| Current
Medicinal Chemistry
ISSN: 0929-8673
Current Medicinal Chemistry
Volume 15, Number 23, 2008
Contents
On the Pathogenesis and Neuroprotective Treatment of Parkinson
Disease: What have we Learned from the Genetic Forms of this
Disease? Pp. 2305-2320
M.A. Mena, J.A. Rodriguez-Navarro, R. Ros
and J.G. de Yebenes
[Abstract]
Hyperphosphorylation of Microtubule-Associated
Protein Tau: A Promising Therapeutic Target for Alzheimer
Disease Pp. 2321-2328
C.-X. Gong and K. Iqbal
[Abstract]
Cells Under Pressure – Treatment
of Eukaryotic Cells with High Hydrostatic Pressure, from Physiologic
Aspects to Pressure Induced Cell Death Pp.
2329-2336
Benjamin Frey, Christina Janko, Nina Ebel,
Silke Meister, Eberhard Schlücker, Roland Meyer-Pittroff,
Rainer Fietkau, Martin Herrmann and Udo S. Gaipl
[Abstract]
Synthetic Glycolipid Ligands for Human iNKT
Cells as Potential Therapeutic Agents for Immunotherapy
Pp. 2337-2345
Manabu Araki, Sachiko Miyake and
Takashi Yamamura
[Abstract]
Cytochrome P450-Activated Prodrugs: Targeted
Drug Delivery Pp. 2346-2365
Kristiina M. Huttunen, Niina Mähönen,
Hannu Raunio and Jarkko Rautio
[Abstract]
New Derivatives of GnRH as Potential Anticancer
Therapeutic Agents Pp. 2366-2379
Gábor Mezo, Marilena Manea, Ildikó
Szabó, Borbála Vincze and Magdolna
Kovács
[Abstract]
Statins And Stroke Pp. 2380-2392
A. Bersano E. Ballabio, S. Lanfranconi, S. Mazzucco, L.
Candelise and S. Monaco
[Abstract]
Clinical Proteomics in Cancer Research–Promises
and Limitations of Current Two-Dimensional Gel Electrophoresis
Pp. 2393-2400
Yasuo Iwadate
[Abstract]
Analysis of Pyridinium Aldoximes - A
Chromatographic Approach Pp. 2401-2418
T. Csermely, H. Kalász, G.A. Petroianu,
K. Kuca, F. Darvas, K. Ludányi, A.A. Mudhafar
and K. Tekes
[Abstract]
Abstracts
[Back to top]
On the Pathogenesis and Neuroprotective Treatment of Parkinson
Disease: What have we Learned from the Genetic Forms of this
Disease?
M.A. Mena, J.A. Rodriguez-Navarro, R. Ros
and J.G. de Yebenes
Parkinson´s disease (PD) is a neurodegenerative
disorder affecting nearly 3 million patients in Europe and
North America, characterized by a core phenotype of motor
deficits, akinesia, rigidity, postural disturbance and tremor,
which is complicated by other neurological deficits during
its long progression. Our knowledge about the pathophisiology
of PD was limited, up to 25 years ago, to the observation
of the lesion of the nigro-striatal dopamine neurons in these
patients. The subjects who developed PD as a consequence of
exposure to neurotoxic compounds, increased our knowledge
about the pathogenesis of this disease. More recently, genetic
alterations have been found in patients with PD.
The function of the proteins coded by the genes involved in
PD has been investigated in genetic models of this disease
from invertebrate to rodents. Mutated proteins responsible
for PD have been tested in vivo and in vitro,
in cellular models or in artificial constructs. A wealth of
important information about the function of α-synuclein,
parkin, DJ-1, PINK and dardarin is available, most notably
about the first two causes of familial PD discovered, α-synuclein
and parkin, responsible for autosomal dominant and autosomal
recessive PD, respectively. Different animal models of α-synuclein
and parkin have been extensively investigated.
