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CNS
& Neurological Disorders - Drug Targets
(Formerly 'Current Drug Targets - CNS & Neurological
Disorders')
ISSN: 1871-5273
Current Drug Targets - CNS
& Neurological Disorders
Volume 4, Number 5, October 2005
Contents
Cognition Therapeutics
Guest Editor: Miao-Kun Sun
Editorial Pp.467
Low Density Lipoprotein Receptor-Related Proteins
(LRPs), Alzheimer’s and Cognition Pp.469
M.E. Harris-White and S.A. Frautschy
[Abstract]
CREB, Synapses and Memory Disorders: Past Progress
and Future Challenges Pp.481
Sheena A. Josselyn and Peter V. Nguyen
[Abstract]
Memantine: A Therapeutic Approach in Treating
Alzheimer's and Vascular Dementia Pp.499
Horst J. Koch, Gökhan Uyanik and David Fischer-Barnicol
[Abstract]
Cannabinoids Pp.507
Franjo Grotenhermen
[Abstract]
Increasing Testosterone Levels and Effects on Cognitive
Functions in Elderly Men and Women: A Review Pp.531
E. Hogervorst, S. Bandelow and S.D. Moffat
[Abstract]
Protein Kinase C Isozymes: Memory Therapeutic Potential Pp.541
Miao-Kun Sun and Daniel L. Alkon
[Abstract]
Cholesterol and Apoe: A Target for Alzheimer's
Disease Therapeutics Pp.553
Daniela Fenili and JoAnne McLaurin
[Abstract]
Abeta Immunotherapy and Other Means
to Remove Amyloid Pp.569
Edith G. McGeer and Patrick L. McGeer
[Abstract]
General Articles
Neuroactive Flavonoids Interacting with GABAA
Receptor Complex Pp.575
Feng Wang, Michael Shing Yan Huen, Shui Ying Tsang and Hong
Xue
[Abstract]
Small Transthyretin (TTR) Ligands as Possible
Therapeutic Agents in TTR Amyloidoses Pp.587
M.R. Almeida, L. Gales, A.M. Damas, I. Cardoso and M.J. Saraiva
[Abstract]
Neuronal Plasticity, Stress and Depression:
Involvement of the Cytoskeletal Microtubular System? Pp.597
M. Bianchi, J.J. Hagan and C.A. Heidbreder
[Abstract]
Abstracts
[Back to top]
Editorial
Scientific research in cognition and cognitive pharmacology
is entering an exciting era. Not only are we beginning through
intensive investigations around the world, to better understand
the synaptic and molecular mechanisms underlying cognition
and cognitive disorders, but several therapeutic targets are
also being examined for developing cognitive therapeutic agents
and many more are starting to emerge.
The excitement is best illustrated by the review articles
in this hot topic theme issue of Current Drug Targets –
CNS and Neurological Disorders. These articles cover important
aspects of cognition therapeutics and therapeutic targets,
including low-density lipoprotein receptor-related protein
(LRP; by Harris-White and Frautschy), the cAMP responsive
element binding protein (CREB; by Sheena A. Josselyn and Peter
V. Nguyen), memantine for the glutamate hyperactivity (by
Horst J. Koch, Gökhan Uyanik and David Fischer-Barnicol),
the cannabinoid system (by Franjo Grotenhermen), the testosterone
system (by E. Hogervorst and S.D. Moffat), the protein kinase
C substrates (by Miao-Kun Sun and Daniel L. Alkon), cholesterol
and the ApoE (by Daniela Fenili and JoAnne McLaurin), and
Aβ
removal/reduction (by Edith G. McGeer and Patrick L. McGeer).
LRP is highly expressed in the pyramidal cells and plays an
important role in synaptic transmission. LRP itself and its
many ligands, including ApoE, α2-macroglobulin,
the transforming growth factor-β,
and the insulin-like growth factor, are important therapeutic
targets in cognition and cognition disorders. Intracellular
Aβ
accumulation leads to impaired neuronal metabolism and synaptic
dysfunctions and is probably responsible for triggering the
onset of cognitive dysfunction in Alzheimer’s disease
(AD). Therefore, blocking Aβ
uptake and intracellular accumulation, including LRP-mediated
neuronal uptake of ApoE-bound Aβ,
has obvious therapeutic values in anti dementia therapy. The
cAMP responsive element binding protein (CREB) represents
another target in developing novel treatment of memory disorders.
