Na,K-ATPase alpha isoforms at the blood-cerebrospinal fluid-trigeminal nerve and blood-retina interfaces in the rat

Background: Cerebrospinal fluid (CSF) sodium concentration increases during migraine attacks, and both CSF and vitreous humor sodium increase in the rat migraine model. The Na,K-ATPase is a probable source of these sodium fluxes. Since Na,K-ATPase isoforms have different locations and physiological roles, our objective was to establish which alpha isoforms are present at sites where sodium homeostasis is disrupted. Methods: Specific Na,K-ATPase alpha isoforms were identified in rat tissues by immunohistochemistry at the blood-CSF barrier at the choroid plexus, at the blood-CSF-trigeminal barrier at the meninges, at the blood-retina barrier, and at the blood-aqueous barrier at the ciliary body. Calcitonin gene-related peptide (CGRP), occludin, or von Willibrand factor (vWF) were co-localized with Na,K-ATPase to identify trigeminal nociceptor fibers, tight junctions, and capillary endothelial cells respectively. Results: The Na,K-ATPase alpha-2 isoform is located on capillaries and intensely at nociceptive trigeminal nerve fibers at the meningeal blood-CSF-trigeminal barrier. Alpha-1 and −3 are lightly expressed on the trigeminal nerve fibers but not at capillaries. Alpha-2 is expressed at the blood-retina barriers and, with alpha-1, at the ciliary body blood aqueous barrier. Intense apical membrane alpha-1 was associated with moderate cytoplasmic alpha-2 expression at the choroid plexus blood-CSF barrier. Conclusion: Na,K-ATPase alpha isoforms are present at the meningeal, choroid plexus, and retinal barriers. Alpha-2 predominates at the capillary endothelial cells in the meninges and retinal ganglion cell layer

Synthesis and Electronic Structure Determination of Uranium(VI) Ligand Radical Complexes

   Pentagonal bipyramidal uranyl complexes of salen ligands, N,N’-bis(3-tert-butyl-(5R)-salicylidene)-1,2-phenylenediamine, in which R = tBu (1a), OMe (1b), and NMe2 (1c), were prepared and the electronic structure of the one-electron oxidized species [1a-c]+ were investigated in solution. The solid-state structures of 1a and 1b were solved by X-ray crystallography, and in the case of 1b an asymmetric UO22+ unit was found due to an intermolecular hydrogen bonding interaction. Electrochemical investigation of 1a-c by cyclic voltammetry showed that each complex exhibited at least one quasi-reversible redox process assigned to the oxidation of the phenolate moieties to phenoxyl radicals. The trend in redox potentials matches the electron-donating ability of the para-phenolate substituents. The electron paramagnetic resonance spectra of cations [1a-c]+ exhibited gav values of 1.997, 1.999, and 1.995, respectively, reflecting the ligand radical character of the oxidized forms, and in addition, spin-orbit coupling to the uranium centre. Chemical oxidation as monitored by ultraviolet-visible-near-infrared (UV-vis-NIR) spectroscopy afforded the one-electron oxidized species. Weak low energy intra-ligand charge transfer (CT) transitions were observed for [1a-c]+ indicating localization of the ligand radical to form a phenolate / phenoxyl radical species. Further analysis using density functional theory (DFT) calculations predicted a localized phenoxyl radical for [1a-c]+ with a small but significant contribution of the phenylenediamine unit to the spin density. Time-dependent DFT (TD-DFT) calculations provided further insight into the nature of the low energy transitions, predicting both phenolate to phenoxyl intervalence charge transfer (IVCT) and phenylenediamine to phenoxyl CT character. Overall, [1a-c]+ are determined to be relatively localized ligand radical complexes, in which localization is enhanced as the electron donating ability of the para-phenolate substituents is increased (NMe2 > OMe > tBu)

Elucidating the Electronic Structure of Transition Metal Complexes Featuring Redox Active Ligands

In this thesis a number of projects involving the design and characterization of complexes bearing redox active ligands are described. Focusing on the phenolate containing ligands, the properties and electronic structure of their corresponding metal complexes were studied by a series of experimental (i.e. electrochemistry, UV-Vis-NIR, EPR, rR etc.) and theoretical (DFT) methods. Specifically, the redox processes of these metal complexes were tuned by varying the para-ring substituents. In one study, nickel-salen (salen is a common abbreviation for N2O2 bis-Schiff-base bis-phenolate ligands) complexes were investigated, where the oxidation potentials of the ligand were predictably decreased as the electron donating ability of the para-ring substituents was increased (NMe2 > OMe > tBu > CF3). Interestingly, the oxidation of these geometrically-symmetric complexes afforded an asymmetric electronic structure in a number of cases, in which the ligand radical was localized on one phenolate rather than delocalized across the ligand framework. This difference in electronic structure was found to be dependent on the electron donating ability of the substituents; a delocalized ligand radical was observed for electron-withdrawing substituents and a localized ligand radical for strongly donating substituents. These studies highlight that para-ring substituents can be used to tune the electronic structure (metal vs. ligand based, localized vs. delocalized radical character) of metallosalen complexes. To evaluate if this electronic tuning can be applied to the metal center, a series of cobalt complexes of these salen ligands were prepared. Indeed, the electronic properties of the metal center were also significantly affected by para-ring substitution. These cobalt-salen complexes were tested as catalysts in organometallic radical-mediated polymerizations, where the most electron rich complexes displayed the best conversion rates. With a firm understanding of the role that the para-ring substituent can play in influencing the electronic structure and reactivity of metallosalen complexes in catalysis, two novel iron complexes, which contain a number of redox active phenolate fragments, were prepared. In addition, these iron-complexes feature a chiral bipyrrolidine backbone. Ligands with this chiral diamine backbone bind metals ions diastereoselectively owing to its increased rigidity, which is critical to stereoselectivity in catalysis. A symmetric (with two phenolates) ligand was prepared by reported methods, and a novel route to synthesize an asymmetric ligand (one phenolate and one pyridine) from symmetric starting materials was established. The neutral iron-complexes were found to be high spin (S = 5/2), and can undergo ligand based oxidation to form an antiferromagnetically-coupled (Stotal = 2) species. The results presented will serve as the basis for catalyst development using complexes of similar ligands

