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

Since agranulocytosis usually occurs 6-8 weeks after the
start of clozapine treatment, we investigated the question
of what influence clozapine usually has on haematopoiesis
before and during this period. In studies of the spontaneous
course, it was clearly shown that clozapine at first causes
oxidative stress in neutrophil granulocytes. The NF kappa B
transcription factor becomes activated and the anti-oxidative
proteins A1, HO1 and NQO1 become expressed. In addition,
there is an increased transgression of CD34-positive stem
cells into the blood and the number of neutrophils increases,
whereas the number of erythrocytes falls. In addition, under
treatment with clozapine the neutrophils live longer and there
is a constitutive expression of the HIF1 alpha transcription
factor. The high proportion of oxygen in the venous blood (86%
versus 44%) of persons treated with clozapine indicates that
mitochondrial respiration is inhibited. Since cellular glucose
uptake is inhibited during clozapine treatment, clozapine
treatment corresponds to a preconditioning of the cells
through the deprivation of oxygen and glucose (OGD). Initial
results show that clozapine causes NO-mediated effects.
Under ischemic conditions, NO inhibits both the electron
transport chain and glucose import into mitochondria. This
ischemia-like condition could also be triggered by clozapine.
S-nitrosylation of the amino acid cysteine in position 93 of the
haemoglobin molecule causes a stronger binding of oxygen
to the haem group of haemoglobin, so that less oxygen is
delivered to the cells. If this preconditioning is disturbed,
cells do not develop protective measures against clozapineinduced
oxidative stress – the neutrophil granulocytes become
apoptotic and agranulocytosis ensues. Armed with this
knowledge, it should be possible to determine markers which
point to imminent agranulocytosis and which differentiate
early on between benign neutropenia and agranulocytosis.
Molecular effects of psychotropic drugs on adipogenesis
K. Fehsel, C. Luckhaus in cooperation with K. Hemmrich
Project period: from middle 2007
Financing: BIOMAT Interdisciplinary Centre for
Departmental Research of the Medical Faculty of RWTH
Aachen (IZKF VVB110-c)
Weight gain is a frequent side effect of treatment with
atypical antipsychotic drugs. Whereas in most drug
therapies a weight plateau is achieved after 1-2 years,
patients treated with clozapine continue to gain weight
and weight increases of 20-30 kg are not rare. We could
show in vitro that clozapine significantly increases the
differentiation of fat precursor cells (pre-adipocytes) and
that oxidative stress plays a decisive role in this process.
In the current project, in cooperation with the Department
of Plastic Surgery of the Heinrich-Heine University
Preparing tests in the Neurobiochemical Research Laboratory
ReseaRch
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