Cognition is impaired by many more pathogenic cascades, which
serve as potential therapeutic targets. Glutamate hyperactivity,
for instance, is involved in AD, vascular dementia, and other
neurodegenerative disorders. Early findings also define an
involvement of cholinergic deficits in AD. These studies have
led to some antidementia drugs, such as cholinesterase inhibitors
and memantine. Although these drugs are used clinically to
treat AD patients, whether they can change over a long period,
the rate of the disease progression is an entirely different
issue. The cannabinoid system plays an important role in signal
transduction. Its receptor agonists reduce Aβ
neurotoxicity and thus possess an anti-AD action. The cannabinoid
receptor1 antagonists, on the other hand, can improve memory
in rats. Further studies are needed to evaluate potentials
of the cannabinoid receptor agonists and antagonists in cognitive
pharmacology. Effects of testosterone on cognition and cognitive
disorders include a reduction in both Aβ
formation and tau hyperphosphorylation, suggesting that the
male hormone has a protective action against AD and cognitive
decline. But further studies are required to define its long-term
benefit. Protein kinase C activators have been found to produce
several promising effects on AD and cognition, including an
enhancement of spatial cognition, a reduction of Aβ
formation and accumulation. Elevated cholesterol and the apolipoprotein
E ε4 allele are important risk factors for AD. Immunization
with Aβ,
inhibitors of Aβ
formation, inhibitors of tau hyper-phosphorylation, cholesterol-lowering
agents, β-sheet
breaker peptides, and various miscellaneous agents and strategies
presented in these review articles are currently the leading
strategies in developing cognitive therapeutics. We hope that
our efforts will be rewarded with new developments and facilitated
emergence of therapeutic agents that are able to slow down
or block the progression of cognitive disorders.
Miao-Kun Sun
Blanchette Rockefeller Neurosciences Institute
9601 Medical Center Dr.
Academic/Research
Bldg., 319
Rockville
MD
20850
USA
E-mail: mksun@brni-jhu.org
[Back to top]
Low Density Lipoprotein Receptor-Related Proteins
(LRPs), Alzheimer’s and Cognition
M.E. Harris-White and S.A. Frautschy
This review will focus primarily on the role of the low
density lipoprotein receptor-related protein (LRP-1) in neuronal
synapse formation and function in Alzheimer’s Disease
(AD). We review the role that its ligands may have in cognition
or AD: apolipoprotein E (ApoE), α2-macroglobulin,
Transforming Growth Factor-Beta (TGFβ),
Tissue Plasminogen Activator (tPA), insulin growth factor
binding protein-3 (IGFBP-3), which all bind LRP-1 and apolipoprotein
J (ApoJ), which is a ligand for LRP-2. After reviewing its
role as a signaling receptor, we discuss the connection between
LRP and the NMDA glutamate receptor via the post
synaptic density 95 (PSD-95) neuronal scaffold protein and
the implications it may have for memory and cognition. Finally,
we discuss the evidence supporting a role for LRP in AD. Although
the evidence for LRP as a genetic risk factor is weak, many
of its ligands impose genetic risk, and have been implicated
in AD pathogenic cascades. We discuss the role of LRP in amyloid
precursor protein (APP) processing and production of beta-amyloid
(Aβ).
We identify LRP ligands that accelerate aggregation of toxic
Aβ
species. LRP mediates crucial pathways in AD pathogenesis
such as Aβ
clearance, Aβ
uptake, intraneuronal Aβ
accumulation and Aβ-associated
neuron death. Interestingly, the TGFβ
-V receptor is LRP-1. Data show that one critical ligand TGFβ2,
associated with neurodegeneration in amyloid diseases, induces
LRP expression in PC12 cells. Data from rodent infusion models
demonstrate the impact of TGFβ2
in modifying Aβ-
induced Long Term Potentiation (LTP) responses, presynaptic
proteins, lipid peroxidation, gliosis and staining for neuronal
nuclei. The evidence supports a complex and significant role
of LRP in cognition and AD
.
