Thermodynamics of the self-assembly of non-ionic chromonic molecules using atomistic simulations. The case of TP6EO2M in aqueous solution.

Atomistic molecular dynamic simulations have been performed for the non-ionic chromonic liquid crystal 2,3,6,7,10,11-hexa-(1,4,7-trioxa-octyl)-triphenylene (TP6EO2M) in aqueous solution. TP6EO2M molecules consist of a central poly-aromatic core (a triphenylene ring) functionalized by six hydrophilic ethyleneoxy (EO) chains, and have a strong tendency to aggregate face-to-face into stacks even in very dilute solution. We have studied self-assembly of the molecules in the low concentration range corresponding to an isotropic solution of aggregates, using two force fields GAFF and OPLS. Our results reveal that the GAFF force field, even though it was successfully used previously for modelling of ionic chromonics, overestimates the attraction of TP6EO2M molecules in water. This results in an aggregation free energy which is too high, a reduced hydration of EO chains and, therefore, molecular self-assembly into compact disordered clusters instead of stacks. In contrast, use of the OPLS force field, leads to self-assembly into ordered stacks in agreement with earlier experimental studies of triphenylene-based chromonics. The free energy of association follows a "quasi-isodesmic" pattern, where the binding free energy of two molecules to form a dimer is of the order of 2.5 RT larger than the corresponding energy of addition of a molecule into a stack. The obtained value for the binding free energy, ΔG=-12 RT, is found to be in line with the published values for typical ionic chromonics (-7 to -12 RT), and agrees reasonably well with the experimental results for this system. The calculated interlayer distance between the molecules in a stack is 0.37 nm, which is at the top of the range found for typical chromonics (0.33-0.37 nm). We suggest that the relatively large layer spacing can be attributed to the repulsion between EO side chains.

How specific are ion specificities? A pilot NMR study.

NMR quadruple splitting measurements are a useful technique to investigate the adsorption behaviour of ions near to charged surfaces in liquid crystals made of surfactants of different headgroups. In the present paper we show the differences in lithium and sodium adsorption on dodecyl carboxylate and dodecyl sulphate bilayers as a function of surfactant concentration and for two temperatures. To this purpose we mixed the pure surfactants and also mixtures of the lithium and sodium surfactants with octanol as a cosurfactant in appropriate ratios and concentrations to obtain liquid crystals. It turned out that the measured specific ion effects are much more pronounced in the case of carboxylates than for sulphates.

Effect of salts on the phase behavior and the stability of nanoemulsions with rapeseed oil and an extended surfactant.

For many decades, the solubilization of long-chain triglycerides in water has been a challenge. A new class of amphiphiles has been created to overcome this solubilization problem. The so-called "extended" surfactants contain a hydrophilic-lipophilic linker to reduce the contrast between the surfactant-water and surfactant-oil interfaces. In the present contribution, the effects of different anions and cations on the phase behavior of a mixture containing an extended surfactant (X-AES), a hydrotrope (sodium xylene sulfonate, SXS), water, and rapeseed oil were determined as a function of temperature. Nanoemulsions were obtained and characterized by conductivity measurements, light scattering, and optical microscopy. All salting-out salts show a transition from a clear region (O/W nanoemulsion), to a lamellar liquid crystalline phase region, a clear phase (bicontinuous L(3)), and again to a lamellar liquid crystalline phase region with increasing temperature. For the phase diagrams with NaSCN and Na(2)SO(4), only one clear region (O/W nanoemulsion) was observed, which turns into a lamellar phase region at elevated temperatures. Furthermore, the stability of the nanoemulsions was investigated by time-dependent measurements: the visual observation of phase separation, droplet size by dynamic light scattering (DLS), and optical microscopy. The mechanism of the different phase transitions is also discussed.

Characterization of perylene diimide dye self-assemblies and their use as templates for the synthesis of hybrid and supermicroporous nanotubules.

