benjamin drukarch - Academia.edu (original) (raw)

Papers by benjamin drukarch

The locus ceruleus is among the earliest affected brain regions in Parkinson’s disease (PD) showi... more The locus ceruleus is among the earliest affected brain regions in Parkinson’s disease (PD) showing Lewy body pathology and neuronal loss. To improve our understanding of the pathogenesis of PD, we performed the first proteomic analysis ever of post-mortem locus ceruleus tissue of six pathologically confirmed PD patients, and six ageand gendermatched non-neurological controls. In total 2495 proteins were identified, of which 87 proteins were differentially expressed in the locus ceruleus of PD patients compared to controls. The majority of these differentially expressed proteins are known to be involved in processes that have been implicated in the pathogenesis of PD previously, including mitochondrial dysfunction, oxidative stress, protein misfolding, cytoskeleton dysregulation and inflammation. Several individual proteins were identified that have hitherto not been associated with PD, such as regucalcin, which plays a role in maintaining intracellular calcium homeostasis, and isof...

Advances in Pharmacology, 1997

ABSTRACT Long-term treatment of Parkinson's disease (PD) patients with L-dopa and/or D2-r... more ABSTRACT Long-term treatment of Parkinson's disease (PD) patients with L-dopa and/or D2-receptor agonists leads to wearing off, on-off effects, and/or dyskinesias. Apart from D2 receptors, D1 receptors also might serve as pharmacotherapeutic targets in PD because D1 receptors also are targets for the action of DA in the striatum and are involved in the regulation of motor behavior. The researchers have elaborated in this issue by testing two newly developed benzazepines in the primate MPTP model for PD. They have focused on the therapeutic and unwanted side effects of the two D1 agonists SKF 81297 and SKF 82958. It is found that SKF 81297 apparently “stimulates” motor behavior, the effects are predominantly dyskinetic, abnormal, and clearly not goal directed. Thus, it cannot be considered as “real” antiparkinsonian. The experiment in bilaterally MPTP-lesioned rhesus monkeys to investigate the effects of a D1 agonist and especially the behavioral effects of chronic treatment shows that the D1 agonists SKF 81297 and SKF 82958 “stimulate” to a certain extent motor behavior. But they lack a clear effect on goal-directed movements that might be considered a real antiparkinsonian effect. However, both agonists clearly induce dyskinetic effects and epileptoid activity. Moreover, it has been reported that the effects of several benzazepines on motor behavior have failed to correlate with their efficacy in stimulating adenylate cyclase activity, a paradigm generally considered the hallmark of D1-receptor efficacy.

Psychopharmacology, 1995

Interactions at the behavioral level between dopamine (DA) and opioid receptors in the mammalian ... more Interactions at the behavioral level between dopamine (DA) and opioid receptors in the mammalian brain have been amply demonstrated. Considering the pivotal role for DA receptors in the pharmacotherapy of Parkinson's disease (PD), these interactions might be clinically relevant. Therefore, in the present study the effects of the opioid antagonist naltrexone and agonist morphine on DI and D2 receptor induced stimulation of motor behavior in the unilateral MPTP monkey model (n = 5) of PD were investigated. The results show that both naltrexone and morphine [0.1-t.0mg/kg; intramuscular injection (IM)] inhibited D2 receptor stimulated contralateral rotational behavior and hand use induced by administration of quinpirole (LY 171555; 0.0t mg/kg, IM) in a dose-related way. However, no effects of these opioid drugs were observed on D~ receptor stimulated contralateral rotational behavior and hand use induced by administration of SKF 81297 (0.3mg/kg, IM). Interestingly, the action of the alleged preferential #-receptor antagonist naltrexone was mimicked by the selective c~-opioid antagonist naltrindole (0.5 mg/kg, IM). From this study it is concluded that in a non-human primate model of PD, alteration of opioid tonus leads to modulation of D2 receptor but not D1 receptor controlled motor behavior. The possible

Neurochemistry International, 1992

European Journal of Pharmacology, 1987

The in vitro release of acetylcholine in rat brain tissue was inhibited by 9-amino-l,2,3,4-tetrah... more The in vitro release of acetylcholine in rat brain tissue was inhibited by 9-amino-l,2,3,4-tetrahydroacridine (THA). Atropine antagonized this effect of THA. As THA does not display an affinity for muscarinic receptors, we conclude that THA inhibits acetylcholinesterase activity. In electrophysiological studies with neurons of Lymnaea stagnalis, THA inhibited the slow outward K + current and consequently increased the duration of the action potentials. It is discussed that both effects of THA possibly contribute to its reported effect in the treatment of patients with Alzheimer's disease.

