Evaluating blood-brain barrier permeability in a rat model of type 2 diabetes.

BACKGROUND: This is an exploratory study using a novel imaging modality, quantitative ultrashort time-to-echo, contrast enhanced (QUTE-CE) magnetic resonance imaging to evaluate the permeability of the blood-brain barrier in a rat model of type 2 diabetes with the presumption that small vessel disease is a contributing factor to neuropathology in diabetes. METHODS: The BBZDR/Wor rat, a model of type 2 diabetes, and age-matched controls were studied for changes in blood-brain barrier permeability. QUTE-CE, a quantitative vascular biomarker, generated angiographic images with over 500,000 voxels that were registered to a 3D MRI rat brain atlas providing site-specific information on blood-brain barrier permeability in 173 different brain areas. RESULTS: In this model of diabetes, without the support of insulin treatment, there was global capillary pathology with over 84% of the brain showing a significant increase in blood-brain barrier permeability over wild-type controls. Areas of the cerebellum and midbrain dopaminergic system were not significantly affected. CONCLUSION: Small vessel disease as assessed by permeability in the blood-brain barrier in type 2 diabetes is pervasive and includes much of the brain. The increase in blood-brain barrier permeability is a likely contributing factor to diabetic encephalopathy and dementia.

Syntheses, X-ray crystal structures, and optical, fluorescence, and nonlinear optical characterizations of diphenylphosphino-substituted bithiophenes.

A series of bithiophene derivatives that are either symmetrically disubstituted with two Ph(2)(X)P groups (X = O, S, Se) or monosubstituted with one Ph(2)(X)P group (X = O, S, Se) and an organic functional group (H, CHO, CH(2)OH, CO(2)Me) have been synthesized. The X-ray crystal structures of Ph(2)(Se)P(C(4)H(2)S)(2)P(Se)Ph(2), Ph(2)(O)P(C(4)H(2)S)(2)H, Ph(2)(S)P(C(4)H(2)S)(2)H, and Ph(2)(O)P(C(4)H(2)S)(2)CH(2)OH exhibit very different solid-state structures depending on the type of intermolecular π-π interactions that occur. The compounds have been characterized by electronic absorption and fluorescence studies. Of particular interest is that the quantum yields of Ph(2)(O)P(C(4)H(2)S)(2)H, Ph(2)(O)P(C(4)H(2)S)(2)P(O)Ph(2), Ph(2)(O)P(C(4)H(2)S)(2)CO(2)Me, and Ph(2)(O)P(C(4)H(2)S)(2)CH(2)OH are significantly larger than that of bithiophene (factors of 13, 14, 14, and 22, respectively). This behavior is quite different from that of analogously substituted terthiophenes in which substitution results in only modest increases in the quantum yields over that of terthiophene (factors of 0.94, 2.7, 1.3, and 1.5, respectively). DFT studies of the emission process suggest that modifying the Ph(2)(X)P group affects both the fluorescence and nonradiative rate constants while modifications of the organic substituents primarily affect the nonradiative rate constants. The higher quantum yields of the substituted bithiophenes make them promising for application in organic light-emitting devices (OLED). The optical power limiting (OPL) performances of these Ph(2)(X)P-substituted bithiophenes were evaluated by nonlinear transmission measurements in the violet-blue spectral region (430-480 nm) with picosecond laser pulses. The OPL performances are enhanced by heavier X groups and when by higher solubilities. Saturated chloroform solutions of Ph(2)(O)P(C(4)H(2)S)(2)H and Ph(2)(S)P(C(4)H(2)S)(2)H exhibit significantly stronger nonlinear absorption than any previously reported compounds and are promising candidates for use in broadband optical power limiters.

Syntheses, and optical, fluorescence, and nonlinear optical characterization of phosphine-substituted terthiophenes.