The self-organizing structures formed by a water-soluble perylene diimide dye (PDI) have been studied by several experimental techniques as potential templates for the preparation of hybrid nanomaterials. The dye forms chromonic-nematic and hexagonal liquid crystals in water. The aggregates in liquid crystals consist of one-molecule-wide stacks. From the changes in the solution proton NMR chemical shifts with concentration, it appears that adjacent molecules are twisted. There is significant broadening of the aromatic resonances at higher concentrations, arising from nonmotionally averaged dipole-dipole coupling between adjacent aromatic hydrogens. This is attributed to slow overall rotation of the aggregates in solution, suggesting that they grow up to several tens of nanometers. Dye aggregates serve as templates for the formation of silica tubules (1-5 µm length, average diameter ≈300 nm), with aligned and very thin (1-2 nm) dye nanostripes embedded in the walls. The silica tubes precipitated from solution are formed by the cooperative interaction between PDI and silica species during the sol-gel reaction. Upon calcination, silica nanotubules with supermicroporous walls are obtained. In comparison with conventional surfactant systems, the use of π-π stacked chromonic aggregates brings new possibilities for the templated fabrication of pores with sizes below the mesoporous range. Materials could find applications in photovoltaics as well as in shape selective catalysis and adsorption.

Hydrotrope-induced inversion of salt effects on the cloud point of an extended surfactant.

We report on the effects of electrolytes spanning a range of anions (NaOc, NaSCN, NaNO(3), NaBr, NaCl, NaBu, NaOAc, Na(2)SO(4), Na(2)HPO(4), and Na(2)CO(3)) and cations (LiCl, NaCl, KCl, CsCl, and choline chloride) on the aqueous solubility of an extended surfactant. The surfactant is anionic with a long hydrophobic tail as well as a significant fraction of propylene oxide groups and ethylene oxide groups (C(12-14)-PO(16)-EO(2)-SO(4)Na, X-AES). In the absence of electrolytes, X-AES exhibits a cloud-point temperature that decreases with increasing surfactant concentration. After the addition of salts to the surfactant solutions, various shifts in the solubility curves are observed. These shifts follow precisely the same Hofmeister series that is found for salting-in and salting-out effects in protein solutions. In the presence of different concentrations of sodium xylene sulfonate (SXS), the solubility of the surfactant increases. In this context, SXS can be considered to be a salting-in salt. However, when the electrolytes are added to an aqueous solution of X-AES and SXS the Hofmeister series reverses for divalent anions such as Na(2)SO(4), Na(2)HPO(4), and Na(2)CO(3). Studies on the phase behavior and micelle structures using polarization microscopy, freeze-etch TEM, and NMR measurements indicate a dramatic change in the coexisting phases on the addition of SXS.

Thermotropic phase behavior of choline soaps.

Choline carboxylates (ChCm with m = 12-18) are simple biocompatible anionic surfactants with very low Krafft temperatures, possessing a rich aqueous phase behavior. In the present work, we have investigated the thermotropic mesomorphism of anhydrous ChCm salts for m = 12-18. Transition temperatures and enthalpies determined by differential scanning calorimetry reveal that all investigated compounds exhibit three different phases between -20 and 95 °C. The phases were further characterized by optical polarizing microscopy, NMR spin-spin relaxation, and X-ray scattering measurements. The nature of the phases was identified with increasing temperature as crystalline, semicrystalline, and liquid-crystalline lamellar. Even long-chain choline carboxylates (m = 18) were found to melt into a lamellar liquid-crystalline phase below 100 °C. Accordingly, with choline as counterion in simple fatty acid soaps, not only the water solubility is considerably enhanced but also the melting points are substantially reduced, hence facilitating thermotropic mesomorphism at temperatures between 35 and 95 °C. Thus, simple choline soaps with m = 12-18 may be classified as ionic liquids.

Chromonic liquid crystalline phases of pinacyanol acetate: characterization and use as templates for the preparation of mesoporous silica nanofibers.

