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CNS
& Neurological Disorders -Drug Targets
ISSN: 1871-5273
CNS & Neurological Disorders
- Drug Targets
Volume 7, Number 1, February 2008
Contents
Neurodegenerative Disorders: From Molecules to Man
(Part 2)
Guest Editors: Giuseppe Di Giovanni, Vincenzo Di Matteo
and Ennio Esposito
Editorial Pp. 1-2
Alzheimer Disease and the Role of Free Radicals in
the Pathogenesis of the Disease Pp. 3-10
Paula I. Moreira, Maria S. Santos, Catarina R. Oliveira, Justin
C. Shenk, Akihiko Nunomura, Mark A. Smith, Xiongwei Zhu and
George Perry
[Abstract]
Molecular Insights and Therapeutic Targets in
Amyotrophic Lateral Sclerosis Pp. 11-19
Vineeta B. Tripathi and Ammar Al-Chalabi
[Abstract]
Is the Deficiency of Vitamin B12 Related to Oxidative
Stress and Neurotoxicity in 20 Parkinson’s Patients?
Pp. 20-27
Ghulam Ali Qureshi, Aftab A. Qureshi, Bika Ram Devrajani,
M.A. Chippa and S. Ali Syed
[Abstract]
Will it Ever Become Possible to Prevent Dopaminergic
Neuronal Degeneration? Pp. 28-44
Giuseppe Di Giovanni
[Abstract]
Targeting Neurotrophic Factors, Their Receptors,
and Signalling Pathways with Small Molecule Mimetics and Modulators
to Achieve Neuroprotection an Regeneration
Guest Editor: Stephen D. Skaper
Editorial Pp. 45
The Biology of Neurotrophins, Signalling Pathways,
and Functional Peptide Mimetics of Neurotrophins
and their Receptors Pp. 46-62
Stephen D. Skaper
[Abstract]
Small Molecule Modulation of p75 Neurotrophin
Receptor Functions Pp. 63-70
Frank M. Longo and Stephen M. Massa
[Abstract]
Targeting Neurotrophin Receptors in the Central
Nervous System Pp. 71-82
Italo Mocchetti and Milton Brown
[Abstract]
MAP Kinase Pathways in Neuronal Cell Death Pp.
83-97
Karen L. Philpott and Laura Facci
[Abstract]
Stem Cells for the Treatment of Neurological
Disorders Pp. 98-109
Aparna Khanna, Soojung Shin and Mahendra S. Rao
[Abstract]
Tandem Repeat Peptide Strategy for the Design
of Neurotrophic Factor Mimetics Pp. 110-119
Francisco Molina-Holgado, Patrick Doherty and Gareth Williams
[Abstract]
Abstracts
[Back to top]
Editorial
Neurons are typically post-mitotic cells. This means that
they are expected to have a life span comparable to that of
their carriers. Unfortunately, sometimes, they die prematurely
as a result of complex processes known as “neurodegeneration”.
Neurodegenerative diseases are now generally considered a
group of disorders that seriously and progressively impair
the functions of the nervous system through causing the selective
neuronal vulnerability of specific brain regions. Neurodegenerative
disorders such as Parkinson's disease (PD), Alzheimer Disease
(AD), Multiple Sclerosis (MS), and prion disease represent
several distinct categories of disease and each manifests
its own unique symptoms. However, the diseases share several
common features, particularly the aggregation and deposition
of abnormal proteins. Neurodegenerative disorders are associated
with high morbidity, and few or no effective treatments have
been available until now. Neurodegenerative diseases represent
a threat to mankind in a variety of guises and induce chronic
suffering and debilitation in about 2% of the worldwide population.
