FILM AUTORADIOGRAPHY IDENTIFIES UNIQUE FEATURES OF [I-125] 3,3',5'-(REVERSE) TRIIODOTHYRONINE TRANSPORT FROM BLOOD TO BRAIN

I, Steady-state iodothyronine profiles in plasma are composed of thyro id gland-synthesized hormones (mainly thyroxine) and tissue iodothyron ine metabolites (mainly triiodothyronine and reverse triiodothyronine) that have entered the bloodstream. The hormones circulate in noncoval ently bound complexes with a panoply of carrier proteins. Transthyreti n (TTR), the major high-affinity thyroid hormone binding protein in ra t plasma, is formed in the liver. It is also actively and independentl y synthesized in choroid plexus, where its function as a chaperone of thyroid hormones from bloodstream to cerebrospinal fluid (CSF) is unde rgoing close scrutiny by several groups of investigators. Because TTR has high-affinity binding sites for both thyroxine and retinol binding protein, its potential role as a mediator of combined thyroid hormone and retinoic acid availability in brain is of further interest. 2. Wh ile they are in the free state relative to their binding proteins, iod othyronines in the cerebral circulation are putatively subject to tran sport across both the blood-brain barrier (BBB) and choroid plexus CSF barrier(CSFB) before entering the brain. Previous autoradiographic st udies had already indicated that after intravenous administration the transport mechanisms governing thyroxine and triiodothyronine entry in to brain were probably similar, whereas those for reverse triiodothyro nine were very different, although the basis for the difference was no t established at that time. Intense labeling seen over brain ventricle s after intravenous administration of all three iodothyronines suggest ed that all were subject to transport across the CSFB. 3. To evaluate the role of the BBB and CSFB in determining iodothyronine access to br ain parenchyma, autoradiograms prepared after intravenous administrati on of[I-125]-labeled hormones (revealing results of transport across b oth barriers) were compared with those prepared after intrathecal (icv ) hormone injection (reflecting only their capacity to penetrate into the brain after successfully navigating the CSFB). 4. Those studies re vealed that thyroxine and triiodothyronine were mainly transported acr oss the BBB. They shared with reverse triiodothyronine a generally sim ilar, limited pattern of penetration from CSF into the brain, with cir cumventricular organs likely to be the main recipients of iodothyronin es (with or without retinol) transported across the CSFB. 5. Analysis of all of the images obtained after intravenous and icv hormone admini stration clarified the basis for the unique distribution of intravenou sly injected reverse triiodothyronine. The hormone is excluded by the BBB but may be subject to limited penetration into brain parenchyma vi a the CSF. 6. Overall the observations single out reverse triiodothyro nine as the iodothyronine showing the most distinctive as well as the most limited pattern of transport from blood to brain. Although it is considered to be a largely inactive metabolic product formed in the se rvice of thyroxine disposal, a number of considerations suggest that r everse triiodothyronine, actively formed from thyroxine within the bra in at selected sites of inner ring monodeiodinase activity, may have a s yet undiscovered functions. The present results raise the possibilit y that, as in the case of other known neuroactive molecules that are f ormed within the brain but excluded by the BBB, reverse triiodothyroni ne generated intracerebrally may exert important brain-specific and si te-specific functional effects.