Central
Nervous System Agents in Medicinal Chemistry
ISSN: 1871-5249
Central Nervous System Agents
in Medicinal Chemistry
Volume 7, Number 4, December 2007
Contents
Involvement of Uridine-Nucleotide-Stimulated P2Y
Receptors in Neuronal Growth and Function Pp. 223-229
Mehmet Cansev
[Abstract]
The Neuroprotective Effect of Ginkgo biloba
Leaf Extract and its Possible Mechanism Pp. 230-235
Y.T. Mak, M.S.M. Wai and D.T. Yew
[Abstract]
Proteasome Modulation in Brain: A New Target for Anti
Aging Drugs? Pp. 236-240
Michele Mishto, Elena Bellavista, Aurelia Santoro and
Claudio Franceschia
[Abstract]
Inhibition of Rho/Rho-Kinase as Therapeutic Strategy
to Promote CNS Axonal Regeneration Pp. 241-250
Mitsuharu Endo and Toshihide Yamashita
[Abstract]
Does Cyclic Dependent Kinase 5 Play a Significant
Role in Determination of Stroke Outcome? Possible Therapeutic
Implications Pp. 251-258
Mark Slevin, Marta Grau-Olivares, John Gaffney, Pat Kumar,
Sajjad Hussain, Shant Kumar and Jurek Krupinski
[Abstract]
Interference of Glycine Transporter 1: Modulation
of Cognitive Functions Via Activation of Glycine-B
Site of the NMDAR Receptor Pp. 259-268
Philipp Singer, Joram Feldon and Benjamin K. Yee
[Abstract]
Nicotinic Receptors and the Treatment of Attentional
and Cognitive Deficits in Neuropsychiatric Disorders: Focus
on the α 7
Nicotinic Acetylcholine Receptor as a Promising Drug Target
for Schizophrenia Pp. 269-288
Christian Chiamulera and Guido Fumagalli
[Abstract]
Actions of Melatonin, Its Structural and Functional
Analogs in the Central Nervous System and the Significance
of Metabolism Pp. 289-303
Rüdiger Hardeland and Burkhard Poeggeler
[Abstract]
Abstracts
[Back to top]
Involvement of Uridine-Nucleotide-Stimulated
P2Y Receptors in Neuronal Growth and Function
Mehmet Cansev
The uridine nucleotides UTP, UDP and UDP-sugars produce
a variety of effects by activating specific G protein-coupled
P2Y receptors, i.e., the P2Y2,
P2Y4, P2Y6
and P2Y14 variants. Except
for P2Y14 which has recently
been defined, stimulation of P2Y receptors by UTP and/or UDP
augments proliferation of adult multipotent neural stem cells;
stimulates dopaminergic differentiation in human mesencephalic
neural stem cells; and enhances neurite outgrowth in nerve
growth factor-differentiated PC12 cells and cultured DRG neurons.
UTP and/or UDP have been shown to affect neuronal function
by depolarizing neurons from cultured amphibian sympathetic
ganglia; increasing firing rates of neurons; enhancing presynaptic
glutamate release and promoting long-term potentiation; and
by stimulating noradrenaline release from cultured sympathetic
neurons. Furthermore, by activating P2Y receptors, UTP and/or
UDP exhibit neuroprotective effects via induction of microglial
convergence and reactive astrogliosis; protection from serum
starvation-induced apoptosis; and stimulation of α
-secretase-dependent APP processing and sAPPα
release. Antagonism of uridine- nucleotide-stimulated
P2Y receptors or the second messengers they generate, or degradation
of extracellular uridine nucleotides, can block the effects
mediated by these receptors. These observations suggest that
uridine-nucleotide-stimulated P2Y receptors may constitute
possible therapeutic targets for diseases affecting neuronal
survival or function.
[Back to top]
The Neuroprotective Effect of Ginkgo biloba Leaf
Extract and its Possible Mechanism
Y.T. Mak, M.S.M. Wai and D.T. Yew
An extract from the leaves of the Ginkgo biloba
tree, labeled EGb761, is one of the most widely used medicinal
products in the West for cardiovascular and brain related
diseases. In particular, it has been used frequently for the
treatment and prevention of neurodegenerative diseases such
as mild cognitive impairment or Alzheimer's disease. The drug
is relatively safe and has been used widely by healthy individuals
as an alternative medicine, even for anti-normal aging. EGb761
consists of two major substances, the flavone glycosides (flavonoid
fraction, 24%) and the terpene lactones (terpenoid fraction,
6%), which might possess the function of neuroprotection.
Possible mechanisms suggested include interactions with the
mitochondria and apoptosis, platelet aggregation antagonism,
free radicals and nitric oxide scavenging, modulation of neurotransmitters,
and induction of growth factors. However, the mechanism of
its therapeutic effect on the central nervous system remains
inconclusive.
In this review article, we will attempt to summarize the molecular
evidence of the neuroprotective mechanism of Ginkgo, and to
explain its possible neuroprotective effect on the central
nervous system. By choosing a suitable biochemical marker,
the neuroprotective effect of Ginkgo could be studied, quantified,
and compared in different studies of the central nervous system
as well as in other organ systems. This would lead to a better
understanding of the mystified anti-aging role of Ginkgo in
human.
