Main Focus

  • Mitochondrial function. Cell organelles playing a major role in aging are mitochondria, due to their central role in energy supply, as major source of oxidative stress, and as critical regulators of apoptosis. During evolution, the brain developed specific mechanisms to compensate oxidative stress, which could be specifically activated by nutrients, such as polyunsaturated fatty acids, Mediterranean plant and berry extracts as well as isolated secondary plant compounds, such as hydroxytyrosol, or curcumin. 

    Mitochondria – key organelles for energy supply and cell death

    Increasing evidence suggests that mitochondrial dysfunction plays an important role not only in brain aging but also in the pathogenesis of neurodegenerative diseases including AD. Mitochondria are complex, network forming organelles, involved in different metabolic pathways, e.g. citric acid cycle (TCA), energy transformation, amino acid metabolism and urea cycle. Mitochondria consist of inner and outer membranes composed of phospholipid bilayers and proteins. The inner mitochondrial membrane harbors the proteins of the electron transfer system (ETS), responsible for oxidative phosphorylation. The mitochondrial oxidative phosphorylation (OXPHOS) system is the final biochemical pathway producing energy in form of ATP by consuming oxygen. Electrons are transferred through the complexes of the mitochondrial respiration chain and simultaneously, an electrochemical proton gradient is build across the inner mitochondrial membrane generating the proton-motive force the production of ATP. 

    Alterations of mitochondrial efficiency and function are mainly related to alterations in mitochondrial mass, amount of respiratory enzymes or changes in enzyme activities. A reduction in mitochondrial content or lowered ETS results in a general limitation of cellular energy production. Dysfunction of single complexes of the respiratory system are frequently accompanied by deleterious side effects, such as loss of mitochondrial membrane potential (MMP) and subsequently decreased ATP levels, but also production of reactive oxygen species (ROS). 

    Mitochondria

    Beside enzymatically produced ROS by NADPH oxidases, cytochrome P450-dependent oxygenases, and xanthine dehydrogenases, mitochondria are regarded as the primary site of ROS production within cells. The ETS constantly generates low physiological levels of ROS, which trigger various defense mechanisms, i.e anti-oxidative molecules (e.g. glutathione or vitamin E) and antioxidant enzymes (e.g. superoxide dismutase (SOD), catalase, glutathione peroxidase and glutathione reductase). Furthermore, slight uncoupling of the ETC, for instance by uncoupling proteins, is one possibility to achieve a reduction in ROS production. Functional failure of this system can lead to deleterious effects, which might exaggerate consequence of mitochondrial dysfunction. Mitochondria are often considered as both the initiator and the first target of oxidative stress. Insufficient defense mechanisms and excessive ROS production (e.g as superoxide anions) can lead to cell damage. The major sources of superoxide anions are redox centers of complex I and III of the ETS and different mitochondrial flavoproteins. Superoxide is a rather weak radical, but it is the precursor of various, potentially more toxic  ROS. Its transformation into hydrogen peroxide, hydroxyl radicals as well as its participation in the formation of peroxynitrate creates strong oxidants. 

    Proteins of the OXPHOS system and lipids are key targets of the deleterious effects of ROS and might lead to membrane depolarization and subsequently impaired mitochondrial function. For example, oxidative damage of omega-3 polyunsaturated fatty acids (PUFA) in the inner mitochondrial membrane has been shown to result in loss of MMP, representing one early hallmark of apoptosis. Mitochondria act as signal-integrating organelles in the on-set of the intrinsic apoptotic pathway. Mitochondrial outer membrane permeabilization and permeability transition result both in the release of pro-apoptotic proteins which in turn activate caspases and further down-stream cell death mechanisms.

    Dysfunction of single mitochondrial enzyme complexes, ROS production, mitochondrial permeability transition pore opening (mPTP), elevated apoptosis, but also structural alterations and a diminished mitochondrial content play a role in brain aging and are believed to be crucial for the onset and progression of neurodegenerative diseases.


  • The mevalonate- (MVA-) pathway is a crucial metabolic pathway for most eukaryotic cells, with cholesterol as its most recognized product. Cholesterol represents a strucural component of neuronal membranes.  

    Cholesterol is also a precursor for neurosteroids which are produced in mitochondria after active import into the organell. Neurosteroidsynthesis links the mevalonate pathway to mitochondrial function. 

