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Medicinal Chemistry Reviews - Online, Volume 2, No. 1, 2005
Contents
The Anabolic Effects of Growth Hormone (GH)
and GH Secretagogues on Bone Mass and Density Pp.1-9
The Blood-brain Barrier and the Outer
Blood-retina Barrier Pp.11-26
Burkhard
Schlosshauer and Heiko Steuer
Impacting Neuronal and Vascular Cellular
Signal Transduction through the Metabotropic Glutamate Receptor System Pp.27-38
Kenneth
Maiese and Zhao Zhong Chong
Targeting Cytokines as an Approach to
Modulate Allergic Diseases: The Clinical Experience Pp.39-47
Teet
Pullerits
Dietary Prevention of Cancer: Anticancer and
Antiangiogenic Properties of Green Tea Polyphenols Pp.49-58
Michel
Demeule, Borhane Annabi, Jonathan Michaud-Levesque, Sylvie Lamy, and Richard
Beliveau
Gene Expression Profiles Induced by
Amphetamine and Phencyclidine; Novel Targets for the Treatment of Drug
Psychosis and Schizophrenia Pp.59-64
Chihiro
Ito and Yuta Ouchi
Prospects for a Human Toxoplasma Vaccine Pp.65-65
D.T.
Bout, M.-N. Mevelec, I. Dimier-Poisson, M. Lebrun and N. Moire
Anticancer Drugs Targeting the Apoptotic
Pathway Pp.67-79
M.
Tolomeo, N. Gebbia and D. Simoni
Use of Deoxyribozymes for Gene Knockdown Pp.81-87
Lun-Quan
Sun
Abstracts
[Back to top] The Anabolic Effects of Growth Hormone (GH)
and GH Secretagogues on Bone Mass and Density
Johan
Svensson
Several
antiresorptive agents have been developed for the treatment of osteoporosis and
bone disorders. Few agents have been introduced that stimulate bone formation.
Treatment with parathyroid hormone induces, however, a potent increase in hip
and lumbar bone mineral density (BMD) and is now available in some countries.
The present review focuses on growth hormone (GH) / GH secretagogues (GHSs).
GH/GHSs stimulates bone turnover, thereby increasing bone mass and density.
[Back to top] The Blood-brain Barrier and the Outer
Blood-retina Barrier
Burkhard
Schlosshauer and Heiko Steuer
The blood-brain
barrier (BBB) represents a functional interface between the blood stream and
the neuronal microenvironment. Distinct cellular and molecular features of
brain microvessel endothelial cells result in barrier and carrier functions
that guarantee exclusion of adverse components such as neurotoxic metabolites
on the one hand and selective passage of essential nutrients on the other hand.
The retina, as an integral part of the central nervous system, is enclosed by
the pigment epithelium, which functions as a barrier interface between the
systemic blood vessels of the neighboring choroid and the retina. Various
BBB-specific markers, tight junction components, and carrier systems including
amino acid- and saccharide transporters have been cloned and are expressed both
in brain microvessels and the retinal pigment epithelium (RPE). P-glycoprotein
has been of special interest because this efflux pump counteracts entry of
numerous therapeutically relevant drugs into the nervous system. Various in
vitro systems of the RPE have been established and employed to analyze
pharmacological aspects and pathological cell interactions. The most advanced
systems are organotypic cultures and acute preparations of the RPE, i.e. fully
intact tissue sheets that can be used as in vivo-like BBB models for
transport studies and drug profiling.
[Back to top] Impacting Neuronal and Vascular Cellular
Signal Transduction through the Metabotropic Glutamate Receptor System
Kenneth
Maiese and Zhao Zhong Chong
The metabotropic
glutamate receptor (mGluR) system plays a critical role to foster the proper
development of an organism. Yet, what has unfolded over the last decade is the
vital interplay between the mGluR system and the fate of a cell during both
acute and chronic neurodegenerative disorders. Through the coupling to
guanosine-nucleotide-binding proteins, the mGluR system drives a series of
cellular pathways that impact upon the apoptotic induction of genomic DNA
fragmentation, membrane phosphatidylserine (PS) residue exposure, and the
inflammatory activation of microglia in the brain. A broad array of cellular
pathways appear to be governed by the mGluR system and include the protein
kinases PKA, PKB, and PKC. In addition, distinct modulation of mitochondrial
membrane potential, caspase activity, intracellular pH, and endonucleases are
required to ultimately preserve the integrity of a cell. Cytoprotection by the
mGluR system is clinically significant, since neuronal and vascular cell
populations can benefit from immediate and delayed protection by mGluRs.
Although mGluR activity may not always promote the survival of a cell and final
outcome can be intimately linked to the environmental stimulus, future work
with the mGluR system will guide the development of novel strategies to prevent
cellular injury by this glutamate receptor family.