European Journal of Morphology, 2002

Biomarker Insights, 2010

von Willebrand Factor (vWF) is a multimeric plasma protein important for platelet plug formation.... more von Willebrand Factor (vWF) is a multimeric plasma protein important for platelet plug formation. As part of its haemostatic role, it is released from endothelial cells during vascular stress or injury and is considered an excellent biomarker of endothelial function. Currently, there are no validated kits available to measure vWF in rabbits. We developed a sensitive and reproducible sandwich enzyme-linked immunosorbent assay (ELISA) for detection of vWF in rabbit plasma using commercially available antibodies and reagents. Purified human vWF was used as a calibrator standard with a dynamic range of 1.56–100 ng/mL. The Minimum Required Dilution for rabbit plasma was 1:100. When plasma was spiked with 3.76 or 10 ng/mL vWF, recovery was 108 ± 2% and 93 ± 2%, respectively. Intra- and inter-assay precision for 8 rabbit plasma samples were 3% and 4%, respectively. The Minimum Detectable Concentration was 254 pg/mL for purified human vWF and 1:10,700 dilution of cholesterol-fed rabbit plas...

Progress in neurobiology, Jan 4, 2018

Nerve impulse generation and propagation are often thought of as solely electrical events. The pr... more Nerve impulse generation and propagation are often thought of as solely electrical events. The prevalence of this view is the result of long and intense study of nerve impulses in electrophysiology culminating in the introduction of the Hodgkin-Huxley model of the action potential in the 1950s. To this day, this model forms the physiological foundation for a broad area of neuroscientific research. However, the Hodgkin-Huxley model cannot account for non-electrical phenomena that accompany nerve impulse propagation, for which there is nevertheless ample evidence. This raises the question whether the Hodgkin-Huxley model is a complete model of the nerve impulse. Several alternative models have been proposed that do take into account non-electrical aspects of the nerve impulse and emphasize their importance in gaining a more complete understanding of the nature of the nerve impulse. In our opinion, these models deserve more attention in neuroscientific research, since, together with th...

Cells

Amyloid-beta (Aβ) deposition in the brain is closely linked with the development of Alzheimer’s d... more Amyloid-beta (Aβ) deposition in the brain is closely linked with the development of Alzheimer’s disease (AD). Unfortunately, therapies specifically targeting Aβ deposition have failed to reach their primary clinical endpoints, emphasizing the need to broaden the search strategy for alternative targets/mechanisms. Transglutaminase-2 (TG2) catalyzes post-translational modifications, is present in AD lesions and interacts with AD-associated proteins. However, an unbiased overview of TG2 interactors is lacking in both control and AD brain. Here we aimed to identify these interactors using a crossbreed of the AD-mimicking APP23 mouse model with wild type and TG2 knock-out (TG2−/−) mice. We found that absence of TG2 had no (statistically) significant effect on Aβ pathology, soluble brain levels of Aβ1–40 and Aβ1–42, and mRNA levels of TG family members compared to APP23 mice at 18 months of age. Quantitative proteomics and network analysis revealed a large cluster of TG2 interactors invol...

