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CNS
& Neurological Disorders -Drug Targets
ISSN: 1871-5273
CNS & Neurological Disorders
- Drug Targets
Volume 6, Number 6, December 2007
Contents
Neurodegenerative Disorders: From Molecules to Man
(Part 1)
Guest Editors: Giuseppe Di Giovanni, Vincenzo
Di Matteo and Ennio Esposit
Editorial Pp. 375-376
Cannabinoids and Neuroprotection in Motor-Related
Disorders Pp. 377-387
Eva de Lago and Javier Fernández-Ruiz
[Abstract]
Microglia- Neuron Interaction in Inflammatory and
Degenerative Diseases: Role of Cholinergic and Noradrenergic
Systems Pp. 388-397
D. Carnevale, R. De Simone and L. Minghetti
[Abstract]
Kynurenine Pathway and Disease: An Overview Pp.
398-410
Verónica Pérez-De La Cruz, Mina Königsberg
and Abel Santamaría
[Abstract]
Neuronal Death and Survival Under Oxidative Stress
in Alzheimer and Parkinson Diseases Pp. 411-423
A. Nunomura, P.I. Moreira, H.G. Lee, X. Zhu, R.J. Castellani,
M.A. Smith and G. Perry
[Abstract]
The Pathogenic Mechanisms of Prion Diseases
Pp. 424-455
U. Unterberger and T. Voigtländer
[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.
de Lago and Fernández-Ruiz provide an extensive description
of the neuroprotective properties of cannabinoids. They focus
their review on the cellular and molecular mechanisms through
which cannabinoids might arrest/delay the degeneration of
specific neuronal subpopulations in neurodegenerative disorders
such as PD, HD, multiple sclerosis (MS) and other motor-related
disorders. The potential use of cannabinoid agonists as novel
therapeutic options is based on their antioxidant, anti-inflammatory
and anti-excitotoxic properties that allow them to afford
neuroprotection in different disorders. Carnevale et al.
review the current information on the reciprocal interactions
between glia and neurons that are essential for many critical
functions in brain health and disease. Microglial cells, the
brain resident macrophages, and astrocytes, the most prevalent
type of cell in brain, are actively involved in the control
of neuronal activities both in developing and adult organisms.
At the same time, neurons influence glial functions, through
direct cell-to cell interactions as well as the release of
soluble mediators. The authors concentrate on signals from
neurons that may have an active role in controlling glial
activation on two major neurotransmitters: acetylcholine (Ach)
and noradrenaline (NA). The cholinergic and adrenergic anti-inflammatory
pathways represent important physiological neuro-immune mechanisms
by which the innate and adaptive immune responses are kept
in control. The authors show evidence indicating that such
mechanisms play a pivotal role in the inflammatory and immune
processes within the CNS. ACh and NA appear to contribute
with their pleiotropic functions to restrain glial activation
and control inflammation and neurodegeneration. The development
of specific agonists and compounds slowing the degradation
of ACh and NA or their re-uptake might have therapeutic potential
as anti-inflammatory agents for treating chronic neurodegenerative
diseases.
A separate review by Pérez-De La Cruz et al.
describes the catabolic route for tryptophan decomposition
known as the kynurenine pathway. This is not only involved
in different neurological disorders, but also possesses neuroactive
metabolites with different biological properties, such as
pro-oxidant and antioxidant regulators. They provide an overview
on the relevance of this route for several disorders, and
also add some further and recent information on the different
biological properties of the neuroactive metabolites of this
pathway and their significance for the design of potential
therapies for those disorders involving excitotoxic, oxidative
and inflammatory components.
Nunomura et al. review the role played by oxidative
stress in the development and progression of AD and PD providing
consistent evidence that oxidative insult is a significant
early event in the pathological cascade of this disorder.
Therefore they show that that pro-longevity gene products
such as forkhead transcription factors and sirtuins are involved
in the insulin-like signaling pathway and oxidative stress
resistance against aging. An enhancement of the pro-longevity
signaling (e.g. caloric restriction) may be a promising approach
as anti-oxidative strategy against age-associated neurodegenerative
diseases.
Unterberger and Voigtländer focused their paper on the
pathogenic mechanisms of prion diseases. Prion diseases are
rare fatal neurodegenerative disorders that may either occur
sporadically, or be inherited or infectiously acquired in
humans. Irrespective of aetiology, they can be transmitted
to other individuals, this fact being responsible for the
public attention prion diseases have received especially since
the nineteen nineties, when a new variant of Creutzfeldt-Jakob
disease linked to the consumption of prion contaminated beef
occurred for the first time in Great Britain. In this review,
they discuss actual and potential drug targets in the context
of the pathogenic mechanisms of prion diseases.
