Carrier-mediated transport of labeled oxytocin from brain to blood.

The transport of 125I-oxytocin from brain to blood was investigated in mice after intraventricular injection of radioactively labeled oxytocin with or without unlabeled candidate inhibitors. Residual radioactivity in the brain detected after decapitation was the principal determinant of transport activity. The half-time disappearance from the central nervous system of labeled oxytocin was 19.1 min. Inhibition by 10 nmol/mouse of oxytocin showed a saturable component to transport. A 10-nmol dose of tyrosine-melanocyte-stimulating hormone release inhibiting factor (Tyr-MIF-1) and pressinamide also significantly inhibited transport of labeled oxytocin (p less than 0.05). There was no inhibition of the system by a 10-nmol dose of tyrosine, iodotyrosine, MIF-1, or arginine vasopressin. Studies performed with 125I-oxytocin injected simultaneously with 131I-Tyr-MIF-1 with or without unlabeled oxytocin or Tyr-MIF-1 were consistent with both peptides being transported by the previously described peptide transport system-1 (PTS-1). Pretreatment with aluminum (100 mg/kg of elemental aluminum given 60-90 min before intraventricular injection), previously shown to inhibit PTS-1 and some other transport systems, inhibited the transport of labeled oxytocin. Radioactivity collected from the blood after intraventricular injection of 125I-oxytocin eluted on HPLC at the same position as the labeled oxytocin standard and differently from tyrosine, Tyr-MIF-1, MIF-1 and tocinamide. It is concluded that a saturable system exists for the transport of intact oxytocin from brain to blood which appears to be the previously described PTS-1.

Permeability of the murine blood-brain barrier to some octapeptide analogs of somatostatin.

Analogs of somatostatin are being investigated clinically for the treatment of various malignancies, including brain tumors. We studied the ability of three therapeutically promising radioactively labeled somatostatin octapeptide analogs, RC-160, RC-121, and RC-161, to cross the blood-brain barrier (BBB) after peripheral or central injection. After i.v. injection, intact RC-160 was recovered from the blood and the brain. The entry rates were different from each compound but were generally low. By contrast, entry across the intact BBB increased 220 times when RC-160 was given in a serum-free perfusate. This suggests that some serum-related factor, probably the previously described protein binding or an aggregation-promoting factor, is the main determinant in limiting the blood-to-brain passage of somatostatin analogs. Entry into the brain was not inhibited by the addition of unlabeled analog to the perfusate, showing that passage was probably by diffusion across the membranes that comprise the BBB rather than by saturable transport. By contrast, a saturable system was found to transport peptide out of the central nervous system (CNS). The clearance from the CNS of RC-160 and RC-121, but not RC-161, was faster than could be accounted for by reabsorption of cerebrospinal fluid. Transport of radioactively labeled RC-160 out of the CNS was inhibited by unlabeled RC-160 or somatostatin but was not affected by some other peptide known to cross the BBB by their own transport systems. More than 80% of the radioactivity recovered from the blood after intracerebroventricular injection of RC-160 was eluted by HPLC at the position of the labeled analog, showing that the peptide had crossed the BBB in intact form. Our results indicate the presence of a saturable transport system in one direction across the BBB for some superactive analogs of somatostatin.

Bidirectional transport of interleukin-1 alpha across the blood-brain barrier.

Circulating interleukin-1 alpha (IL-1 alpha) has multiple effects on the central nervous system. We investigated the ability of radioiodinated IL-1 alpha (rIL-1 alpha) to cross the rodent blood-brain barrier and found its entry rate to be 43.9 times greater than that predicted by leakage alone. The rIL-1 alpha entered multiple regions of the brain, with over 40% entering at the cortex. The hypothalamus had the highest entry rate on a weight basis but only accounted for 2% of total entry. In all experiments, the entry rate of rIL-1 alpha greatly exceeded that of simultaneously injected radiolabeled albumin. The half-time disappearance of rIL-1 alpha from the brain after central injection was 21.9 min, a time that exceeds the reabsorption rate of cerebrospinal fluid. Pretreatment of animals with aluminum decreased both entry and exit rates, which is compatible with a saturable component of transport. Thus, rIL-1 alpha has access to many regions of the brain with bidirectional transport rates across the blood-brain barrier exceeding those predicted by nonspecific mechanisms.