Wolfgang Linert

The role of transition metals in the pathogenesis of Parkinson's disease

The mechanisms that lead to degeneration of melanized dopaminergic neurons in the brain stem, and particularly in the substantia nigra (SN) in patients with Parkinsons disease (PD) are still unknown. Demonstration of increased iron (Fe) in SN of PD brain has suggested that Fe-melanin interaction may contribute to oxidative neuronal damage. Energy dispersive X-ray electron microscopic analysis of the cellular distribution of trace elements revealed significant Fe peaks, similar to those of a synthetic melanin-Fe3+ complex, in intraneuronal electron-dense neuromelanin granules of the SN zona compacta, with highest levels in a case of PD and Alzheimers disease (AD). No Fe increase was found in Lewy bodies or in SN neurons of control specimens. The relevance of the in vitro chemical reactions of dopamine (DA), 5-hydroxydopamine (5-OHDA), and 6-hydroxydopamine (6-OHDA) with Fe3+ and with dioxygens for the pathogenesis of PD was investigated. An initiating mechanism for a chain reaction is suggested by which excessive Fe3+ arises. Melanin can act as an efficient antioxidant and in the presence of Fe can promote the formation of cytotoxic hydroxyl free radicals (.OH) which, in turn, initiate lipid peroxidation and consequent cell damage. While in vitro studies indicate that DA oxidation leading to melanin formation is independent of metal ions, saturation of melanin with large amounts of Fe3+ causes a significant generation of free .OH radicals. The relevance of the events induced by the melanin-Fe complex for the degeneration of dopaminergic neurons in PD is discussed. Free redox-active metal ions in the cytoplasm may cause site-specific peroxidation and thus exert neurotoxic effects. Excessive hydrogen peroxide in post mortem frontal cortex of a patient with PD and AD could be shown by confocal fluorescence microscopy, and this observation may be a direct indicator of oxidative stress.

Chromotropism of coordination compounds and its applications in solution

Abstract Chromotropic properties of coordination varying solvent, ionic species in solution, temperature, pressure, magnetic field or light irradiation are reviewed. Structural varieties and changeabilities of coordination compounds connected with these effects are discussed. Applications of solvatochromic Lewis-acid and Lewis-base indicators are presented in some detail.

New aspects on the hydrogen bond donor (HBD) strength of 1-butyl-3-methylimidazolium room temperature ionic liquids

Improved hydrogen bond donor (HBD) strength parameters of 1-butyl-3-methylimidazolium room temperature ionic liquids (RTILs), acceptor number (AN) of Gutmann and α of Kamlet–Taft, have been determined using [Fe(phen)2(CN)2]ClO4 as an original solvatochromic probe. Each of the parameters shows an excellent correlation with the independently determined HBA strength β (Kamlet–Taft) of the anion which demonstrates that empirical polarity parameters of RTILs can be utilized independently of each other.

False isokinetic relationships found in the nonisothermal decomposition of solids

Abstract Three types of false isokinetic relationships (IKR) arising due to variation of (i) reaction model, (ii) conversion, (iii) heating rate are discussed. Both the origin of IKRs and the meaning of the isokinetic temperature (Tiso) is elucidated. It is shown that IKRs (ii) and (iii) in nonisothermal reactions are inherent only to multi-step processes. Tiso evaluated from an IKR (i) is a temperature related to a specific conversion. Tiso evaluated from IKRs (ii) and (iii) is an arbitrary temperature within the temperature region of the process provided that a valid reaction model is used to describe the kinetics of the process.

In vitro and in vivo studies investigating possible antioxidant actions of nicotine: relevance to Parkinson’s and Alzheimer’s diseases

An inverse relationship appears to exist between cigarette smoking and the risk of Parkinsons and Alzheimers diseases. Since both diseases are characterized by enhanced oxidative stress, we investigated the antioxidant potential of nicotine, a primary component of cigarette smoke. Initial chromatographic studies suggest that nicotine can affect the formation of the neurotoxin 6-hydroxydopamine resulting from the addition of dopamine to Fentons reagent (i.e., Fe2+ and H2O2). Thus, under certain circumstances, nicotine can strongly affect the course of the Fenton reaction. In in vivo studies, adult male rats being treated with nicotine showed greater memory retention than controls in a water maze task. However, neurochemical analysis of neocortex, hippocampus, and neostriatum from these same animals revealed that nicotine treatment had no effect on the formation of reactive oxygen species or on lipid peroxidation for any brain region studied. In an in vitro study, addition of various concentrations of nicotine to rat neocortical homogenates had no effect on lipid peroxidation compared to saline controls. The results of these studies suggest that the beneficial/protective effects of nicotine in both Parkinsons disease and Alzheimers disease may be, at least partly, due to antioxidant mechanisms.

Highly reactive oxygen species: detection, formation, and possible functions

The so-called reactive oxygen species (ROS) are defined as oxygen-containing species that are more reactive than O2 itself, which include hydrogen peroxide and superoxide. Although these are quite stable, they may be converted in the presence of transition metal ions, such as Fe(II), to the highly reactive oxygen species (hROS). hROS may exist as free hydroxyl radicals (HO·), as bound (“crypto”) radicals or as Fe(IV)-oxo (ferryl) species and the somewhat less reactive, non-radical species, singlet oxygen. This review outlines the processes by which hROS may be formed, their damaging potential, and the evidence that they might have signaling functions. Since our understanding of the formation and actions of hROS depends on reliable procedures for their detection, particular attention is given to procedures for hROS detection and quantitation and their applicability to in vivo studies.