The in vitro and in vivo studies performed
in genetic models of PD have shown that the proteins involved
in the pathogenesis of PD interact with one another and have
multiple mechanisms of cell toxicity. From the available data,
it is clear that the mechanisms leading to cell degeneration
in PD are variable in the different subtypes of this disease.
Neuroprotective therapies should, therefore, be multiple and
tailored according to the factors involved in the different
cases. In this study, we review what we have learned from
the genetic models of PD and the putative strategies to be
tested in the near future.
[Back to top]
Hyperphosphorylation of Microtubule-Associated
Protein Tau: A Promising Therapeutic Target for Alzheimer
Disease
C.-X. Gong and K. Iqbal
Alzheimer disease (AD) is the most common cause of dementia
in adults. The current therapy for AD has only moderate efficacy
in controlling symptoms, and it does not cure the disease.
Recent studies have suggested that abnormal hyperphosphorylation
of tau in the brain plays a vital role in the molecular pathogenesis
of AD and in neurodegeneration. This article reviews the current
advances in understanding of tau protein, regulation of tau
phosphorylation, and the role of its abnormal hyperphosphorylation
in neurofibrillary degeneration. Furthermore, several therapeutic
strategies for treating AD on the basis of the important role
of tau hyperphosphorylation in the pathogenesis of the disease
are described. These strategies include (1) inhibition of
glycogen synthase kinase-3β
(GSK-3β),
cyclin-dependent kinase 5 (cdk5), and other tau kinases; (2)
restoration of PP2A activity; and (3) targeting tau O-GlcNAcylation.
Development of drugs on the basis of these strategies is likely
to lead to disease-modifying therapies for AD.
[Back to top]
Cells Under Pressure – Treatment of Eukaryotic Cells
with High Hydrostatic Pressure, from Physiologic Aspects to
Pressure Induced Cell Death
Benjamin Frey, Christina Janko, Nina Ebel,
Silke Meister, Eberhard Schlücker, Roland Meyer-Pittroff,
Rainer Fietkau, Martin Herrmann and Udo S. Gaipl
The research on high hydrostatic pressure in medicine
and life sciences is multifaceted. According to the used pressure
head the research has to be divided into two different parts.
To study physiological aspects of pressure on eukaryotic cells
physiological pressure (pHHP; <
100 MPa) is used. pHHP induces morphological alterations in
the cellular organelles and evokes a reversible stress response
similar to the well known heat shock response. pHHP induces
highly reversible alterations and normally does not affect
cellular viability. The treatment of eukaryotic cells with
non-physiological pressure (HHP; ≥
100 MPa) reveals different outcomes. Treatment with HHP <
150 MPa does not markedly affect viability of human cells,
but induces apoptosis in murine cells. In human cells apoptosis
is observed after treatment with ≥
200 MPa. Moreover, HHP treatment with >
300 MPa leads to necrosis. Therefore, HHP plays a role for
the sterilisation of human transplants, of food stuff, and
pharmaceuticals. Human tumour cells subjected to HHP >
300 MPa display a necrotic phenotype along with a gelificated
cytoplasm, preserve their shape, and retain their immunogenicity.
These observations favour the use of HHP to produce whole
cell based tumour vaccines. Further experiments revealed that
the increment of pressure as well as the pressure holding
time influences the cell death of tumour cells. We conclude
that high hydrostatic pressure offers both, an economic, easy
to apply, clean, and fast technique for the generation of
vaccines, and a promising tool to study physiological aspects.