    The mevalonate pathway also provides the cell with isoprenoids - another class of indispensable lipids. The short-chain isoprenoids farnesylpyrophosphate (FPP) and geranylgeranylpyrophosphate (GGPP) covalently attach to small GTPases, which act as molecular switches in various biochemical pathway. 

    Synaptic dysfunction reprents another common hallmark of brain aging and neurodegenerative diseases.  The Rho family of small GTPases are one of the major regulators in synaptic plasticity, both in dendrite morphogenesis and stability as well as in growth cone motility. Prenylation is a requirement for their correct funtion. 

    A tentative conclusion our recent results is that the regulation of isoprenoids is altered in brain aging and AD and such changes may alter protein prenylation and contribute to AD neuropathophysiology. Our latest un-published data indeed strongly indicate that Rho GPTases are mislocolized in brain ageing and neurodegeneration. 

    Mevalonate neurosteroids

    We are currently evaluating the potency of 7,8-dihydroxyflavone and of natural isoprenoids occurring in food, like tocotrienols or monoterpenes to interfere with the MVA-pathway and to modify Rho-GTPase signalling.



  • Nutritional neuroscience. In spite of its relative small seize the brain consumes disproportionally high amounts of oxygen due to its high metabolic activity. In case of a deficit of antioxidants and antioxidant cellular mechanisms the high turnover of oxygen results in the production of reactive oxygen species and oxidative stress. Damage of biomolecules such as fatty acids, proteins, or DNA results in impairment of cells, tissues and organs. Those deleterious effects accumulate especially in differentiated tissues like the brain. Strategies for long-term prevention from oxidative stress would also delay the onset of age related diseases.

    A sufficient supply of micronutrients and secondary plant products, e.g. by functional food or supplementation represents a promising way for prevention. Insufficient penetration of the blood brain barrier is one problem of the preventive consumption of supplements or food enriched in secondary plant products. Recently, we reported potent antioxidative and cytoprotective properties of hydroxytyrosol, a ortho-diphenol in vitro, which is enriched in the polyphenolic fraction of olive oil. However, its protective properties were much smaller in dissociated brain cells isolated from brains of hydroxytyrosol feed mice. Hence, the modulation of neurochemical processes by biofunctional food represents a special challenge.

    Nutraceuticals contain food ingredients, such as vitamins, minerals and isolated phytochemicals in a concentrated form and in parts in relatively high concentrations. Thus, the issue of food safety has to be considered beside the assessment of physiological effects. Moreover, regarding food physiological effects have to be discriminated from pharmacological effects. As food-chemist and pharmacologist with special expertise in toxicology, I believe to be qualified for a competent evaluation of biofunctional food.

    Leads under investigation

    In the focus of our scientific interests are: polyunsaturated fatty acids, Mediterranean plant extracts, billberry extract, and isolated secondary plant compounds, such as hydroxytyrosol, monoterpenes, or curcumin.


  • Other neuroprotective compounds. 

    Statins protect from mitochondrial induced apoptosis

    Regulation of central cholesterol homeostasis and neuropharmacology of statins.The use of statins for the prevention or treatment of different neurodegenerative diseases has generated considerable interest albeit with some controversy. Mechanisms of statin-induced neuroprotection are not well understood. Recently, we reported that simvastatin stimulated neuronal gene expression and protein levels of the major antiapoptotic protein Bcl-2 in vivo and in vitro. We have recently shown that simvastatin administration in vivo and in vitro up-regulates gene expression and protein levels of the major antiapoptotic protein Bcl-2 in mouse and guinea pig brain tissue and in mouse primary neurons and SH-SY5Y human neuroblastoma cells. Suppression of Bcl-2 protein levels markedly reduced the neuroprotective effects of simvastatin in SH-SY5Y cells and dissociated brain cells ex vivo. Effects were independent of cholesterol and other products of the 3-hydroxy-3-methylglutaryl-CoA reductase pathway. Recently, we reported novel findings showing that up-regulation of Bcl-2 by simvastatin involves ET-1 and the transcription factor NFATc3.

    MVA groß

    We currently investigate if this novel neuroprotective mechanism may provide benefit in stroke models.

    Olesoxime for mitochondrial protection in neurodegeneration

    TRO19622

    The cholesterol-oxime Olesoxime, represents a novel mitochondrial pore modulator that was identified in the neuronal cell screening platform developed at Trophos Inc. Preclinical studies have demonstrated that this compound promote the function and survival of neurons and other cell types under disease relevant stress conditions (Bordet et al., JPET 322:709-720, 2007) through interactions with the mitochondrial permeability transition pore (mPTP). 

