not yet been identified.
The absence of DCHR7 provides a critical insight into brain cholesterol biosynthesis. The brain must not be using the Kandutsch-Russell pathway for the synthesis of cholesterol but only uses that pathway for the synthesis of SPEDs. This makes the known decrease in DCHR24 in patients with Alzheimer’s syndrome a critical factor in cholesterol biosynthesis in the brain. Further, the resulting shutdown of the Bloch pathway probably leads to increased synthesis of SPED γ-lactones in the brain and may be a key factor in dementia and stroke.

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