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New Targets of HMG-CoA
Reductase Inhibitors (Statins)
in the Central Nervous System
Statins are
potent inhibitors of the hydroxymethylglutaryl-coenzyme
A (HMG-CoA) reductase a key
enzyme of the cellular cholesterol
synthesis. They can induce
comparatively large reductions
in plasma cholesterol levels
and are well proven drugs for
the treatment of hypercholesterolaemia.
Although the pharmacology of
statins is well established
for the peripheral system,
data about their effects in
the central nervous system
(CNS) are still lacking. Clinical
and epidemiological findings
indicate prevention of stroke
and possibly a beneficial effect
on the progression of Alzheimer’s
Disease (AD). Hence, statins
are considered a promising
drug in the CNS. Abnormal processing
of amyloid precursor protein
(APP) in the AD brain results
in deposits of neurotoxic ß-amyloid
(Aß) that represents one pathological
hallmark of this disease. Statins
lower the amyloidogenic processing
of APP in vitro and in vivo.
This effect is linked to the
cellular cholesterol homeostasis,
since reducing membrane cholesterol
lowers the amyloidogenic processing
of APP in vitro. Thus, statins
lower the risk of AD by reducing
Aß. However, statins’ mode
of action in the CNS is not
well understood yet. The consortium
under the ZAFES network aims
to elucidate the pharmacological
basis for the central effects
of statins observed in AD and
stroke. Our approach involves
the investigation of pathomolecular
mechanisms, drug analytics,
in vitro and in vivo studies,
and gene expression profiling.
Elucidation of pathomolecular
mechanisms and effects of statins
on brain lipid homeostasis
are assessed by the Institute
of Interdisciplinary Pharmacology
(Prof. Müller,
ZAFES). The Institute of Pharmaceutical
Chemistry, together with an
industrial partner, applies
a recently developed rapid
high performance liquid chromatography
coupled with tandem mass spectroscopy
using electrospray ionisation
to assess brain availability
and brain concentrations reached
after pharmacological doses
of statins (Prof. Schubert-Zsilavecz,
Prof. Karas,
ZAFES; Dr. Fechner, Applied
Biosystems, Darmstadt).
AD-related animal models are
provided by Aventis (Dr. Benavides,
Dr. Pradier, Paris). The University
of Minnesota adds gene expression
pattern analysis of the brain
(Prof. Wood, VA Medical Center,
Minneapolis) [Figure].
The consortium aims to discover
underlying mechanisms to better
understood the potential therapeutic
efficacy of statins in AD and
possibly other neurodegenerative
diseases.
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