[Back to top]
CREB, Synapses and Memory Disorders: Past Progress
and Future Challenges
Sheena A. Josselyn and Peter V. Nguyen
In neurons, appropriate long-term adaptive responses to
changes in the environment require the conversion of extracellular
stimuli into discrete intracellular signals. Many of these
signals involve the regulation of gene expression. The cAMP
responsive element binding protein (CREB) is a nuclear transcription
factor that modulates transcription of genes containing cAMP
responsive elements (CRE sites) in their promoters. CREB is
a key part of many intracellular signaling events that critically
regulate many neural functions. Numerous studies on invertebrates
and vertebrates demonstrate that CREB is critical for long-term
memory. Here, we review the key features of CREB-dependent
transcription and critically evaluate the data examining the
roles of CREB in different forms of plasticity, including
long-term memory in mammals. Because learning and memory have
been linked to specific types of synaptic plasticity in several
species, we also review studies on the role of CREB in long-term
facilitation in Aplysia and in hippocampal long-term
potentiation (LTP). Several human cognitive disorders have
been linked to alterations of CREB-regulated gene expression.
Therefore, we explore the possibility of targeting CREB function
in developing novel treatment strategies. Finally, we highlight
areas of research on CREB that are ripe for further advancement.
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Memantine: A Therapeutic Approach in Treating Alzheimer's
and Vascular Dementia
Horst J. Koch, Gökhan Uyanik and David Fischer-Barnicol
Memantine has been clinically used in the treatment of organic
disorders in Germany for over ten years and has now been approved
in Europe and also in the US for moderate to severe Alzheimer´s
disease. The rationale for this indication is strongly related
to the physiological and pathological role of glutamate in
neurotransmission. Glutamate is an agonist of NMDA, kainate
and AMPA (ionotropic) receptors, where its influence on NMDA
receptors plays an important role with regard to neuronal
plasticity effecting memory and learning. Excessive levels
of glutamate result in neurotoxicity, in part by overactivation
of NMDA receptors. Memantine acts as an uncompetitive antagonist
of NMDA receptors and therefore compensates for this overactivation.
Furthermore, memantine is a neuroprotective agent in various
animal models based on both neurodegenerative and vascular
processes, as it ameliorates cognitive and memory deficits.
Memantine was effective and safe in several clinical studies,
particularly in Alzheimer´s disease. The compound is
completely absorbed after oral intake and undergoes little
metabolism. Having a low probability for drug-drug interactions,
memantine, in principle, is suited for elderly patients exposed
to multiple therapeutic therapies.
[Back to top]
Cannabinoids
Franjo Grotenhermen
Since the discovery of an endogenous cannabinoid system,
research into the pharmacology and therapeutic potential of
cannabinoids has steadily increased. Two subtypes of G-protein
coupled cannabinoid receptors, CB1 and CB2, have been cloned
and several putative endogenous ligands (endocannabinoids)
have been detected during the past 15 years. The main endocannabinoids
are arachidonoyl ethanolamide (anandamide) and 2-arachidonoyl
glycerol (2-AG), derivatives of arachidonic acid, that are
produced “on demand” by cleavage of membrane lipid
precursors. Besides phytocannabinoids of the cannabis plant,
modulators of the cannabinoid system comprise synthetic agonists
and antagonists at the CB receptors and inhibitors of endocannabinoid
degradation. Cannabinoid receptors are distributed in the
central nervous system and many peripheral tissues, including
immune system, reproductive and gastrointestinal tracts, sympathetic
ganglia, endocrine glands, arteries, lung and heart. There
is evidence for some non-receptor dependent mechanisms of
cannabinoids and for endocannabinoid effects mediated by vanilloid
receptors.
Properties of CB receptor agonists that are of therapeutic
interest include analgesia, muscle relaxation, immunosuppression,
anti-inflammation, antiallergic effects, improvement of mood,
stimulation of appetite, antiemesis, lowering of intraocular
pressure, bronchodilation, neuroprotection and antineoplastic
effects. The current main focus of clinical research is their
efficacy in chronic pain and neurological disorders. CB receptor
antagonists are under investigation for medical use in obesity
and nicotine addiction. Additional potential was proposed
for the treatment of alcohol and heroine dependency, schizophrenia,
conditions with lowered blood pressure, Parkinson's disease
and memory impairment in Alzheimer's disease.
