Central
Nervous System Agents in Medicinal Chemistry
ISSN: 1871-5249
Central Nervous System Agents
in Medicinal Chemistry
Volume 6, Number 3, September 2006
Contents
Neuroprotective Properties of Erythropoietin in
Cerebral Ischemia Pp. 153-161
Asterios Karagiannis and Konstantinos Tziomalos
[Abstract]
Functional Role of β-Turn
in Polypeptide Structure and its use as Template to Design
Therapeutic Agents Pp. 163-173
Noureddine Brakch, Boutaïna El Abida and Mohamed
Rholam
[Abstract]
The Role of Glucose in the Pathogenesis of Alzheimer’s
Disease Revisited: What Does it Tell us About the Therapeutic
use of Lithium? Pp. 175-192
Anna Strunecká and Paul Grof
[Abstract]
ADP-Ribosyl Cyclase as a Therapeutic Target for
Central Nervous System Diseases Pp. 193-210
Alla B. Salmina, Raissa Ya. Olovyannikova, Mami Noda and
Haruhiro Higashida
[Abstract]
Plants Indicated by Brazilian Indians for Disturbances
of the Central Nervous System: A Bibliographical Survey Pp.
211-244
Eliana Rodrigues, Fulvio R. Mendes and Giuseppina Negri
[Abstract]
Abstracts
[Back to top]
Neuroprotective Properties of Erythropoietin in Cerebral
Ischemia
Asterios Karagiannis and Konstantinos Tziomalos
Since the human erythropoietin (EPO) gene was cloned in 1983,
use of recombinant human EPO (rh-EPO) has become widespread
for treating anemia in patients with end stage renal failure.
Rh-EPO has a direct effect on haematopoiesis, reflected by
increased hemoglobin levels. However, recent studies have
shown that nerve cells also have erythropoietin receptors
and that this cytokine is made in the nervous system and can
function as a neuroprotective agent. In the last decade, it
has been shown that EPO exerts general tissue protection including
anti-apoptotic, antioxidant and angiogenesis effects. Perhaps
best characterized is the mechanism whereby EPO inhibits apoptosis,
with the effect believed to occur mostly by activation of
the PI-3K-Akt axis or JAK2-STAT5 axis. This anti-apoptotic
mechanism is not only important for erythropoiesis, but also
appears to play an important role in other processes with
high apoptotic activity, such as in stroke, retinal diseases
and possibly chronic heart failure and myocardial infarction.
Experimental studies in rats have shown that administration
of EPO after six hours of arterial occlusion of the middle
cerebral artery provided a 50% reduction in infarct size.
Moreover, a recent phase 1-2 clinical trial has suggested
that EPO can ameliorate neural damage in patients who have
had a stroke. In this review, we discuss the neuroprotective
properties and the future of rh-EPO therapy in patients with
ischaemic stroke.
[Back to top]
Functional Role of β-Turn
in Polypeptide Structure and its use as Template to Design
Therapeutic Agents
Noureddine Brakch, Boutaïna El Abida and Mohamed
Rholam
Since proteins and peptides play critical roles in many biological
phenomena, their use as drugs is of great interest. However,
their development is limited due to their poor bioavailability,
antigenicity and unfavorable pharmacokinetics. In the majority
of cases, not all domains of proteins are essential protein-protein
interactions necessary for biological activities but only
small regions of their folded structure, perform the interactions.
Usually, these particular secondary structures are β-turns,
occurring on the exposed surface of proteins, constitute the
functional elements involved in molecular recognition processes
between proteins, and in interactions between ligands and
receptors. Moreover, there are also several examples of the
design of modified peptides as therapeutic agents by mimicking
β-turn
structures. In view of this, this review will be focused on
the importance of β-turn
in some biological phenomena, such as prohormone proteolytic
processing. This report will also address the use of β-turn
mimicking strategies and its application in the design of
potent peptide analogues which play an equally important role.
Due to the optimal surface conformation, β-turn
mimetics lead to productive interaction with receptors and
antibodies.
[Back to top]
The Role of Glucose in the Pathogenesis of Alzheimer’s
Disease Revisited: What Does it Tell us About the Therapeutic
use of Lithium?