[Back to top]
Synthetic Glycolipid Ligands for Human iNKT
Cells as Potential Therapeutic Agents for Immunotherapy
Manabu Araki, Sachiko Miyake and
Takashi Yamamura
Invariant natural killer T (iNKT) cells are
an attractive therapeutic target in autoimmune diseases, since
they play a major role in immune regulation. iNKT
cells recognize glycolipid antigens presented by CD1d molecules
that resemble the non-polymorphic MHC class I protein. α-galactosylceramide
(α-GalCer)
isolated from marine sponge has long been used as a prototype
iNKT cell ligand in the laboratory. As α-GalCer
is the most efficacious ligand for iNKT cells, its
potential to treat autoimmune disease has been evaluated in
animal models. Previous studies showed that α-GalCer
effectively suppressed disease in some autoimmunity models,
but not in others. This inconsistency may be attributed to
the ability of α-GalCer
to induce the production of both proinflammatory Th1 and anti-inflammatory
Th2 cytokines by iNKT cells. To overcome this issue,
we and other groups have synthesized new, unnatural glycolipids
by modifying the structure of α-GalCer.
These efforts have led to an identification of glycolipid
compounds that provoke the production of Th2 (but not Th1)
cytokines by iNKT cells. Among these novel ligands,
an α-GalCer
analogue named OCH, which contains a truncated sphingosine
chain, induces a Th2 biased response by murine iNKT
cells. Here we describe that OCH also polarizes human iNKT
cells towards Th2, which opens up a new avenue for the clinical
application of glycolipid compounds in treating of autoimmune
diseases such as multiple sclerosis. The pursuit of synthetic
glycolipid antigens has the great potential to lead to a better
understanding of the regulatory effects of human iNKT
cells and development of a new therapeutic agent for autoimmune
diseases.
[Back to top]
Cytochrome P450-Activated Prodrugs: Targeted Drug Delivery
Kristiina M. Huttunen, Niina Mähönen,
Hannu Raunio and Jarkko Rautio
Cytochrome P450 (CYP) enzymes are a superfamily of heme
containing proteins that catalyze xenobiotic metabolism phase
I reactions. Oxidation reactions are the most common CYP-catalyzed
reactions for both endogenous substrates and exogenous compounds,
including drugs, although CYP enzymes are capable also to
catalyze reduction reactions. Whereas the majority of clinically
used drugs are inactivated by CYPs, several prodrugs are bioconverted
to their active species by these enzymes. Therefore, this
mechanism could be exploited to a greater extend, e.g. by
taking advantage of the different CYP enzymes to achieve targeted
drug delivery, to improve efficacy or to decrease the unwanted
adverse effects of existing and novel drug molecules. This
review describes the potential of CYP enzymes in prodrug design
and summarizes a wide variety of CYP-activated prodrug structures,
which are on the market or under the development. The bioactivation
mechanisms of each CYP-activated prodrug structure are described
and the specificity for the different forms of CYP enzymes
is discussed.
[Back to top]
New Derivatives of GnRH as Potential Anticancer
Therapeutic Agents
Gábor Mezo, Marilena Manea, Ildikó
Szabó, Borbála Vincze and Magdolna
Kovács
GnRH (gonadotropin-releasing hormone), a decapeptide
produced by the hypothalamus, plays an important role in the
reproduction by regulating the pituitary-gonadal axis. Continuous
high doses of GnRH or its superactive agonists result in desensitization
of the pituitary gonadotropes and a suppression of sex steroid
production by the gonads (chemical castration). Based on these
effects, the treatment with GnRH agonists has become a widely
used hormonal therapy of the sex-steroid dependent tumors.
It was also demonstrated that most tumor cells contain GnRH
receptors, and the direct antiproliferative effect of GnRH
analogs on cancer cells might be mediated by these receptors.
Development of new GnRH derivatives is focused on the decrease
of their hormonal potency resulting in higher selectivity
of the antitumor activity. One of the most promising natural
GnRH analogs, lamprey (l) lGnRH-III, was isolated from see
lamprey. This variant of GnRH binds to GnRH receptors and
inhibits proliferation of various cancer cells. However, its
endocrine effect is insignificant in mammals. lGnRH-III dimers
and conjugates were prepared and were shown to have increased
antiproliferative effects on various cancer cells, while their
hormonal activity was lower than that of the native hormone.
lGnRH-III was applied as targeting moiety to deliver anticancer
agents to tumor cells. Research data concerning lGnRH-III
and its analogs represent a new outlook for research trends
of the application of GnRH compounds in cancer chemotherapy.