Moreover, the increase in lifespan of western populations
will mean that these neurodegenerative diseases will become
more common. Consequently, it is estimated that the number
of PD patients will double to between 8.7 and 9.3 million
by 2030. As a group, these disorders are a major burden on
health care systems compared with other causes of death and
the costs of treatment are expected to rise sharply. Despite
the enormous amount of progress we have made in terms of understanding
the aetiologies of these diseases in the last few years, important
questions remain unanswered. This special number deals with
this hot topic and is produced by leading groups in the neuroscience
field with the aim of summarizing recent advances in genetic,
epideniological, molecular and cellular biology research that
have increased our knowledge of the mechanisms that give rise
to degenerative processes and, in general, to alterations
of the structure and function of the nervous system. These
contributions give insight into new pharmacological therapies
for their treatment and review new and old drugs aimed at
interrupting or at attenuating different pathogenic pathways
of neurodegeneration and/or at ameliorating symptoms. The
pharmaceutical industry faces arguably its most difficult
challenge in attempting to develop therapeutics for neurodegenerative
disease. The development of disease-modifying therapeutics
that addresses the principal causes of neurodegenerative disease
is still in its infancy.
Moreira et al. review the role played by oxidative
stress in the development and progression of AD and show how
ROS-mediated oxidative damages proteins, lipids, nucleic acids
and sugars in AD and how this damage results from extensive
mitochondrial and metal abnormalities. They present data supporting
the notion that the oxidative modifications that occur in
AD may elicit compensatory mechanisms, such as Aβ
deposition and hyperphosphorylated tau that try to restore
the redox balance in an attempt to avoid neuronal death. However,
with the progression of AD and the consequent increase of
reactive species, efficient removal of Aβ-metal
complexes and hyperphosphorylated tau would be overtaken by
their disproportionately high generation, resulting in an
uncontrollable growth of plaques and NFTs and, consequently,
an increase in reactive species generation.
Amyotrophic lateral sclerosis (ALS) is the disorder reviewed
by Tripathi and Al-Chalabi. This is a neurodegenerative disease
of motor neurons resulting in progressive paralysis and respiratory
failure. About 1 in 250,000 people suffer from ALS. The causes
of ALS are largely unknown, but the only disease-modifying
therapy, riluzole, was designed based on one hypothesis of
disease causation, the excitotoxic hypothesis. In this paper
they review the current situation regarding ALS and new therapeutic
opportunities.
The last two papers are about PD. Ali Qureshi et al.
review the relation between vitamin B12 deficiency and neurotoxicity
of homocysteine and nitrite (a metabolite of nitric oxide)
in PD patients treated with levodopa (L-Dopa). A linear relationship
between the CSF levels of nitrite with Glutamic acid and homocysteine
exists and suggests that the production of nitrite is interrelated
with the neurotoxic level of homocysteine. The levels of nitrite
and homocysteine resulting in the deficiency of vitamin B12
are some of the factors promoting degeneration in PD through
neurotoxic effects. Therefore, higher dietary intakes of folate,
vitamin B12, and vitamin
B6 might decrease the risk of PD through decreasing plasma
homocysteine. Finally, Di Giovanni tries to answer the difficult
question of the possibility of preventing PD in the future.
Indeed, PD is still fatal, there is at present no cure for
it and there are no proven therapies for prevention. Although
there is evidence of the existence of risk and protective
factors, these are not strong enough to warrant specific measures
in an attempt to diminish risk or enhance protection. In the
first part of his review new neuroprotective and neurorestorative
therapies with their advantages and disadvantages are discussed.
In the latter section, various dietary recommendations, lifestyle,
environmental and other factors in reducing the risk of PD
are analysed.
The scenario that results from this special issue is that,
despite the enormous research focused on neurodegenerative
disorders, the underlying pathophysiology is not yet understood
in sufficient detail. The situation is certainly a consequence
of the complex interplay of genes, environment and their myriad
interactions. There is not as yet a clear means of establishing
efficacy in slowly progressing, late-onset disorders. Given
the nature of these diseases, future therapeutics will need
to be paired with tests for biomarkers indicating onset of
brain pathology that precedes overt clinical symptoms. Therefore,
it is of paramount importance to reveal those who are at high
risk of developing these neurological disorders and allow
them start an early program of prevention. This might involve
a brain-healthy diet, very similar to a heart-healthy diet,
and moderate physical activity with the aim of avoiding the
other risk factors known so far.