[Back to top]
Proteasome Modulation in Brain: A New Target for Anti Aging
Drugs?
Michele Mishto, Elena Bellavista, Aurelia Santoro and
Claudio Franceschia
Proteasomes (including constitutive proteasome, immunoproteasome,
and their regulatory complexes) are multicatalytic complexes
crucial for cell and body homeostasis and survival, being
responsible for a consistent part of protein degradation.
In the central nervous system (CNS), the activity of proteasomes
affects a variety of crucial brain activities. While proteasome
alteration (content and activity) during aging has been studied
in several tissues and cellular models, few data are available
regarding human CNS, and the identification of an appropriate
and reliable model for the role of proteasome in human brain
aging is still lacking. In this review, the available data
on proteasome and brain aging in rodents, as well as the few
data on non human primates, are critically revised. On the
whole, the data regarding changes of proteasome activity and
content with age are far from being clear, not only due to
the heterogeneity of the models (differences between species,
among strains of the same species) but also due to the brain
areas considered. We paid particular attention to recent data
obtained in human brain of non-demented donors and subjects
affected by Alzheimer Disease (AD) demented subjects, as well
as to new data on non human primate brain. The study of the
possible role of proteasomes in brain aging, and the identification
of reliable animal models, is pivotal for the development
of possible ad hoc therapeutic interventions capable
of retarding/counteracting brain aging and age-related brain
pathologies. The therapeutic capability and limits of Vitamin
E, the possible set up of proteasome modifiers (activators)
as well as the effects on proteasomes of other drugs used
for AD therapy are discussed within a scenario which deserves
more attention and further investigations.
[Back to top]
Inhibition of Rho/Rho-Kinase as Therapeutic Strategy to Promote
CNS Axonal Regeneration
Mitsuharu Endo and Toshihide Yamashita
After injury to the central nervous system (CNS) of adult
vertebrates, axonal regeneration is extremely limited because
inhibitory proteins existing around the injury site prevent
the regrowth of the lesioned axons. Previous studies have
reported that several myelin-derived proteins (such as Nogo,
MAG, OMgp) and developmental guidance proteins (such as RGM,
semaphorin, ephrin) contribute to the inhibition of axonal
regeneration after injury in the adult CNS. Although each
neurite growth inhibitory protein induces neurite retraction
and growth cone collapse through specific receptors, they
commonly utilize the function of small GTPases, including
Rho, Rac, Cdc42, and Ras, that regulate neurite outgrowth
by controlling actin and microtubule cytoskeleton. The small
GTPase Rho and its effector Rho-kinase play critical roles
in the induction of neurite retraction and growth cone collapse
in vitro and the inhibition of axonal regeneration
in vivo. Therefore, the Rho inhibitor C3 transferase
and Rho-kinase inhibitors are thought to be effective therapeutic
candidates involved in the promotion of axonal regeneration
after human CNS injuries such as spinal cord injury.
[Back to top]
Does Cyclic Dependent Kinase 5 Play a Significant Role in
Determination of Stroke Outcome? Possible Therapeutic Implications
Mark Slevin, Marta Grau-Olivares, John Gaffney, Pat Kumar,
Sajjad Hussain, Shant Kumar and Jurek Krupinski
Ischaemic stroke is a leading cause of death and disability
in the Western world and usually occurs as a consequence of
progressing atherothrombosis resulting in embolism and associated
local tissue damage due to loss of cell membrane integrity
and altered signal transduction activity. Survival of neurones,
particularly in peri-infarcted regions determines the extent
of patient recovery. A significant proportion of neurones
in these areas undergo programmed cell death by apoptosis,
resulting in a worse prognosis. Angiogenesis is critical for
the development of new microvessels and leads to re-formation
of collateral circulation, reperfusion, enhanced neuronal
survival and improved recovery. Recent evidence has suggested
that both angiogenesis and neuronal survival may be affected
following activation of cyclin-dependent kinase-5 (Cdk5).
In this review, the functional roles of Cdk5 in stroke will
be described, followed by an analysis and comparison of available
pharmacological inhibitors with a view to their potential
use in the future treatment of this disease.