We report on the self-aggregation of the cationic dye pinacyanol acetate and its use for the preparation of nanostructured silica via templated sol-gel reaction. The dye forms nematic and hexagonal chromonic liquid crystals at low concentrations in water (i.e., from 0.75 wt %); the type of counterion appears to play an important role in liquid crystal formation. From analysis of small X-ray scattering (SAXS) curves, it is inferred that dye aggregates have the morphology of hollow long tubes with one-molecule-thick walls; the diameter of the tubes does not to change much with concentration. The dye aggregates can be aligned by shear or by a magnetic field. The high-resolution (1)H NMR spectra show that aggregation takes place over a range of concentrations rather than having a sharp "critical" aggregation. Within the aggregates the conjugated moiety, including the three-carbon link, is in close proximity to the aromatic groups of stack neighbors. On the other hand, dye aggregates direct the formation of silica nanofibers synthesized via sol-gel reaction, mimicking the elongated structures found in aqueous media. The nanofibers show a hierarchical organization; i.e., they contain hexagonal arrays of 3 nm cylindrical mesopores left after calcination of the templating molecules, and the pore walls are 2.7 nm thick. As the nanofibers form entangled networks, the obtained materials also show interparticle porosity. The present findings open new possibilities for the use of commercial cationic dyes in the synthesis of nanostructured materials.

Phase behavior of an extended surfactant in water and a detailed characterization of the concentrated phases.

The formation of microemulsions with triglycerides at ambient conditions can be improved by increasing the surfactant-water and surfactant-oil interactions. Therefore, extended surfactants were developed, which contain hydrophilic/lipophilic linkers. They have the ability to stretch further into the oil and water phase and enhance the solubility of oil in water. In this work, the phase behavior of a chosen extended surfactant (C(12-14)-PO(16)-EO(2)-SO(4)Na, X-AES) in H(2)O/D(2)O at high surfactant concentrations (30-100 wt %) and at temperatures between 0 and 90 °C is studied for the first time. The lyotropic liquid crystals formed were determined by optical microscopy, small-angle X-ray scattering (SAXS), and (2)H and (23)Na NMR, and a detailed phase diagram of the concentrated area is given. The obtained mesophases are a hexagonal phase (H(1)), at low temperatures and small concentrations, a lamellar phase (L(α)) at high temperatures or concentrations, a bicontinuous cubic phase (V(2)) as well as a reverse hexagonal phase (H(2)). To our knowledge, this is the first surfactant that forms both H(1) and H(2) phases without the addition of a third compound. From the (2)H NMR quadrupole splittings of D(2)O, we have examined water binding in the L(α) and the H(2) phases. There is no marked difference in the bound water between the two phases. Where sufficient water is present, the number of bound water molecules per X-AES is estimated to be ca. 18 with only small changes at different temperatures. Similar results were obtained from the (23)Na NMR data, which again showed little difference in the ion binding between the L(α) and the H(2) phases. The X-ray diffraction data show that X-AES has a much smaller average length in the L(α) phase compared to the all-trans length than in the case for conventional surfactants. At very high surfactant concentrations an inverse isotropic solution (L(2)), containing a small fraction of solid particles, is formed. This isotropic solution is clearly identified and the size of the reversed micelles was determined using (1)H NMR measurements. Furthermore, the solid particles within the L(2) phase and the neat surfactant were analyzed. The observed results were compared to common conventional surfactants (e.g., sodium dodecyl sulfate, sodium lauryl ether sulfate, and sodium dodecyl-p-benzene sulfonate), and the influence of the hydrophilic/lipophilic linkers on the phase behavior was discussed.

Phase behavior of an extended surfactant in water and a detailed characterization of the dilute and semidilute phases.

The formation of microemulsions with triglycerides under ambient conditions has been a challenge for scientists for many decades. For this reason, so-called extended surfactants were developed that contained hydrophilic/lipophilic linkers to stretch further into the oil and water phase, and enhance the solubility of triglycerides in water. Currently, only limited information about the properties of these surfactants and its behavior in water is available. Therefore, in this work, mixtures of a chosen extended surfactant (C(12-14)-PO(16)-EO(2)-SO(4)Na, X-AES) with H(2)O/D(2)O over the whole concentration range were studied by optical microscopy. A schematic phase diagram has been obtained, which shows two isotropic liquid phases at the lowest and highest surfactant concentrations. Furthermore, between the isotropic solutions, four liquid-crystalline phases occur: a hexagonal phase (H(1)), a lamellar phase (L(alpha)) with a change in birefringence, a bicontinuous cubic phase (V(2)), and a reverse hexagonal phase (H(2)). The structure of the micellar solution (L(1)) was determined by cryo-TEM, dynamic light scattering, and (1)H NMR, which gave information about the size, the aggregation number, and the area per molecule of the micelles. Liquid-crystal formation occurs from the micellar solution in two different ways. The first route appeared by increasing the temperature, going from an L(1) to an L(alpha) phase. By increasing the surfactant concentration (at low temperatures), a second route showed a transition from L(1) to H(1). In addition, the effect of sodium chloride on the cloud point of the extended surfactant was examined, indicating that small amounts of NaCl have no influence on the phase behavior. The monolayer behavior of the extended surfactant at the air-water interface was also determined. Despite its water solubility, an isotherm on the water subphase was found, showing slow kinetics of the molecules to go into the bulk. Thus, the determination of the cmc of the extended surfactant using conventional methods was found to be impossible.