[Back to top]
Increasing Testosterone Levels and Effects on Cognitive
Functions in Elderly Men and Women: A Review
E. Hogervorst, S. Bandelow and S.D. Moffat
Low testosterone (T) levels may predispose to Alzheimer
disease (AD), but it is unclear whether this is a co-morbid
effect due to cachexia, subclinical hyperthyroidism or other
co-morbidity. The biological plausibility for potential protective
effects of T on brain functions is substantial. In addition,
higher levels of gonadotropins found in older cases with AD
suggest that low levels of T are not due to brain degeneration
and that the hypothalamic-pituitary-gonadal (HPG) axis is
still intact. Men genetically at risk for AD were also already
found to have lower levels of T. However, despite having lower
levels of T, women do not show accelerated cognitive decline
with age when compared to men. In addition, castration has
not necessarily shown a decline in cognitive functions; some
studies even found improvement of memory recall. Age may be
an important factor when assessing optimal levels of T and
several studies suggest that free or bioavailable T may be
a better marker than total T levels when investigating associations
of androgen activity with cognitive function. Small-scale
T intervention trials in elderly men with and without dementia
suggest that some cognitive deficits may be reversed, at least
in part, by short term T supplementation. Age and prior hypogonadism
may play an important role in therapy success and these factors
should be investigated in more detail in future large scale
randomized controlled studies. For elderly women, T treatment
does not seem to have additional benefits over estrogen treatment
for postmenopausal complaints and cognitive decline and may
increase cardiovascular disease.
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Protein Kinase C Isozymes: Memory Therapeutic Potential
Miao-Kun Sun and Daniel L. Alkon
PKC plays an important role in many types of learning and
memory. Evidence has been provided that PKC activation and
translocation are induced in associative learning tasks. PKC
inhibition, on the other hand, impairs learning and memory,
consistent with the observations that transgenic animal models
with a particular PKC isoform deficit exhibit impaired capacity
in cognition. The dramatic impact of PKC pharmacology on learning
and memory is further emphasized by a regulatory role of PKC
isozymes in amyloid production and accumulation. Recent study
reveals that PKC activation greatly reduces neurotoxic amyloid
production and accumulation. PKC activators, therefore, may
have important therapeutic values in the treatment of dementia,
especially when fine-tuning of selective isoform activity
can be effectively achieved pharmacologically, with further
development of isozymes-specific agents. The success of antidementia
therapy with agents that act on PKC signaling cascades depends
on whether such agents at their effective doses would significantly
disrupt or interfere with other vital functions that rely
on a narrow range of PKC activities.
[Back to top]
Cholesterol and Apoe: A Target for Alzheimer's Disease
Therapeutics
Daniela Fenili and JoAnne McLaurin
Alzheimer’s disease (AD) is a debilitating disease
that affects many people. In order to reduce the number of
people diagnosed with this disease, drug strategies need to
be implemented that target early steps in disease pathogenesis.
Elevated cholesterol levels and presence of the apolipoprotein
E ε4
allele increase AD risk. How these two factors may contribute
to AD pathogenesis and some therapeutic strategies for alleviating
AD risk will be discussed.
[Back to top]
Abeta Immunotherapy and Other Means to Remove Amyloid
Edith G. McGeer and Patrick L. McGeer
The amyloid cascade hypothesis postulates that accumulation
of beta-amyloid (Abeta) plays a key role in the development
of Alzheimer’s disease (AD). Accordingly, much effort
has gone into reducing the amyloid burden, especially in transgenic
mice expressing mutations in human amyloid precursor protein.
Such mice develop amyloid plaques but not neurofibrillary
tangles. Immunization with Abeta and other inflammatory stimuli,
inhibitors of Abeta formation, cholesterol lowering agents,
beta-sheet breaker peptides, antioxidants and various miscellaneous
agents have been found to reduce the more soluble Abeta in
such transgenic mice. Whether they would affect the more consolidated,
cross-linked Abeta of AD and, if they did, whether that would
really prove an effective treatment for the disease remains
for future research to determine.
