LVR-Klinikum Düsseldorf Hospital of the Heinrich-Heine University ...

LVR-KLINIKUM DÜsseLDORF – hOsPITaL OF The heINRIch-heINe UNIVeRsITY DÜsseLDORF
Investigations into the change of functional protein
patterns (proteomes) of B-lymphoblasts in test persons
with different stress reactibility resulting from the effects
of antidepressant drug components
K. Krieger, U. Henning, A. Klimke
Project period: 2002–2005
Financing: Departmental research budget
The proteome, which is defined as the total of all proteins in
one cell, is of great significance in disorders, especially in
mental disorders, because, for example, synapse receptor
proteins trigger spike generation and other phenomena of
cellular excitation.
After in vitro hydrocortisone exposure, B-lymphoblasts from
persons with hereditary affective psychoses demonstrated
a greater decrease of the glucocorticoid receptors than
B-lymphoblasts from healthy controls, which indicates
differences in glucocorticoid receptor auto-regulation. We
investigated these tumour cell lines (B-lymphoblasts) for
differences in the proteome. In this regard it is interesting
how, on the one hand, there were inter-individual differences
in the proteome and, on the other, changes of the functional
protein pattern caused by the action of drug components.
Genetic variants and function of the oestrogen
receptors in Alzheimer’s Dementia
C. Luckhaus, A. Boers, A. Klimke, U. Henning
in cooperation with P. Sand (Regensburg)
Project period: from 2002
Financing: Departmental research budget
Basic scientific investigations document neurotrophic,
neuroprotective and connectivity-promoting effects of
oestrogen in the CNS. In middle-aged women experimental
oestrogen administration resulted in improved performance
in memory tasks, which differs between the sexes.
Epidemiological investigations also indicate the positive
effect of oestrogen substitution on the risk of developing
Alzheimer’s Dementia (AD). However, current study results do
not support a general effectiveness of oestrogen substitution
as a prophylaxis for or treatment of AD in postmenopausal
women. The oestrogen hypothesis of AD is still particularly
relevant for early disorder mechanisms: oestrogen availability
or its effects in the CNS would undergo long-term changes
due to a genetically determined or acquired biological trait,
promoting neurodegenerative processes.
In a candidate-gene–related approach, we investigated
frequently occurring genetic variants of the oestrogen
receptors and the oestrogen sulphotransferase in association
with AD and found positive associations of individual
68
haplotypes. We could not demonstrate an oestrogen receptor
dysregulation using the IL-6 regulation in monocytes.
Cellular uptake and transportation of psychotropic drugs
U. Henning, K. Krieger, C. Luckhaus, A. Klimke
Project period: from 1998
Financing: Departmental research budget
In addition to the communication of cells using
neurotransmitter receptors, which are associated with
the regulation of downstream intracellular signalling
pathways, the intracellular accumulation of agents, which
are taken up both passively (e. g. through diffusion) and
actively via transporter proteins in cells and can influence
the cellular metabolism as far as apoptosis, is also of
interest from a research point of view. In order to investigate
the active transportation of clozapine – the agent of the
atypical antipsychotic drug Leponex® – promyeloid human
HL-60 tumour cells were used, which are established
as models for neutrophil granulocytes. These cells
appeared suitable for investigating the cytotoxic effects
of clozapine after its possible intracellular accumulation
with regard to the aetiopathogenesis of clozapine-induced
agranulocytosis. Our results show a temperature- and
pH-dependent accumulation of clozapine which is clearly
inhibitable through sodium azide, an agent decoupling the
mitochondrial respiratory chain, and by means of transport
inhibitors (e.g. indatraline). In addition, the main metabolites
of clozapine (desmethyl clozapine and clozapine N oxide) are
actively accumulated intracellularly. An intracellular uptake
of clozapine could be measured in glial and neuroblastoma
cells. Experiments currently being carried out into the
pharmacological characterisation of the transporter indicate
that this involves the intracellular transportation of clozapine
in storage vesicles, particularly in synaptic vesicles, which
occurs through the vesicular mono-amine transporter
system.
Influence of clozapine on haematopoiesis
K. Fehsel, S. Ferrea, C. Luckhaus in cooperation S. Loeffler,
G. Kobbe, V. Kolb-Bachofen and T. Königshausen
Project period: from 1999
Financing: Research commission of the Faculty of Medicine
at the Heinrich-Heine University, Düsseldorf (until 2001)
The most dangerous side effect of clozapine, agranulocytosis,
draws attention to the drug’s effects on the haematopoietic
system. At the acute stage of agranulocytosis, we find an
extremely significant production of superoxide anions in
neutrophil granulocytes, as well as a strong p53 and Bax a
expression. Most of the remaining neutrophil granulocytes are
apoptotic.