Anna Strunecká and Paul Grof
The ultimate aim of many researchers is to design a drug,
which could arrest or delay specifically the clinical evolution
of symptoms of Alzheimer’s disease (AD). The association
of increased activity of glycogen synthase kinase-3 (GSK-3)
with neuronal apoptosis, amyloid metabolism, and hyperphosphorylation
of protein tau makes this kinase an attractive target for
the therapy of neurodegenerative diseases. Lithium has been
shown to be an important inhibitor of GSK-3 activity and therefore
recently suggested as one of the treatment of AD. For some
time, the most widely accepted mechanism of action of lithium
was its inhibitory effect on inositol monophosphatase, resulting
in depletion of inositol with profound effects on phosphoinositide
signaling system. Although much evidence has not supported
the inositol depletion hypothesis subsequently, the important
role of inositol and inositides in the CNS, in addition to
their role in phosphoinositide signaling pathways, has been
discussed. A new perspective on the role of glucose in neurodegenerative
changes in the CNS has been emerging from several lines of
evidence. These accumulated observations may improve our understanding
of the links between deficient glucose metabolism in the aging
brain and the events leading to the onset of AD. The impairment
of glucose utilization might act as the common denominator
for the development of pathological hallmarks of AD.
[Back to top]
ADP-Ribosyl Cyclase as a Therapeutic Target for
Central Nervous System Diseases
Alla B. Salmina, Raissa Ya. Olovyannikova, Mami Noda and
Haruhiro Higashida
NAD+ is as abundant as ATP in neuronal cells. NAD+
functions not only as a coenzyme but also as a substrate.
NAD+ metabolism in neuronal cells is tightly controlled
under physiological conditions, since NAD+ has
a great impact on functional activity of neurons upon stimulation.
NAD+ -utilizing enzymes is involved in signal transduction.
We focus on ADP-ribosyl cyclase/CD38 which synthesizes cyclic
ADP-ribose (cADPR), a Ca2+ mobilizing messenger.
Structural analysis defined the active site of the enzyme.
ADP-ribosyl cyclase associated with CD38 was detected in the
central nervous system (CNS) where its activity and expression
were developmentally regulated. CD38 has been reported to
have different subcellular locations either in neurons or
in glial cells, suggesting multiple roles. cADPR, acts as
a universal calcium mobilizer from intracellular stores independently
from inositol trisphosphate which acts through activation/modulation
of ryanodine receptor channels involving FKBP12.6. cADPR was
also involved in the regulation of some potassium currents
in synaptic activity. cADPR synthesis in neuronal cells is
stimulated or modulated via different pathways and
various factors. Subtype-specific coupling of various neurotransmitter
receptors with ADP-ribosyl cyclase confirms the involvement
of the enzyme in signal transduction in neurons and glial
cells. Therefore, it is possible that pharmacological manipulation
of intracellular cADPR levels through ADP-ribosyl cyclase
activity or expression, in the CNS may provide new therapeutic
opportunities for treatment of neurological disorders.
[Back to top]
Plants Indicated by Brazilian Indians for Disturbances
of the Central Nervous System: A Bibliographical Survey
Eliana Rodrigues, Fulvio R. Mendes and Giuseppina Negri
Brazil possesses great biological and cultural diversity,
above all, in view of the great number of indigenous ethnic
groups – 218 in all - that inhabit the five main biomas
in Brazil. The purpose of this review is to analyze the relationship
between chemical constituents of species utilized by several
groups of Brazilian Indians and the uses/indications made
of the species by these same groups using ethnopharmacological
surveys by different researchers, as from the seventies. The
34 publications selected, involving 26 indigenous ethnic groups,
showed a total of 307 species utilized for 67 different diseases
or effects possibly related to the Central Nervous System
(CNS). These plants belong to 85 taxonomic families, mostly
Fabaceae, Asteraceae, Rubiaceae, Poaceae, Apocynaceae, Bignoniaceae,
Euphorbiaceae, and Solanaceae. The chemical constitution of
these plants was researched as from the Pubmed and Web of
Science and the information ob-tained was crossed with different
indigenous uses, grouped in 12 categories according to similarities
between their expected effects on the CNS: analgesics, to
counteract fever, tonics and/or adaptogens, hallucinogens,
anxiolytics, anticon-vulsants, head illnesses, hypnotics,
stimulants, weight control, memory enhancers, and others.
Some phytochemical classes were observed to be more common
among plants utilized for certain purposes: flavonoids (analgesia,
fever, anxiety, hypnotic, weight control, and as a stimulant),
alkaloids (hallucinogens, head illnesses, and as a stimulant),
essential oils (fever and anxiety), lignans (hallucinogen),
tannins (anxiety), triterpenes and saponins (hypnotic). These
data suggest that these phytochemical classes possibly possess
a greater number of chemical constituents that perform the
effects described or that, in some way, assist in determining
the use of the plant by the Indians.
|