[Back to top] Targeting Cytokines as an Approach to
Modulate Allergic Diseases: The Clinical Experience
Teet Pullerits
The inflammation
in the airways of allergic patients is the result of a complex process
involving several cytokines. Modulation of the effect of these cytokines can
provide alternative and more specific treatment approach to currently widely used
systemic immunosuppression by glucocorticoids. Theoretically, cytokine
modulation can be achieved via several pathways, including inhibition of
released cytokines by using antibodies or soluble receptors, blocking cytokine
receptors, inhibiting signal transduction or preventing cytokine gene
transcription. On the other hand, some cytokines are known to possess
anti-inflammatory effects in allergic inflammation, being potentially used as a
therapeutic agent. The more novel approaches for cytokine modulation include
high affinity blockade of cytokines with cytokine traps and use of
oligodeoxynucleotides for Th2 type cytokines. The current review addresses
cytokine modulation as a strategy in targeting allergic diseases with emphasis
on the clinical experience.
[Back to top] Dietary Prevention of Cancer: Anticancer and
Antiangiogenic Properties of Green Tea Polyphenols
Michel
Demeule, Borhane Annabi, Jonathan Michaud-Levesque, Sylvie Lamy, and Richard
Beliveau
Both epidemiological
and laboratory studies have suggested an inverse association between
consumption of green tea and the prevalence of some cancers. The
anti-tumorigenicity of green tea has been related to its content of specific
polyphenols. The molecular mechanisms underlying the anticancer and
antiangiogenic effects of green tea polyphenols (GTPs) are currently under
intensive investigation. The purpose of this article is to update a previous
review on the effects and biological activities of GTPs in relation to their
therapeutic usefulness in preventing cancer in humans [1]. GTPs mainly consist
of catechins (3-flavanols), of which epigallocatechin gallate (EGCG) is the
most abundant in green tea and the most extensively studied. Moreover, the
biological effects reported for GTPs have been mainly associated to EGCG. New
perspectives on the applications of dietary GTPs as potential therapeutic and
preventive agents against cancer are presented.
[Back to top] Gene Expression Profiles Induced by
Amphetamine and Phencyclidine; Novel Targets for the Treatment of Drug
Psychosis and Schizophrenia
Chihiro
Ito and Yuta Ouchi
Although the
aetiology of drug psychosis or schizophrenia is still unknown, molecular and
biochemical researches have recently made significant advances in the search
for the candidate genes of these disorders. Among such studies are animal
models of drug psychosis or schizophrenia such as amphetamine-induced
behavioural sensitisation or phencyclidine-treated animals. In this review, it
is suggested that amphetamine or phencyclidine change the gene expressions
related to cell damage/ neuroplasticity. These alterable gene expressions may
lead to the discovery for candidate genes of drug psychosis or schizophrenia
and thus to novel antipsychotics.
[Back to top] Prospects for a Human Toxoplasma Vaccine
D.T.
Bout, M.-N. Mevelec, I. Dimier-Poisson, M. Lebrun and N. Moire
Two recent lines
of data open the way to development of subunit vaccines. It is now clearly
established that ligands of TLR or signalling receptors of DCs could be used as
potent adjuvants for vaccination purposes. In addition, it is possible to
potentiate DNA vaccines by including cytokine genes.
[Back to top] Anticancer Drugs Targeting the Apoptotic
Pathway
M.
Tolomeo, N. Gebbia and D. Simoni
Chemotherapy is
currently the most important medical modality of treatment of cancer. Several
studies have shown that most, if not all, chemotherapeutic agents exert their
anticancer activity by inducing apoptosis (programmed cell death). Although
successful treatment of some malignancies has been achieved, most of solid
tumors are scarcely responsive to chemotherapeutic agents. The progress made in
the area of apoptosis has led to the development of several apoptosis
stimulators compounds for the control of cancer. A number of compounds able to
activate directly apoptosis by acting on molecules involved in the apoptotic
pathway, such as TRAIL receptor, caspases and the Bcl-2 family of proteins have
been recently developed. Most are still in the preclinical study, but some have
already shown promising results. Other recently developed anticancer drugs induce
indirectly apoptosis by acting on targets different from that of classic
chemotherapeutic drugs. Here, we review the experimental and clinical results
of several promising pro-apoptotic anti-cancer compounds.
[Back to top] Use of Deoxyribozymes for Gene Knockdown
Lun-Quan
Sun
The most
established nucleic acid based approach to gene suppression at the RNA level is
through antisense oligodeoxynucleotides (ODNs). These compounds form
heteroduplex with target RNA, which are thought to either block its function or mediate its destruction by
activation of RNase H. Alternatively, RNA can be targeted by catalytic RNA such
as the hammerhead ribozyme. Ribozymes have the advantage of being equipped with
their own RNA cleavage apparatus, and are therefore independent of host nuclear
protein activity. At present, the utility of ribozyme oligonucleotides is
restricted by the relative difficulty in synthesising active molecules with
sufficient resistance to nuclease degradation. Recently the power of in
vitro selection has been used to evolve catalytic DNA sequences with RNA
cleavage specificity and activity rivalling the very best ribozymes, while
maintaining the more robust chemistry of an ODN. These deoxyribozymes or
DNAzymes have tremendous potential as gene suppression agents for both target
validation and therapeutic applications. A number of studies evaluating the
biological activity of these compounds have shown promising results. However,
as with other oligonucleotide-based strategies, future exploitation of this
approach may depend on accessory technology to assist with the accessibility of
a target, which is folded by its own secondary structure and hidden within the
intracellular compartment.