Earlier studies of phosphine-substituted terthiophenes have demonstrated that some of these materials exhibit nonlinear absorption at 532 nm. However, this wavelength is significantly removed from the linear absorption maxima of the complexes, suggesting that better nonlinear absorption might be observed at wavelengths closer to the linear absorption maxima. To investigate this possibility, a library of compounds has been prepared either by varying the group attached to the nonbonding pair of electrons on the phosphorus atoms of 5,5''-bis(diphenylphosphino)-2,2':5',2''-terthiophene (PT(3)P), or by introducing additional substituents on the 5''-position of 5-(diphenylphosphino)-2,2':5',2''-terthiophene (PT(3)). All these compounds have been characterized using multinuclear NMR, UV-vis, and fluorescence spectroscopy. The compounds are strongly fluorescent, and both the fluorescence wavelength and the intensity depend upon the thiophene substituents. The nonlinear optical properties have also been evaluated at various wavelengths in the blue region. Each compound exhibits reverse saturable absorption, and the intensity of the reverse saturable absorption at a particular wavelength depends on the chemical structure of the compound.

Using multimodal MRI to investigate alterations in brain structure and function in the BBZDR/Wor rat model of type 2 diabetes.

BACKGROUND: This is an exploratory study using multimodal magnetic resonance imaging (MRI) to interrogate the brain of rats with type 2 diabetes (T2DM) as compared to controls. It was hypothesized there would be changes in brain structure and function that reflected the human disorder, thus providing a model system by which to follow disease progression with noninvasive MRI. METHODS: The transgenic BBZDR/Wor rat, an animal model of T2MD, and age-matched controls were studied for changes in brain structure using voxel-based morphometry, alteration in white and gray matter microarchitecture using diffusion weighted imaging with indices of anisotropy, and functional coupling using resting-state BOLD functional connectivity. Images from each modality were registered to, and analyzed, using a 3D MRI rat atlas providing site-specific data on over 168 different brain areas. RESULTS: There was an overall reduction in brain volume focused primarily on the somatosensory cortex, cerebellum, and white matter tracts. The putative changes in white and gray matter microarchitecture were pervasive affecting much of the brain and not localized to any region. There was a general increase in connectivity in T2DM rats as compared to controls. The cerebellum presented with strong functional coupling to pons and brainstem in T2DM rats but negative connectivity to hippocampus. CONCLUSION: The neuroradiological measures collected in BBBKZ/Wor rats using multimodal imaging methods did not reflect those reported for T2DB patients in the clinic. The data would suggest the BBBKZ/Wor rat is not an appropriate imaging model for T2DM.

Synthesis, linear and nonlinear optical properties of phosphonato-substituted bithiophenes derived from 2,2'-biphenol.

Two new series of phosphonato-substituted bithiophenes, BpP(X)(C4H2S)2H and BpP(X)(C4H2S)2P(X)Bp (Bp = 2,2'-C12H8O2, X = O, S, Se), have been synthesized and characterized using linear absorption and emission spectra, and third-order nonlinear absorption measurements at 430 nm with 27 ps laser pulses. The compounds were synthesized in three steps: (1) reacting lithiated bithiophene with (Et2N)2PCl; (2) reacting the product from the first step with biphenol; and (3) reacting the product from the second step with the appropriate chalcogen. The X-ray crystal structures of two of the compounds, BpP(O)(C4H2S)2P(O)Bp and BpP(Se)(C4H2S)2P(Se)Bp, are reported and show a number of intermolecular π-π interactions. The linear absorption spectra, emission spectra, and emission quantum yields show distinct trends with respect to the chalcogen and the number of phosphorus substituents attached to the 2,2'-bithiophene ring. The compounds show emission maxima at wavelengths ranging from 380-400 nm and, BpP(S)(C4H2S)2H shows a 23-fold increase in fluorescence quantum yield relative to that of 2,2'-bithiophene. Fluorescence lifetimes and radiative and non-radiative decay rate constants for the first singlet excited state have been extracted from the quantum yields using time-dependent DFT calculations. Nonlinear transmission measurements indicate that all of the compounds show nonlinear absorption at 430 nm with 27 ps laser pulses in spite of their low solubilities. Notably, the nonlinear absorption threshold of a 0.16 mol L(-1) CH2Cl2 solution of BpP(Se)(C4H2S)2H is 0.9 J cm(-2). The excellent emission quantum yields and good nonlinear absorptions make these compounds promising candidates for optical power limiting applications and as host materials for violet-blue organic light emitting diodes.