Lyotropic liquid crystal behaviour of azelate and succinate monoester surfactants based on fragrance alcohols.

Azelaic acid was used as a starting material for the preparation of new monoester surfactants based on fragrance alcohols. Sodium monocitronellyl azelate (citroC(9)Na) and sodium monomenthyl azelate (menC(9)Na) were synthesized and their aqueous phase behaviour was studied. For comparison, monoesters derived from succinic anhydride, i.e. sodium monocitronellyl succinate (citroC(4)Na) and sodium monomenthyl succinate (menC(4)Na), were also prepared as well as sodium monodecyl succinate (C(10)C(4)Na) and sodium monodecyl azelate (C(10)C(9)Na) in order to study the effect of the position of the ester function inside the hydrophobic tail and of branching and unsaturation respectively. Liquid crystal structures were examined by optical polarising microscopy and schematic partial binary phase diagrams (surfactant+water, 0-100 wt%, 10-90 degrees C) of the surfactants were established. Succinate surfactants behave as longer alkyl chain surfactants than their azelate counterparts, meaning that these last ones probably adopt a more folded conformation, with the ester function more frequently present at the micelle surface. This conformation would result in a rougher micelle surface, making it slightly less easy for micelles to pack in liquid crystalline phases. It was also shown that the tendency to adopt a more folded conformation and to form smaller micelles is ranked in this order: monomenthyl>monocitronellyl>monodecyl.

Lateral phase separation gives multiple lamellar phases in a "binary" surfactant/water system: the phase behavior of sodium alkyl benzene sulfonate/water mixtures.

We have examined the structure of the lamellar phase (Lalpha) that coexists with a micellar solution (L1) for a commercial sodium alkyl benzene sulfonate (LAS) mixed with water. The surfactant is a mixture containing C10-C13 alkyl chains, having all positional isomers of the benzene sulfonate group present except the 1-isomer. Unusually for ionic surfactants, the difference in compositions between the coexisting L1 and Lalpha phases is large (L1 = approximately 20 wt % LAS; Lalpha = approximately 65 wt %). The main technique employed was X-ray diffraction, supplemented by optical microscopy and differential scanning calorimetry (DSC). At ambient temperatures, the lamellar phase gives a single diffraction pattern with the main reflection (d) at approximately 32.5 A, whatever the composition. However, above 40 degrees C, the diffraction peak becomes broader and moves to higher d values. At higher temperatures still, several distinct and different diffraction peaks are observed, differing in detail according to composition. The largest d values (approximately 42-4 A) are observed for the lowest LAS concentrations, while the largest number of separate reflections (five) occurs for samples with approximately 44-50% LAS, both at the highest temperatures. Although there are some differences in the data between heating and cooling cycles, the d values return to the original value at low temperature. There are no observable transitions in DSC, nor is there any heterogeneity in the lamellar phase observable by microscopy. The data clearly indicate that there is some lateral separation of the different LAS isomers within the bilayers, which results in the formation of local lamellar regions having different surfactant compositions. This lateral phase separation may arise from the presence of an (electrostatic) attractive interaction, which gives rise to an upper consolute loop within the lamellar phase region of a pure LAS isomer. Similar mechanisms may occur in biological membranes and could be responsible for the occurrence of membrane lipid patches.

Synthesis and phase characterization of a double-tailed pyrrole-containing surfactant: a novel tecton for the production of functional nanostructured materials.