Influence of Electron-Withdrawing Substituents on the Electronic Structure of Oxidized Ni and Cu Salen Complexes

International audienc

Detailed Geometric and Electronic Structures of a One-Electron-Oxidized Ni Salophen Complex and Its Amido Derivatives

International audienc

Indolylbenzothiadiazoles as highly tunable fluorophores for imaging lipid droplet accumulation in astrocytes and glioblastoma cells

We present an extensive photophysical study of a series of fluorescent indolylbenzothiadiazole derivatives and their ability to specifically image lipid droplets in astrocytes and glioblastoma cells. All compounds in the series displayed positive solvatochromism together with large Stokes shifts, and π-extended derivatives exhibited elevated brightness. It was shown that the fluorescence properties were highly tunable by varying the electronic character or size of the N-substituent on the indole motif. Three compounds proved capable as probes for detecting small quantities of lipid deposits in healthy and cancerous brain cells. In addition, all twelve compounds in the series were predicted to cross the blood–brain barrier, which raises the prospect for future in vivo studies for exploring the role of lipid droplets in the central nervous system

Ligand-Centered Redox Activity in Cobalt(II) and Nickel(II) Bis(phenolate)-Dipyrrin Complexes

International audienc

The structure of a one-electron oxidized Mn( iii )-bis(phenolate)dipyrrin radical complex and oxidation catalysis control via ligand-centered redox activity

International audienc

Fe^III Bipyrrolidine Phenoxide Complexes and Their Oxidized Analogues

Fe^III complexes of the symmetric (2<i>S</i>,2′<i>S</i>)-[<i>N</i>,<i>N</i>′-bis­(1-(2-hydroxy-3,5-di-<i>tert</i>-butylphenylmethyl))]-2,2′-bipyrrolidine (<b>H</b>_<b>2</b><b>L</b>^<b>1</b>) and dissymmetric (2<i>S</i>,2′<i>S</i>)-[<i>N</i>,<i>N</i>′-(1-(2-hydroxy-3,5-di-<i>tert</i>-butylphenylmethyl))-2-(pyridylmethyl)]-2,2′-bipyrrolidine (<b>HL</b>^<b>2</b>) ligands incorporating the bipyrrolidine backbone were prepared, and the electronic structure of the neutral and one-electron oxidized species was investigated. Cyclic voltammograms (CV) of <b>FeL</b>^<b>1</b><b>Cl</b> and <b>FeL</b>^<b>2</b><b>Cl</b>_<b>2</b> showed expected redox waves corresponding to the oxidation of phenoxide moieties to phenoxyl radicals, which was achieved by treating the complexes with 1 equiv of a suitable chemical oxidant. The clean conversion of the neutral complexes to their oxidized forms was monitored by UV–vis-NIR spectroscopy, where an intense π–π* transition characteristic of a phenoxyl radical emerged (<b>[FeL</b>^<b>1</b><b>Cl]</b>^+•: 25 500 cm^–1 (9000 M^–1 cm^–1); [<b>FeL</b>^<b>2</b><b>Cl</b>_<b>2</b>]^+•: 24 100 cm^–1 (8300 M^–1 cm^–1). The resonance Raman (rR) spectra of <b>[FeL</b>^<b>1</b><b>Cl]</b>^+• and <b>[FeL</b>^<b>2</b><b>Cl</b>_<b>2</b><b>]</b>^<b>+</b>• displayed the characteristic phenoxyl radical ν_7a band at 1501 and 1504 cm^–1, respectively, confirming ligand-based oxidation. Electron paramagnetic resonance (EPR) spectroscopy exhibited a typical high spin Fe^III (<i>S</i> = 5/2) signal for the neutral complexes in perpendicular mode. Upon oxidation, a signal at <i>g</i> ≈ 9 was observed in parallel mode, suggesting the formation of a spin integer system arising from magnetic interactions between the high spin Fe^III center and the phenoxyl radical. Density functional theory (DFT) calculations further supports this formulation, where weak antiferromagnetic coupling was predicted for both <b>[FeL</b>^<b>1</b><b>Cl]</b>^+• and <b>[FeL</b>^<b>2</b><b>Cl</b>_<b>2</b><b>]</b>^+•