Vincenzo Di Matteo and Ennio Esposito
Istituto di Ricerche Farmacologiche "Mario Negri"
Consorzio "Mario Negri" Sud
Via Nazionale 8
66030 Santa Maria Imbaro, Chieti
Italy
Giuseppe Di Giovanni
Istituto di Ricerche Farmacologiche
Sezione di Fisiologia Umana, “G. Pagano”
Università degli Studi di Palermo
66030 Santa Maria Imbaro,
Tuköry 129, 90134, Palermo
Italy
E-mail: g.digiovanni@unipa.it
[Back to top]
Alzheimer Disease and the Role of Free Radicals in the Pathogenesis
of the Disease 3
Paula I. Moreira, Maria S. Santos, Catarina R. Oliveira, Justin
C. Shenk, Akihiko Nunomura, Mark A. Smith, Xiongwei Zhu and
George Perry
Oxidative stress occurs early in the progression of Alzheimer
disease, significantly before the development of the pathologic
hallmarks, neurofibrillary tangles and senile plaques. All
classes of macromolecules (sugar, lipids, proteins, and nucleic
acids) are affected by oxidative stress leading, inevitably,
to neuronal dysfunction. Extensive data from the literature
support the notion that mitochondrial and metal abnormalities
are key sources of oxidative stress in Alzheimer disease.
Furthermore, it has been suggested that in the initial stages
of the development of Alzheimer disease, amyloid-β
deposition and hyperphosphorylated tau function as compensatory
responses to ensure that neuronal cells do not succumb to
oxidative damage. However, during the progression of the disease,
the antioxidant activity of both agents is either overwhelmed
or, according to others, evolves into pro-oxidant activity
resulting in the exacerbation of reactive species production.
[Back to top]
Molecular Insights and Therapeutic Targets in Amyotrophic
Lateral Sclerosis
Vineeta B. Tripathi and Ammar Al-Chalabi
Amyotrophic lateral sclerosis (ALS) is a neurodegenerative
disease of motor neurons resulting in progressive paralysis
and respiratory failure. About 1 in every 400 people dies
of ALS, usually within 3 to 5 years of symptom onset. The
lack of effective therapy means that although the incidence
is comparable to that of multiple sclerosis, the prevalence
is low. The causes of ALS are largely unknown, but the only
disease-modifying therapy, riluzole, was designed based on
one hypothesis of disease causation, the excitotoxic hypothesis.
In this paper we will review current ideas about the causes
of ALS and the therapeutic opportunities they suggest.
[Back to top]
Is the Deficiency of Vitamin B12 Related to Oxidative Stress
and Neurotoxicity in 20 Parkinson’s Patients? Ghulam
Ali Qureshi, Aftab A. Qureshi, Bika Ram Devrajani, M.A. Chippa
and S. Ali Syed
This review deals with the results showing the relation
between vitamin B12 deficiency and neurotoxicity of homocysteine
and nitrite (a metabolite of nitric oxide) in Parkinson’s
patients treated with levodopa (L-Dopa). We have already reported
a linear relationship between the CSF levels of nitrite with
glutamic acid and homocysteine suggesting that the production
of nitrite is interrelated with the neurotoxic level of homocysteine.
The levels of nitrite and homocysteine resulting in the deficiency
of vitamin B12 are some of
the factors promoting degeneration in Parkinson’s disease.
This review emphasizes the importance of these parameters
in designing suitable drug therapy for Parkinson disease.
Additionally, there is evidence that increased homocysteine
levels might accelerate dopaminergic cell death in Parkinson
disease (PD), through neurotoxic effects. Furthermore, levodopa
(L-Dopa) treatment of PD results in hyperhomocysteinemia as
a consequence of L-Dopa methylation by catechol-O-methyltransferase
(COMT). Therefore, higher dietary intakes of folate, vitamin
B12, and vitamin B6 might
decrease the risk of PD through decreasing plasma homocysteine.