Donor numbers of anions in solution: the use of solvatochromic Lewis acid–base indicators

The shift of the visible d–d absorption bands of [Cu(acac)(tmen)]+(acac = acetylacetonate, tmen =N,N,N′,N′-tetramethylethylenediamine) in various solvents resulting from the co-ordination of solvent molecules and anionic species X has been investigated. The results have been used to establish donor numbers (DNX, dce) of anions dissolved in 1,2-dichloroethane (dce) on the same scale as that already established for solvents. Apparent donor numbers for anions dissolved in various solvents other than dce (DNX, solv) are also given and used to show that the donor properties of anions are directly related to the acceptor number (ANsolv) of the solvent. This arises from competition between solvent and acceptor ion for the anion leading to a steady decrease in the effective donor number of the anion as ANsolv increases, culminating in an effective donor number of zero for all anions in the strong acceptor solvent water (ion pairing is at a minimum in water). The values of the anion donor numbers are related to some experimental results such as spectral, equilibrium, kinetic and thermodynamic data for selected systems. This method of establishing donor numbers for anions is shown to be reliable and easy to apply.

Redox reactions of neurotransmitters possibly involved in the progression of Parkinson's Disease

In Parkinsons Disease the neuromelanin in the substania nigra is known to contain considerably increased amounts of iron suggesting the presence of free, unprotected iron ions during its formation. Iron(II) is known to interact with peroxide via Fentons reaction producing OH-radicals or ferryl (Fe(IV)) species. This can readily oxidize the neurotransmitter dopamine to the neurotoxic 6-hydroxydopamine (6-OHDA) which is a strong reducing agent. The produced 6-OHDA is, in turn, able to reduce and possibly release iron, as iron(II), from the iron storage protein ferritin. This cycle of events could well explain the development of Parkinsons Disease due to a continuous production of cell damaging species. The contrasting behaviour of 6-OHDA with some other important catecholamines is discussed.

catena-[μ-Tris(1,2-bis(tetrazol-1-yl)ethane-N4,N4′)iron(II)] bis(tetrafluoroborate): synthesis, structure, spectroscopic and magnetic characterization of a chain-type coordination polymer spin-crossover compound

In analogy to a common synthesis of 1-substituted 5-H tetrazoles (Tetrahedron Lett. 36 (1995)1759; Beloruss. Gos. Univ., Minsk, USSR. Khim. Geterotsikl. Soedin. 11 (1985) 1521; Beloruss. Gos. Univ., Minsk, USSR. Khim. Geterotsikl. Soedin. 1 (1991) 66; BGU, Belarus. Vestsi Akad. Navuk Belarusi, Ser. Khim. Navuk 1 (1992) 73), the new bidentate ligand 1,2-bis(tetrazol-1-yl)ethane [endi] was synthesized and characterized by X-ray diffraction, NMR, IR and UV–Vis spectroscopy. By using iron(II) tetrafluoroborate hexahydrate the complexation with this ligand yields a 1-dimensional linear coordination polymer similar to the recently published chain compound (Inorg. Chem. 39 (2000) 1891) exhibiting a thermally induced spin-crossover phenomenon. Similar to the 1,2-bis(tetrazol-1-yl)propane-bridged compound, our 1,2-bis(tetrazol-1-yl)ethane-bridged compound shows a gradual spin transition, but the spin-crossover temperature T1/2≈140 K is found to be 10 K above the other T1/2. The T1/2 was determined by temperature-dependent 57Fe-Mossbauer, far FT-IR and UV–Vis spectroscopy as well as by temperature-dependent magnetic susceptibility measurements. Single crystals of the complex were grown in situ from a solution of the ligand and iron(II) tetrafluoroborate. The X-ray structure determinations of both the high spin as well as the low spin state of the compound revealed a solid state structure, which is comparable to that of catena-[Fe(1,2-bis(tetrazole-1-yl)propane)3](ClO4)2 (Inorg. Chem. 39 (2000) 1891; 2nd TMR-TOSS Meeting, 4th Spin Crossover Family Meeting, Lufthansa Training Center, Seeheim/Germany, April 30–May 2, 1999). Both the 1,2-bis(tetrazol-1-yl)propane-bridged and our compound do not show a thermal hysteresis effect (J. Am. Chem. Soc. 115 (1993) 9810; Inorg. Chim. Acta 37 (1979) 169; Chem. Phys. Lett. 93 (1982) 567). The synthesis of the complex described in the experimental section yielded a fine powdered product being poorly soluble in most common solvents. The single crystal measurements were done with crystals obtained by various diffusion methods. Most of them yielded either thin needles or small hexagonal prism crystals depending on the specific conditions.

The use of the isokinetic relationship and molecular mechanics to investigate molecular interactions in inclusion complexes of cyclodextrins

Abstract The formation of 1:1 inclusion complexes of α- and β-cyclodextrin with various compounds in aqueous medium has been investigated for the isokinetic behavior. The included compounds fall clearly into definite groups, showing that the isokinetic behavior, when based on proper statistical methods, can be used as a tool for the interpretation and dissection of different interaction and reaction mechanisms in similar chemical reactions. Theoretical free energies, enthalpies and entropies of the formation of the inclusion complexes are calculated using the “rigid molecule approximation” of the molecular mechanics approach. The calculated results are in good agreement with the experimental values. The orientations of the embedded guest molecules in cyclodextrins obtained from the calculations are in agreement with experimental findings. The classification of the guest molecules can be explained in terms of different interaction energies.