Studies on the effects of lGnRH-III derivatives including
antiproliferative effects, cytotoxicity, hormonal actions,
and enzymatic stability are reviewed in this article.
[Back to top]
Statins And Stroke
A. Bersano E. Ballabio, S. Lanfranconi, S. Mazzucco, L.
Candelise and S. Monaco
Pharmacological studies highlighted pleiotropic effects
of statins, that seem to influence atherogenesis not only
by increasing atherosclerotic plaque stability but also by
modulating endothelial function and inflammation and acting
on platelet aggregation and thrombosis. Despite a strong association
between increased levels of low-density lipoprotein cholesterol
(LDL-C) and the incidence of coronary heart disease (CHD)
has been well proven, it not yet established whether serum
LDL-C levels are related to stroke incidence. The major aim
of this paper is to perform a comprehensive up-to-date review
of research papers, meta-analyses and randomized controlled
clinical trials reporting the effects of statins in primary
and secondary stroke prevention strategies. In addition, our
work provides an overview on statin chemical structure, mechanism
of action and pharmacological properties, investigating also
most common adverse effects and relationship between statin
therapy and haemorrhagic stroke risk, in order to assess drugs
safety. Although studies are heterogeneous, our analysis shows
that statins reduce the risk of stroke occurrence in high
risk patients and seem also to reduce stroke recurrence. Moreover,
the low incidence and reversibility of adverse effects, and
the unclear association with hemorrhagic events, support the
safe use of these drugs.
[Back to top]
Clinical Proteomics in Cancer Research–Promises and
Limitations of Current Two-Dimensional Gel Electrophoresis
Yasuo Iwadate
Cancer can be defined as a deviated protein network system
toward dysregulated cellular proliferation. Alteration in
the content and functional state of the proteins with many
linkages may shift the equilibrium state of the protein signaling
network to enhance a survival advantage of the affected cells.
Searching for such hub proteins is the main purpose of the
cancer proteomics. Although the progression in the vanguard
proteomic technologies would largely contribute to cancer
diagnosis and treatment in the future, the technology most
frequently used for the analysis of clinical tissue samples
is the two-dimensional gel electrophoresis (2DE) combined
with matrix assisted laser desorption/ionization time of flight
mass spectrometry (MALDI-TOF MS). Accumulation of 2DE data
has generated many candidate biomarkers with potential clinical
value. The identified proteins are restricted to a subset
of the predicted human proteome, and ubiquitously exist in
all normal cells taking important roles in the basic biological
functions. Although these proteins can be used as valuable
prognostic markers, the low-abundance proteins which is tissue-specific
and useful as diagnostic markers could not easily be found
by the standard 2DE technology alone. None of the current
proteomic technologies can identify the whole proteome by
themselves. Adequate combinations of different approaches
not only in proteomics but in immunological methods would
be necessary for the tissue specific markers.
[Back to top]
Analysis of Pyridinium Aldoximes - A Chromatographic Approach
T. Csermely, H. Kalász, G.A. Petroianu,
K. Kuca, F. Darvas, K. Ludányi, A.A. Mudhafar
and K. Tekes
Pyridinium aldoximes are used as antidotes to organophosphorus
cholinesterase inhibitors. All pyridinium aldoximes (oximes)
are highly polar quaternary ammonium compounds showing low
to minimal blood-brain-barrier (BBB) penetration. Oximes are
separated using reversed-phase (RP) HPLC methods and/or thin-layer
chromatography (TLC).
The chemical structures, elementary compositions, molecular
sizes and the calculated logP values of several mono and bis-pyridinium
aldoximes are given. Chromatographic and electrophoretic analyses
of oximes are detailed, including the stationary and mobile
phase composition and the mode of detection. Degradation pathways
and products are also discussed.
To characterize oximes lipophilicity/hydrophilicity an in
silico method was used and expanded as to describe organophosphorus
compound adducts with several pyridinium aldoximes.
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