    Olesoxieme has successfully completed phase I studies in healthy volunteers and phase Ib studies in ALS and SMA patients. These clinical trials demonstrated that the product is well tolerated, has an excellent safety profile and that once-a-day oral dosing achieves the predicted exposure level required for efficacy, based on preclinical models. 

    Logo Mitotarget new

    In the frame of the EU-funded research project MitoTarget we are currently characterize Olesoxime`s mitochondrial function in neurons to better understand how mitochondrial dysfunction, leading to oxidative stress and activation of cell death pathways, is implicated in various neurodegenerative diseases and aging. Using preclinical model systems, we and the other partners investigate the ability of this new cholesterol-oxime compound to correct mitochondrial dysfunction and promote neuron survival and axonal growth.

    fp7logoban



  • Francesco Visioli, Madrid, Spain

    W. Gibson Wood, Minneapolis, USA

    Nicolas Bazan, New Orleans, USA

    MariVi Tejada-Simon, Houston, USA

    Ling Li, Minneapolis, USA

    Shaowu Cheng, Changsha, China

    Wei Yi Ong, Singapore

    Michael Heinrich, London, UK

    Bernd Fiebich, Freiburg, Germany

    Jan Frank, Hohenheim, Germany

    Clemens Kunz, Gießen, Germany

    Sabine Kuntz, Gießen, Germany

    Silvia Rudloff, Gießen, Germany

    Gerald Rimbach, Kiel, Germany

    Kristina Friedland, Mainz, Germany

    Jochen Klein, Frankfurt, Germany

    Manfred Schubert-Zsilavecz, Frankfurt, Germany

    Donat Kögel, Frankfurt, Germany

    Johannes Pantel, Frankfurt, Germany

    Ulrich Pilatus, Frankfurt, Germany

    Michael Göbel, Frankfurt, Germany

    Nils H. Schebb, Wuppertal, Germany

    Hans Zischka, Munich, Germany


  • Curcumin

    Curcumin is the yellow pigment derived from the rhizome of the plant turmeric (Curcuma longa), a major component in the spice curry, and frequently used as a natural colorant (E 100) by the food industry. Curcumin is a bis-α, β-unsaturated β-diketone with two ferulic acid moieties joined by a methylene bridge and known for its potent antioxidant and antiinflammatory activities.

    In the frame of the BMBF-project "Novel strategies for the enhancement of the potency of nutraceuticals with low oral bioavailability and their application in novel functional foods for optimum protection of the aging brain"  and in close collaboration with the lab of Jan Frank, we are testing the hypothesis, that consumption of the curry constituent curcumin reduces oxidative stress and prevents the age-dependent mitochondrial dysfunction in brain cells. 

    Mitochondrial dysfunction is characterized by a decrease in mitochondrial membrane potential (MMP) and ATP production and represents an early event in aging and age-related neuronal cell death. An excess production of reactive species is thought to contribute to mitochondrial dysfunction and, consequently, dietary antioxidants may be protective. Our data indicate that curcumin functioned as an antioxidant and dose-dependently increased MMP in dissociated murine brain cells. 

    curry.jpg

    Curcumin intake did not alter MDA concentrations but reversed the age-dependent decline in MMP and ATP production observed in SAMP8 mice fed a curcumin-free control diet. Curcumin feeding did not alter mitochondrial membrane fluidity or the protein content of complexes I-V of the respiratory chain. In conclusion, in vitro, but not ex vivo, curcumin protected DMBC from oxidation, which is explained by its low concentrations in the brain. 

    Regardless, curcumin potently prevented mitochondrial dysfunction, albeit not by inducing expression of complexes I-V, and up-regulated Nrf2-target genes in accordance with literature. Studies regarding potential signaling pathways involved in the prevention of mitochondrial dysfunction by curcumin are underway in our laboratories.

    Mediterranean diet

    Oryzanol & Tocotrienols

    Flavonols

    Omega-3-fatty acids

The main focus of our research activities lies on biochemical mechanisms of age related neurodegenerative diseases and the modulation thereof by food-based prevention and pharmacological intervention.


© Prof. Dr. Gunter P. Eckert 2017