[Back to top]
Will it Ever Become Possible to Prevent Dopaminergic Neuronal
Degeneration?
Giuseppe Di Giovanni
Parkinson's disease (PD) is the second leading age-related
degenerative brain disease in the world affecting millions
of people. This neurological disorder disrupts the quality
of life of patients and their families, exerts an enormous
emotional and physical strain on caregivers, and has a large
cost for society. Moreover, the increasing numbers of elderly
people in the population will result in a sharp increase in
the prevalence of PD. The understanding of its pathophysiology
and treatment has advanced at a very impressive rate during
past decades. Nevertheless, PD is still fatal and there is
at present no cure for it. Furthermore, there are no proven
therapies for prevention of PD and although evidence exists
of risk and protective factors, this is not strong enough
to warrant specific measures in an attempt to diminish risk
or enhance protection. Drug development programmes are engaged
in finding neuroprotective and neurorestorative therapies
or, even better, discovering drugs able to rejuvenate
the dopaminergic neurons. The latest developments in this
promising field will be discussed with reference to the current
literature together with the advantages and pitfalls of suggested
drugs. Finally, an analysis of the role of various dietary
recommendations, lifestyle, environmental and other factors
in reducing the risk of PD is carried out.
[Back to top]
Editorial
Neurotrophic factors were originally identified based on their
ability to prevent naturally occurring cell death in the developing
nervous system. Many of these proteins also promote survival
after injury or protect neurons in toxin-disease models in
animals. In addition to neuroprotective effects, these factors
exert trophic effects on neurons, stimulating increases in
neuronal metabolism, cell size, and process outgrowth. These
properties underlie expectations for neurorestoration, in
which growth of new axons and synapses could lead to functional
improvement, which is of great interest for those patients
who are already significantly disabled by disease. In spite
of such encouraging experimental findings, clinical studies
have proven largely disappointing. Although these proteins
are natural products, they cannot be given orally, present
uncertain pharmacokinetic behaviour, and large-scale production
is labour and cost-intensive. For CNS diseases, the advantages
of small molecule mimetics over proteins are evident. Small
organic molecules can be modified to penetrate freely into
the brain parenchyma and can be designed for oral administration.
A detailed understanding of neurotrophic factor-receptor structure
and interactions and intracellular signalling has been crucial
in the design of peptidyl and non-peptidyl small molecule
neurotrophin mimetics which interact directly with the receptor,
or which potentiate neurotrophin activation of its cognate
receptor. Another example of how such knowledge has been exploited
is that of the low-affinity pan-neurotrophin receptor p75NTR,
which can promote cell survival in the absence of Trk receptors.
A pharmacophore designed to capture selected structural and
physico-chemical features of a neurotrophin domain known to
interact with p75NTR was
applied to in silico screening of small molecule libraries
to select neurotrophic compounds. Other strategies include
intracellular effector-targeting approaches, which capitalise
on knowledge of signalling pathways involved in neuronal cell
survival and demise, and which can be agonised or antagonised
to promote neuroprotection. This issue will begin with a brief
overview on the biology neurotrophic proteins, followed by
articles describing strategies taken towards the development
of small molecule mimetics for neurotrophic factors and the
emerging drug candidates, and will encompass both receptor-directed
as well as intracellular signalling approaches. Moreover,
exciting recent data describing G-protein-coupled receptor
transactivation of Trk receptors and their downstream signalling
pathways raise the possibility of using small molecule G-protein-coupled
receptor ligands as a new strategy for promoting trophic effects
during neurodegeneration.
While many challenges lie ahead, the development of neurotrophic
compounds is potentially very rewarding and appears to offer
real promise for disease modification. Neurotrophic drug development,
however, has historically been a high-risk approach. Nonetheless,
novel emerging targets and technological improvements, as
well as the development of biomarkers that can act as surrogates
to assess drug activity at the defined molecular target together
with a more focused effort on translational medicine approaches
may facilitate the development of neurotrophic small molecules
with lower associated attrition rates.