[Back to top]
Neuroactive Flavonoids Interacting with GABAA
Receptor Complex
Feng Wang, Michael Shing Yan Huen, Shui Ying Tsang and Hong
Xue
Classical benzodiazepines (BZs) are the most widely prescribed
drugs acting on the central nervous system (CNS). They exert
their therapeutic effects via binding to the BZ-site of GABAA
receptors, and allosterically modulating the chloride flux
through the ion channel complex. Given the multiple actions
of classical BZs, the serious limitations to their usefulness
have directed much research into development of novel ligands
for the BZ-site with retained therapeutic effectiveness and
minimal side effects. From the studies of CNS-active chemical
constituents of medicinal herbs, some members of the family
of flavonoids were demonstrated to have moderate binding affinities
for the BZ-site. In vivo studies revealed that these
compounds were mostly partial agonists of GABAA
receptors, and only a few flavonoids were shown to possess
antagonistic activities. At effective anxiolytic doses, the
actions of partial agonistic flavonoids were often not accompanied
by sedative and myorelaxant side effects. Based on structure-activity
relationship (SAR) studies, incorporation of electronegative
groups to the C6 and C3’ on the flavone backbone was
found to yield significant increases in the binding affinities
for the BZ-site. It was also shown that 2’-hydroxyl
was a critical moiety on flavonoids with regard to BZ-site
binding. These have guided the identification of several synthetic
flavonoids with high BZ-site binding affinity and in vivo
activity, and further quantitative SAR studies resulted
in the development of several pharmacophore models. This review
attempts to summarize these findings, which has led to the
establishment of flavonoids as potential therapeutics for
GABAA receptor-mediated disorders.
[Back to top]
Small Transthyretin (TTR) Ligands as Possible Therapeutic
Agents in TTR Amyloidoses
M.R. Almeida, L. Gales, A.M. Damas, I. Cardoso, M.J. Saraiva
In transthyretin (TTR) amyloidosis TTR variants deposit
as amyloid fibrils giving origin, in most cases, to peripheral
polyneuropathy, cardiomyopathy, carpal tunnel syndrome and/or
amyloid deposition in the eye. More than eighty TTR variants
are known, most of them being pathogenic. The mechanism of
TTR fibril formation is still not completely elucidated. However
it is widely accepted that the amino acid substitutions in
the TTR variants contribute to a destabilizing effect on the
TTR tetramer molecule, which in particular conditions dissociate
into non native monomeric intermediates that aggregate and
polymerize in amyloid fibrils that further elongate. Since
this is a multi-step process there is the possibility to impair
TTR amyloid fibril formation at different stages of the process
namely by tetramer stabilization, inhibition of fibril formation
or fibril disruption. Till now the only efficient therapy
available is liver transplant when performed in an early phase
of the onset of the disease symptoms. Since this is a very
invasive therapy alternatives are desirable. In that sense,
several compounds have been proposed to impair amyloid formation
or disruption. Based on the proposed mechanism for TTR amyloid
fibril formation we discuss the action of some of the proposed
TTR stabilizers such as derivatives of some NSAIDs (diflunisal,
diclofenac, flufenamic acid, and derivatives) and the action
of amyloid disrupters such as 4’-iodo-4’-deoxydoxorubicin
(I-DOX) and tetracyclines. Among all these compounds, TTR
stabilizers seem to be the most interesting since they would
impair very early the process of amyloid formation and could
also have a prophylactic effect.
[Back to top]
Neuronal Plasticity, Stress and Depression: Involvement
of the Cytoskeletal Microtubular System?
M. Bianchi, J.J. Hagan and C.A. Heidbreder
In susceptible individuals, stressors can increase the risk
of onset of depression and recent brain imaging studies have
shown morphometric alterations in the limbic system of patients
affected by depression. The volume loss observed in the hippocampus
of depressed individuals suggests a possible involvement of
structural neuronal plasticity in the pathogenesis of depression.
Stressful conditions in animals can result in impaired structural
neuronal plasticity in the hippocampus, characterised by retraction
of apical dendrites and decreased neurogenesis. The intrinsic
dynamic instability of the cytoskeletal microtubular system
is essential for neuronal remodelling and plasticity. We have
recently shown that both acute and chronic stress decrease
microtubular dynamics in the rat hippocampus. Other authors
have demonstrated that proteins functionally involved in the
regulation of microtubule dynamics can be altered by stress
in the rodent hippocampus. Furthermore, the existence of a
link between stress-induced microtubular changes and depression
is further strengthened by evidence showing that both acute
and chronic treatment with antidepressant drugs can affect
the expression of microtubular proteins. The present review
will introduce a growing body of evidence suggesting that
stress-induced alterations in neuronal plasticity might be
considered the final result of activation and/or inhibition
of molecular cascades regulating the dynamics of the microtubular
system. In addition, the prospect of targeting microtubules
as a pharmacotherapeutic approach to treat mood disorders
will be discussed.
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