[Back to top]
Interference of Glycine Transporter 1: Modulation of Cognitive
Functions Via Activation of Glycine-B Site of the
NMDAR Receptor
Philipp Singer, Joram Feldon and Benjamin K. Yee
The high-affinity glycine transporter 1 (GlyT1) is the
primary endogenous regulator of glycine levels in the vicinity
of the N-methyl-D-aspartate receptor (NMDAR). As
a co-agonist, glycine can allosterically modulate NMDAR functions
through its binding to the glycine binding site (glycine-B
site). Under homeostatic conditions, GlyT1 mediated re-uptake
is believed to maintain the synaptic glycine concentration
below the saturation level of the glycine-B site. Given that
glycine-B site occupation is obligatory for glutamatergic
activation of the NMDAR, increased availability of glycine
in the vicinity of NMDAR’s glycine-B site has been suggested
as an alternate strategy to enhance NMDAR functions. Because
exogenously administered glycine shows poor blood-brain barrier
penetration and must overcome potent regulatory brain mechanisms
in order to efficiently enhance NMDAR function, one currently
favored strategy is to target the glycine clearance mechanism
through inhibition of GlyT1 mediated re-uptake. Numerous studies
have demonstrated that pharmacological blockade or molecular
down-regulation of GlyT1 leads to enhanced NMDAR functions
and thus may provide novel therapeutic avenues in the treatment
of neurological and psychiatric disorders in which NDMAR hypofunction
has been implicated, including schizophrenia. Several modulatory
agents targeted at the glycine-B site are currently undergoing
pre-clinical and clinical development as potential antipsychotic
drugs. Parallel research in animals with pharmacological inhibition
of GlyT1 or GlyT1 knock-out mice has also generated promising
results, reinforcing the hypothesis that disruption of glycine
reuptake via GlyT1 may entail therapeutic value against primarily
negative and cognitive symptoms of schizophrenia.
[Back to top]
Nicotinic Receptors and the Treatment of Attentional and Cognitive
Deficits in Neuropsychiatric Disorders: Focus on the α
7 Nicotinic Acetylcholine Receptor as a Promisin Drug
Target for Schizophrenia
Christian Chiamulera and Guido Fumagalli
A large body of evidence shows that α
7 nicotinic acetylcholine receptor (nAChR) is an important
mechanism underlying attentional and cognitive deficits in
schizophrenia. Several compounds acting as activators of α
7 nAChRs have been identified and investigated for
a potential therapeutic application. However, considering
the complexity of neuropsychiatric disorders and the difficulty
to meet an ideal product profile for drug discovery in the
field, there is the need to define empirical product profiles
from available data for the major α
7 activators. Two classes of compounds are described,
partial/full α
7 agonists and α
7 positive allosteric modulators (PAMs). Their critical
pharmacological features are analysed by focussing on type
of activity/selectivity at α
7 nAChR, action in vivo in laboratory animal
models, desired clinical activity, pharmacokinetics (PK)/dosing
and safety/tolerability issues. Although the characterization
of type of efficacy in vitro succeeded in the extrapolation
to animal models and to patients, more efforts are needed
to improve selectivity, PK/dosing and safety/tolerability
features for α
7 agonists. Such as limitations have not been seen
for α 7
PAMs, so that this class may offer a potential back-up strategy
for α 7
activators development. The empirical profiles proposed here
might give pragmatical indications for the development and
the optimization of α
7 activators. Few issues need to be further optimized,
i), in the clinic, mostly PK profiling, and, ii), at a preclinical
level, downstream α
7 receptors mechanisms involved in cognitive deficits.
A successfully translation of α
7 activators research for the treatment of schizophrenic
patients will rely on a continuous clinical/preclinical cross-talk
approach.
[Back to top]
Actions of Melatonin, Its Structural and Functional Analogs
in the Central Nervous System and the Significance of Metabolism
Rüdiger Hardeland and Burkhard Poeggeler
The CNS is both source and target of melatonin. It is
released from the pineal to the circulation and, in elevated
concentrations, into the third ventricle. Levels by 3 orders
of magnitude higher than in the circulation have been found
in the CNS. The mammalian circadian pacemaker, suprachiasmatic
nucleus (SCN), controls the pineal, but is also major subject
to feedback information on darkness, transduced by two G-protein
coupled melatonin receptors, MT1
and MT2, which cause suppression
of neuronal firing and circadian phase resetting. Two MT1
and MT2 agonists, ramelteon
and agomelatine, display sleep-promoting properties. Agomelatine
additionally inhibits 5-HT2c
receptors, the basis of an antidepressant effect. Melatonin,
ramelteon and agomelatine have been tested in clinical trials.
Only ramelteon has received approval by the FDA, as a sleeping
pill. Bioactive melatonin analogs, N-acetylserotonin,
5-methoxytryptamine, N,N-dimethyl-5-methoxytryptamine,
and 5-methoxytryptophol are produced in the CNS. Interplays
between these compounds, including the serotoninergic system,
are likely. N-Acetylserotonin is abundant in hippocampus,
cerebellum, midbrain, pons and medulla. Neuroprotective actions
of melatonin include antiamyloidogenic, antiexcitatory/antiexcitotoxic,
antioxidant effects and modulation of mitochondrial metabolism,
with consequences for radical formation and aging. The remarkable
pleiotropy of melatonin includes other binding sites, such
as calmodulin, calreticulin and a nuclear calreticulin homolog,
members of the ROR/RZR family, quinone reductase 2 and specific
mitochondrial sites. N1-acetyl-N2-formyl-5-methoxykynuramine
(AFMK) and N1-acetyl-5-methoxykynuramine
(AMK) are major melatonin metabolites in the CNS and also
display biological activities. For instance, AMK inhibits
neuronal NO synthase already at 10-11
M, and modulates mitochondrial metabolism. By interacting
with NO, AMK forms 3-acetamidomethyl-6-methoxycinnolinone
(AMMC).
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