Stephen D. Skaper
Neurology Centre of Excellence for Drug Discovery
GlaxoSmithKline Research & Development Limited
New Frontiers Science Park
Third Avenue, CM19 5AW
Harlow, Essex
UK
E-mail: Stephen_d_Skaper@gsk.com
[Back to top]
The Biology of Neurotrophins, Signalling Pathways, and Functional
Peptide Mimetics of Neurotrophins and their
Receptors
Stephen D. Skaper
The neurotrophins are a family of closely related proteins
that were first identified as survival factors for sympathetic
and sensory neurons, and have since been shown to control
a number of aspects of survival, development and function
of neurons in both the central and peripheral nervous systems.
Limiting quantities of neurotrophins during development control
the numbers of surviving neurons to ensure a match between
neurons and the requirement for a suitable density of target
innervation. Biological effects of each of the four mammalian
neurotrophins are mediated through activation of one or more
of the three members of the tropomyosin-related kinase (Trk)
family of receptor tyrosine kinases (TrkA, TrkB and TrkC).
In addition, all neurotrophins activate the p75 neurotrophin
receptor (p75NTR), a member
of the tumour necrosis factor receptor superfamily. Nerve
growth factor (NGF), the best characterised member of the
neurotrophin family, sends its survival signals through activation
of TrkA and can induce death by binding to p75NTR.
Neurotrophin engagement of Trk receptors leads to activation
of Ras, phosphatidylinositol 3-kinase, phospholipase C-γ1
and signalling pathways controlled through these proteins,
including the mitogen-activated protein kinases. Neurotrophin
availability is required into adulthood, where they control
synaptic function and plasticity, and sustain neuronal cell
survival, morphology and differentiation. Preclinical studies
point to the therapeutic potential of neurotrophic factors
in preventing or slowing the progression of neurodegenerative
conditions. Given the difficulties inherent with a protein
therapeutic approach to treating central nervous system disorders,
increasing attention has turned to the development of alternative
strategies and, in particular, small molecule mimetics. This
article will provide an overview of neurotrophin biology,
their receptors, and signalling pathways, followed by a description
of functional mimetics of neurotrophins acting at Trk receptors.
Moreover, exciting recent data describing G-protein-coupled
receptor transactivation of Trk receptors and their downstream
signalling pathways raise the possibility of using small molecules
to elicit neuroprotective effects.
[Back to top]
Small Molecule Modulation of p75 Neurotrophin Receptor Functions
Frank M. Longo and Stephen M. Massa
Ligand-independent and/or proNGF-induced p75NTR
signaling has emerged as a potential major contributor to
a number of pathological states, including axotomy-induced
death, motor neuron degeneration, neuronal degeneration in
Alzheimer’s disease and oligodendrocyte death following
spinal cord injury. A long standing goal in the neurotrophin
field has been the development of non-peptide, small molecules
capable of functioning as specific ligands at neurotrophin
receptors such as p75NTR
to promote desired biological outcomes. Synthetic peptides
modeled on neurotrophin protein domains have been found to
bind to and activate various neurotrophin receptors, raising
the possibility that active, non-peptide, small molecule ligands
might also be identified; however, traditional high-throughput
screening approaches have been largely ineffective in identifying
such compounds. Using pharmacophores derived from the structure
of loop 1 of nerve growth factor, non-peptide, small molecules
that function as p75NTR ligands
to promote survival and block proNGF-induced death have recently
been identified. Small molecule p75NTR
ligands, with high potency and specificity, may provide novel
therapeutic approaches for neurodegenerative diseases, neurotrauma
and other pathologic states.