Biomedicine & Pharmacotherapy

There is an urgent need for the introduction of novel and better (i.e., improved risk-benefit pro... more There is an urgent need for the introduction of novel and better (i.e., improved risk-benefit profile) compounds for the treatment of major psychiatric disorders, in particular mood and psychotic disorders. However, despite increased societal awareness and a rising public and professional demand for such agents from patients and physicians, the pharmaceutical industry continues to close down its psychopharmacology research facilities in reaction to the lack of success with the search for new psychotropics. It is high time to stop this untoward trend and explore "new" lines of investigation to solve the current crisis in psychopharmacological research. In line with the prevailing molecular view in drug research in general, also in psychopharmacology mechanistic explanations for drug effects are "traditionally" looked for at the level of molecular targets, like receptors and transporters. Also, more recent approaches, although using so-called systems-and function-based approaches to model the multidimensional characteristics of psychiatric disorders and psychotropic drug action, still emphasize this search strategy for new therapeutic leads by identification of single molecules or molecular pathways. This "psychomolecular gaze" overlooks and disregards the fact that psychotropic agents usually are highly hydrophobic and amphipathic/amphiphilic agents that, in addition to their interaction with membrane-bound proteins in the form of e.g. receptors or transporters, also interact strongly with the lipid component of cellular membranes. Here we suggest to develop a program of systematic, whole-cell level based, investigation into the role of these physical-chemical cellular membrane interactions in the therapeutic action of known psychotherapeutics. This complementary yet conceptually different approach, in our opinion, will complement drug development in psychopharmacology and thereby assist in overcoming the current crisis. In this way the "old" physical theory of drug action, which antedates the current, primary molecular, paradigm may offer "new" options for lead discovery in psychopharmacological research.

Cytokine

Macrophages exert either a detrimental or beneficial role in Multiple Sclerosis (MS) pathology, d... more Macrophages exert either a detrimental or beneficial role in Multiple Sclerosis (MS) pathology, depending on their inflammatory environment. Tissue Transglutaminase (TG2), a calcium-dependent cross-linking enzyme, has been described as a novel marker for anti-inflammatory, interleukin-4 (IL-4) polarized macrophages (M(IL-4)), which represent a subpopulation of macrophages with phagocytic abilities. Since TG2 is expressed in macrophages in active human MS lesions, we questioned whether TG2 drives the differentiation of M(IL-4) into an anti-inflammatory phenotype and whether it plays a role in the phagocytosis of myelin by these cells. In macrophage-differentiated THP-1 monocytes, TG2 was increased upon IL-4 treatment. Reducing TG2 expression impairs the differentiation of M(IL-4) macrophages into an anti-inflammatory phenotype and drives them into a pro-inflammatory state. In addition, reduced TG2 expression resulted in increased presence of myelin basic protein in macrophages upon myelin exposure of M(IL-4) macrophages. Moreover, the elevated presence of an early endosome marker and equal expression of a lysosome marker compared to control macrophages, suggest that TG2 plays a role in phagosome maturation in M(IL-4) macrophages These data suggest that tuning macrophages into TG2 producing anti-inflammatory cells by IL-4 treatment may benefit effective myelin phagocytosis in e.g. demyelinating MS lesions and open avenues for successful regeneration.

HEC Forum

The aim of this research was to gain insight into the experiences and perspectives of individual ... more The aim of this research was to gain insight into the experiences and perspectives of individual members of a Medical Research Ethics Committee (MREC) regarding their individual roles and possible tensions within and between these roles. We conducted a qualitative interview study among members of a large MREC, supplemented by a focus group meeting. Respondents distinguish five roles: protector, facilitator, educator, advisor and assessor. Central to the role of protector is securing valid informed consent and a proper risk-benefit analysis. The role of facilitator implies that respondents want to think along with and assist researchers in order to help medical science progress. As educators, the respondents want to raise ethical and methodological awareness of researchers. The role of advisor implies that respondents bring in their own expertise. The role of assessor points to contributing to the overall evaluation of the research proposal. Various tensions were identified within an...

Frontiers in Cellular Neuroscience

The Journal of Neuroscience

Journal of neuroinflammation, Jan 21, 2017

Leukocyte infiltration into the central nervous system is an important feature of multiple sclero... more Leukocyte infiltration into the central nervous system is an important feature of multiple sclerosis (MS) pathology. Among the infiltrating cells, monocytes comprise the largest population and are considered to play a dual role in the course of the disease. The enzyme tissue transglutaminase (TG2), produced by monocytes, plays a central role in monocyte adhesion/migration in animal models of MS. In the present study, we questioned whether TG2 expression is altered in monocytes from MS patients compared to healthy control (HC) subjects. Moreover, we determined the inflammatory status of these TG2-expressing monocytes, what inflammatory factor regulates TG2 expression, and whether TG2 can functionally contribute to their adhesion/migration processes. Primary human monocytes from MS patients and HC subjects were collected, RNA isolated and subjected to qPCR analysis. Human THP-1 monocytes were lentivirally transduced with TG2 siRNA or control and treated with various cytokines. Subsequ...