A double-tailed polymerizable (pyrrolylalkyl) ammonium amphiphile has been synthesized, and its interfacial properties and aqueous phase behavior have been studied by polarized optical microscopy and X-ray diffraction. The Krafft temperature is about 27 degrees C, and the critical micelle concentration at 40 degrees C is about 1 mM, as obtained from surface tension measurements, potentiometry, and isothermal titration calorimetry. The lyotropic behavior of the surfactant is found to be of a complex nature. At concentrations higher than the micellar (L1) region, two mesophases have been identified: a second isotropic (L2) phase, which is probably micellar but not fully miscible with water, and a lamellar (L(alpha)) phase, showing interesting alignment properties. Small-angle X-ray scattering analysis of the mesophases has been evaluated in terms of a model of spherical micelles, which describes a mutual arrangement by a structure factor derived from a hard-sphere potential (Percus-Yevick, "PY", approach). Interest in the comprehensive phase behavior of the polymerizable surfactant is based on the desire to integrate the system into a composite material to obtain potentially conducting self-assembled hybrid mesostructures.

Evidence that 3,3',5-triiodothyronine is concentrated in and delivered from the locus coeruleus to its noradrenergic targets via anterograde axonal transport.

Recent immunohistochemical studies of rat brain triiodothyronine reveal heaviest localization in locus coeruleus perikarya. The cellular distribution is similar to that observed in concomitant studies of tyrosine hydroxylase immunohistochemistry: heavy clumps of immunoreactive triiodothyronine are distributed within locus coeruleus cytosol and in cell processes, leaving cell nuclei unstained. At the same time, in locus coeruleus targets, cell nuclei as well as surrounding neuropil are prominently triiodothyronine labeled. These observations, combined with diverse evidence linking thyroid hormone with norepinephrine at many levels of physiological and pathophysiological function, led to the hypothesis that the locus coeruleus binds and accumulates triiodothyronine and delivers the hormone via anterograde axonal transport to postsynaptic locus coeruleus targets, where nuclear triiodothyronine receptors are densely concentrated. Furthermore, the hypothesis predicts that destruction of locus coeruleus nerve terminals would interrupt this neural route of triiodothyronine delivery and prevent or reduce triiodothyronine labeling of nuclear receptors in noradrenergic target cells. To test this formulation, we gave the specific locus coeruleus lesioning agent, N-(2-chloroethyl)-N-2-bromobenzylamine hydrochloride (DSP-4), to adult male rats and examined their brains three, five and seven days thereafter by triiodothyronine and, in alternate sections, tyrosine hydroxylase immunohistochemistry. Treatment with DSP-4 resulted in specific and selective reduction in tyrosine hydroxylase and triiodothyronine immunohistochemical labeling in cell nuclei and in nerve cell processes within the neuropil of the hippocampus and cerebral cortex at all time periods examined. The results demonstrate that full occupancy of locus coeruleus target cells by triiodothyronine requires the presence of intact locus coeruleus projections and supports the proposal that, like norepinephrine, triiodothyronine delivery to noradrenergic targets occurs through delivery by locus coeruleus terminals. These findings provide strong support for earlier proposals that triiodothyronine functions as a co-transmitter with norepinephrine in addition to or as part of its genomic role in the cells receiving noradrenergic innervation.

Thyroid hormones as neurotransmitters.

During brain development, before the apparatus of neurotransmission has been set into place, many neurotransmitters act as growth regulators. In adult brain, their role in neurotransmission comes to the fore but neuronal plasticity and other growth-related processes are their continuing responsibility. This has been clearly demonstrated for catecholamines. Previous as well as recent evidence now indicates that thyroid hormones may participate in the developing and adult brain through similar mechanisms. Immunohistochemical mapping of brain triiodothyronine (antibody specificity established by numerous appropriate tests) demonstrated that the hormone was concentrated in both noradrenergic centers and noradrenergic projection sites. In the centers (locus coeruleus and lateral tegmental system) triiodothyronine staining, like that of tyrosine hydroxylase, was heavily concentrated in cytosol and cell processes. By contrast, in noradrenergic targets, label was most prominent in cell nuclei. Combined biochemical and morphologic data allows a construct of thyroid hormone circuitry to unfold: The locus coeruleus is conveniently located just beneath the ependyma of the 4th ventricle. Thyroxine, entering the brain via the choroid plexus, is preferentially delivered to subependymal brain structures. High concentrations of locus coeruleus norepinephrine promote active conversion of thyroxine to triiodothyronine, leading to the preeminence of the locus coeruleus as a site of triiodothyronine concentration. Results of treatment with the locus coeruleus neurotoxin DSP-4 established that axonal transport accounts for delivery of both triiodothyronine and norepinephrine from locus coeruleus to noradrenergic terminal fields. The apparatus for transduction of thyronergic and noradrenergic signals at both membrane and nuclear sites resides in the postsynaptic target cells. Upon internalization of hormone in post-synaptic target cells, genomic effects of triiodothyronine, norepinephrine, and/or their second messengers are possible and expected. The evidence establishes a direct morphologic connection between central thyronergic and noradrenergic systems, supporting earlier proposals that triiodothyronine or its proximate metabolites may serve as cotransmitters with norepinephrine in the adrenergic nervous system.