[Back to top]
Targeting Neurotrophin Receptors in the Central Nervous System
Italo Mocchetti and Milton Brown
Neurotrophic factors, and in particular the neurotrophins,
restore the function of damaged neurons and prevent apoptosis
in adults. The potential therapeutic property of the neurotrophins
is however, complicated by the peptidergic structure of these
trophic factors, which impairs their penetration into the
brain parenchyma, and therefore makes their pharmaco-therapeutic
properties difficult to evaluate. In this article we will
focus on the neurotrophin Brain-derived neurotrophic factor
(BDNF) and its receptors to address various therapeutic strategies
that may overcome this problem. We will call this strategy
“small molecule approach” because it relies on
increasing the function of endogenous neurotrophins by pharmacological
compounds that induce synthesis and release of neurotrophins
in relevant brain areas or by small synthetic molecules that
bind and activate specific neurotrophin receptors. The ability
of small molecules to mimic BDNF has a potential therapeutic
importance in preventing neuronal damage in several chronic
neurodegenerative diseases including Parkinson’s Disease,
Alzheimer’s Disease, and AIDS dementia.
[Back to top]
MAP Kinase Pathways in Neuronal Cell Death
Karen L. Philpott and Laura Facci
The signaling pathways which contribute to neuronal death
during development, aging and disease have been extensively
studied. While initial efforts focused on developmental death,
increasing evidence suggests that mitogen-activated protein
kinase pathways play a role in human pathology. In particular,
the c-Jun N-terminal kinases (JNKs), mitogen-activated protein
kinases activated by extracellular stimuli including stress,
are a major focus. Knock-out mouse studies have demonstrated
that removing particular JNK genes can reduce the severity
in various disease scenarios, including those which are used
to model Parkinson’s disease and cerebral ischemia.
In addition, activation of JNKs can be seen in human disease
tissue. In this review we bring together the evidence for
JNK being an important regulator of neuronal loss and outline
the advancement of small molecule inhibitors for future therapeutic
intervention.
[Back to top]
Stem Cells for the Treatment of Neurological Disorders
Aparna Khanna, Soojung Shin and Mahendra S. Rao
Embryonic stem cells (ESC) are a source of renewable
cells, which possess a phenomenal potential to differentiate
into a myriad of cell types. Thus, ESCs offer a potentially
unlimited supply of cells, which can be deployed in developing
cell-based therapies. The in vitro differentiation
capacity of ESC into derivatives of the neuronal lineage has
been demonstrated and the functionality of the ESC derived
neuroprogenitors, upon transplantation into in vivo
models has been substantiated. In this review, we discuss
various approaches to directing ESC towards neural lineages
and protocols for sorting and selection of differentiated
progenies.
We examine in particular in vitro differentiation
of ESC to mid-brain dopaminergic (DA) neurons and glial cells
and the potential issues related to the transition to the
clinic.
[Back to top]
Tandem Repeat Peptide Strategy for the Design of Neurotrophic
Factor Mimetics
Francisco Molina-Holgado, Patrick Doherty and Gareth Williams
Neurotrophic factors comprise a broad family of secreted
proteins that have growth promoting, survival promoting and
differentiation inducing activities. Disruption of neurotrophic
factor signalling is a characteristic of many central and
peripheral nervous system disorders, such as Alzheimer’s
disease, Parkinson’s disease, amyotrophic lateral sclerosis,
multiple sclerosis, stroke, and peripheral neuropathy and
pain. It follows that treating patients with neurotrophic
factors might be beneficial in a range of neurological diseases.
However, the promising results seen in animal models of disease
have not translated well into clinical trials due to the poor
pharmacokinetics associated with the intact proteins, in particular,
their short in vivo half-life, low blood brain barrier
permeability, limited diffusion, and undesirable effects through
multiple receptor interactions. This has been the main motivation
for the design of small molecule modulators of the neurotrophic
factor pathways. The review gives a brief survey of the various
strategies to design mimetics that have been reported in the
literature with special emphasis on the tandem repeat peptide
agonist approach for BDNF/NT-4/5 and N-cadherin mimetics.
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