We developed a redox system for brain-enhanced delivery of
estradiol based on an interconvertible
dihydropyridine in equilibrium pyridinium
salt carrier.
Estradiol (E2), when combined with the lipoidal carrier, readily crosses the blood-brain barrier. The carrier, when oxidized, reduces the rate of exit of the
estradiol-carrier complex from the brain. Subsequent hydrolysis of the carrier provides sustained production of
estradiol in the brain. The aim of the study was to evaluate the effects of single vs. multiple
injections of the
estradiol-chemical delivery system (E2-CDS) on both central and peripheral
estrogen-responsive tissues. Ovariectomized Sprague-Dawley rats received an
intravenous injection of
E2-CDS at 10, 33, 100 or 333 micrograms/kg BW or the
drug vehicle,
dimethyl sulfoxide (
DMSO; 0.5 ml/kg) every 2 days for 7
injections (2 weeks) or a single injection only at 2 days before sacrifice. With a single injection,
E2-CDS did not affect serum
luteinizing hormone (LH) levels at the 10 micrograms/kg dose but caused a dose-dependent reduction in serum LH of 39-52% at the dose range of 33 to 333 micrograms/kg. By contrast, multiple
injections of
E2-CDS caused a 32 to 76% reduction in serum LH levels at doses ranging from 10 micrograms/kg to 333 micrograms/kg. Additionally, multiple doses of
E2-CDs caused a dose-dependent reduction in
body weight at the 10 and 33 micrograms/kg doses with the higher doses causing no further
weight reduction. For both single and multiple dosage groups, serum E2 levels remained unchanged after doses of
E2-CDS of 10 and 33 micrograms/kg, then increased to 21 pg/ml for the single dosage group and to 23 pg/ml for the multiple dosage group at the 100 micrograms/kg dose, and to 59 pg/ml for singly-injected rats and 60 pg/ml for multiply-injected rats at the 333 micrograms/kg dose. Serum
prolactin concentrations were closely correlated with serum E2 levels for both the single and multiple dose groups. These data reveal that a single or multiple doses of
E2-CDS can reduce serum LH levels without elevating serum E2 or
prolactin concentrations, supporting the concept of brain-enhanced delivery of
estradiol with an
estradiol chemical delivery system.