An acute dose of desmethylimipramine inhibits brain uptake of [125I]3,3',5-triiodothyronine (T3) in thyroxine-induced but not T3-induced hyperthyroid rats: implications for tricyclic antidepressant therapy.

The tricyclic antidepressant, desmethylimipramine (DMI), a highly selective inhibitor of presynaptic uptake of norepinephrine (NE), has also been shown to reduce [125I]3,3',5-triiodothyronine (T3) uptake in rat brain synaptosomes. Using DMI as a probe to examine 1) possible noradrenergic influences on thyroid hormone (TH) actions in brain and 2) TH:affective disorder relationships, we found that a single dose of DMI produces a small (7.4-25%) but significant (P < or = .05) decrease in brain uptake of both labeled T3 (T3) and labeled thyroxine (T4) across the spectrum of thyroid states from hypothyroid (HYPO) to euthyroid to T4-induced hyperthyroid. Therefore, it was noted with considerable interest that DMI appeared not to interfere with brain T3 uptake in T3-induced hyperthyroid (T3-HYPER) rats. To confirm this finding, thyroidectomized male rats were made T3-HYPER through administration of T3 (20 micrograms/kg) for 3 weeks or maintained without TH supplement for 6 weeks, becoming HYPO. Rats were given i.v. T3 and 5 min later i.p. DMI or saline. They were decapitated at 3 hr and brains retrieved for radiochemical analysis. Each experiment was run in three separate trials, with three to four rats in each treatment category (DMI or saline). Evaluation by analysis of variance showed that T3 concentrations (percentage of dose) were significantly lower in DMI than in saline-treated rat brain for HYPO (-15%; P = .0034) but not T3-HYPER rats (-2%; P = .6595). These results suggest that, as it does in the case of NE, DMI tends to block TH uptake sites in rat brain. The data also demonstrate a differential affinity for those sites in which T3 > DMI > T4 and suggest that T3 might augment tricyclic antidepressant therapy more effectively than T4.

Film autoradiography identifies unique features of [125I]3,3'5'-(reverse) triiodothyronine transport from blood to brain.

1. Steady-state iodothyronine profiles in plasma are composed of thyroid gland-synthesized hormones (mainly thyroxine) and tissue iodothyronine metabolites (mainly triiodothyronine and reverse triiodothyronine) that have entered the bloodstream. The hormones circulate in noncovalently bound complexes with a panoply of carrier proteins. Transthyretin (TTR), the major high-affinity thyroid hormone binding protein in rat plasma, is formed in the liver. It is also actively and independently synthesized in choroid plexus, where its function as a chaperone of thyroid hormones from bloodstream to cerebrospinal fluid (CSF) is undergoing 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. While they are in the free state relative to their binding proteins, iodothyronines in the cerebral circulation are putatively subject to transport across both the blood-brain barrier (BBB) and choroid plexus CSF barrier (CSFB) before entering the brain. Previous autoradiographic studies had already indicated that after intravenous administration the transport mechanisms governing thyroxine and triiodothyronine entry into brain were probably similar, whereas those for reverse triiodothyronine were very different, although the basis for the difference was not established at that time. Intense labeling seen over brain ventricles after intravenous administration of all three iodothyronines suggested that all were subject to transport across the CSFB. 3. To evaluate the role of the BBB and CSFB in determining iodothyronine access to brain parenchyma, autoradiograms prepared after intravenous administration of [125I]-labeled hormones (revealing results of transport across both 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 revealed that thyroxine and triiodothyronine were mainly transported across the BBB. They shared with reverse triiodothyronine a generally similar, limited pattern of penetration from CSF into the brain, with circumventricular organs likely to be the main recipients of iodothyronines (with or without retinol) transported across the CSFB. 5. Analysis of all of the images obtained after intravenous and icv hormone administration clarified the basis for the unique distribution of intravenously injected reverse triiodothyronine. The hormone is excluded by the BBB but may be subject to limited penetration into brain parenchyma via the CSF. 6. Overall the observations single out reverse triiodothyronine as the iodothyronine showing the most distinctive as well as the most limited pattern of transport from blood to brain.(ABSTRACT TRUNCATED AT 400 WORDS)

Desmethylimipramine, a potent inhibitor of synaptosomal norepinephrine uptake, has diverse effects on thyroid hormone processing in rat brain. II. Effect on in vivo 5'-deiodination of [125I]thyroxine.

We have studied the effects of desmethylimipramine (DMI), a tricyclic antidepressant, on thyroid hormone (TH) handling in rat brain in an effort to discover a pharmacological basis for reported interactions between TH, affective disorders and psychotropic drugs. An acute dose of DMI has been used in order to determine the primary effects of the drug in brain without perturbations from secondary effects. Recently we have reported that a single dose of DMI significantly decreases brain uptake of both [125I]thyroxine (T4) and [125I]3,3',5-triiodothyronine (T3) across the spectrum of thyroid states from hypothyroid (HYPO) to euthyroid (EU) to T4-induced hyperthyroid (HYPER). To investigate further the effects of DMI on brain processing of TH, we have measured effects of the drug on in vivo rates of T4 to T3 conversion in a series of experiments in which DMI (25 mg/kg) was given to HYPO, EU and HYPER male rats in conjunction with i.v. [125I]T4. Decreased in vivo conversion ratios (T3/T4 ratios) suggest that acute DMI treatment causes a significant decrease in 5'-deiodinase activity in balance of brain (but not cerebellum) in all DMI treated rats as compared to their saline treated controls (ANOVA, P < 0.0001). For assurance that reduced T3/T4 in DMI treated rat brain is not the result of DMI enhancement of 5-deiodination of T3 or T4, the effect of DMI on concentrations of labeled I-, rT3, and T2 (3,3'- and 3',5'-) was also observed. In no case was there a significant increase in any metabolite in DMI treated rats for any tissue studied.(ABSTRACT TRUNCATED AT 250 WORDS)

Desmethylimipramine, a potent inhibitor of synaptosomal norepinephrine uptake, has diverse effects on thyroid hormone processing in rat brain. I. Effects on in vivo uptake of 125I-labeled thyroid hormones in rat brain.

Several lines of evidence point to an interaction between amine uptake inhibitors (tricyclic antidepressants) and thyroid hormones. To examine this issue under conditions which would minimize secondary effects of drug treatment, desmethylimipramine (DMI), a highly specific norepinephrine uptake inhibitor, was given acutely as a single i.p. dose one hour before i.v. [125I]triiodothyronine (T3*) or [125I]thyroxine (T4*). Tissues were analysed after rat decapitation at 3, 5, 10, and 20 min intervals thereafter. DMI had a small but significant inhibitory effect on the brain uptake of both T3* (7.4%) and T4* (19%) over their respective 20-min time courses as indicated by two-way ANOVA. To examine the drug response further and to determine the effect of thyroid status on the response, hypothyroid (HYPO) and T4-induced hyperthyroid (HYPER) rats, were given i.v. T3* and, 5 min later, i.p. DMI or saline. They were killed 3 h later and tissue analysed. Because DMI effects on T4* uptake could not be evaluated over a 3 h period without blocking T4* to T3* conversion, sodium ipodate (60 mg/kg) was given in 2 doses before i.v. T4*. Under these conditions, DMI significantly reduced brain concentrations of the administered T3* and T4* in HYPO (15% and 19%) and in HYPER rats (13% and 25%). These results suggest that, as it does in the case of norepinephrine, DMI blocks the uptake site for T3 and T4 in rat brain. No information is available regarding the relationship, if any, between the thyroid hormone and norepinephrine uptake sites.