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
Dipartimento di Medicina Sperimentale
Sezione di Fisiologia Umana, “G. Pagano”
Università degli Studi di Palermo
Corso Tuköry 129, 90134, Palermo
Italy
E-mail:
g.digiovanni@unipa.it
[Back to top]
Cannabinoids and Neuroprotection in Motor-Related
Disorders
Eva de Lago and Javier Fernández-Ruiz
Neuroprotective properties of cannabinoids have been
extensively studied in the last years in different neurodegenerative
pathologies. This potential is based on the antioxidant, anti-inflammatory
and anti-excitotoxic properties exhibited by these compounds
that allow them to afford neuroprotection in different neurodegenerative
disorders like Parkinson´s disease (PD), Huntington`s
disease (HD), multiple sclerosis (MS) and others. PD and HD
are chronic pathologies that are caused by the degeneration
of specific structures within the basal ganglia. In both disorders,
the key mechanisms involved in the neuroprotection provided
by cannabinoids include cannabinoid receptor-independent effects
aimed at reducing the oxidative injury, and also cannabinoid
2 receptors (CB2)-mediated
effects exerted by regulating the influence of reactive microglia
on neuronal homeostasis. MS is an inflammatory demyelinating
disorder primarily affecting spinal neurons and secondarily
producing a malfunctioning and/or degeneration of other neuronal
subpopulations located in supraspinal brain structures. There
is evidence that both cannabinoid 1 receptors (CB1)
and CB2 may afford a protective
effect in this disease due to their immunomodulatory, anti-inflammatory
and anti-excitotoxic properties. Lastly, neuroprotective effects
of cannabinoids exerted by the activation of CB1
but also CB2 receptors have
been also identified in amyotrophic lateral sclerosis (ALS),
another degenerative disease characterized by the selective
death of spinal motoneurons. In the present review, we will
collect the latest advances in the knowledge of the cellular
and molecular mechanisms through which cannabinoids might
arrest/delay the degeneration of specific neuronal subpopulations
in these motor-related disorders. This should serve to encourage
that the present promising evidence obtained mainly at the
preclinical level might progress to a real exploitation of
neuroprotective benefits of potential cannabinoid-based medicines.
[Back to top]
Microglia- Neuron Interaction in Inflammatory and Degenerative
Diseases: Role of Cholinergic and Noradrenergic Systems
D. Carnevale, R. De Simone and L. Minghetti
Reciprocal interactions between glia and neurons are
essential for many critical functions in brain health and
disease. Microglial cells, the brain resident macrophages,
and astrocytes, the most prevalent type of cell in brain,
are actively involved in the control of neuronal activities
both in developing and adult organisms. At the same time,
neurons influence glial functions, through direct cell-to-cell
interactions as well as the release of soluble mediators.
Among signals from neurons that may have an active role in
controlling glial activation are two major neurotransmitters:
acetylcholine and noradrenaline. Several studies indicate
that microglia and astrocytes express adrenergic receptors,
whose activation influences the release of pro-inflammatory
mediators, controlling the extent of glial reactivity. Acetylcholine
receptors are also expressed by glial cells. In particular,
microglial cells express the nicotinic receptor α7
and its activation attenuates the pro-inflammatory response
of microglial cultures, suggesting that acetylcholine may
control brain inflammation, in analogy to what demonstrated
in peripheral tissues. Deficiencies of noradrenergic and cholinergic
systems are linked to important neurodegenerative diseases
such as Parkinson’s disease (PD) and Alzheimer’s
disease (AD) and it has been suggested that in addition to
impairing neuron-to-neuron transmission, noradrenergic and
cholinergic hypofunction may contribute to dysregulation of
the normal neuron-glia interaction, abnormal glial reaction
and, eventually, neurodegeneration. A deeper knowledge of
role of cholinergic and noradrenergic systems in controlling
neuron-glia interactions may offer new venues for disease
treatments.
[Back to top]
Kynurenine Pathway and Disease: An Overview
Verónica Pérez-De La Cruz, Mina Königsberg
and Abel Santamaría
Kynurenine pathway is gaining more and more attention
every day in biomedical research since this catabolic route
for tryptophan decomposition is not only implicated in different
neurological disorders, but also possesses neuroactive metabolites
with different biological properties, such as pro-oxidant
and antioxidant regulators. Thus, the intensive research on
this metabolic pathway is helping us to understand those mechanisms
underlying neurodegenerative events during the occurrence
of pathological process in the central nervous system (CNS),
thereby allowing the design of potential therapies for those
disorders involving excitotoxic, oxidative and inflammatory
components. Here we intend to provide a brief overview on
the relevance of this route for several CNS disorders, and
discuss recent information on the different biological properties
of the neuroactive metabolites of this pathway and their significance
for further research.
[Back to top]
Neuronal Death and Survival Under Oxidative Stress in Alzheimer
and Parkinson Diseases
A. Nunomura, P.I. Moreira, H.G. Lee, X. Zhu, R.J. Castellani,
M.A. Smith and G. Perry
Neuronal death is a common feature in neurodegenerative
diseases including Alzheimer disease (AD) and Parkinson disease
(PD). This occurs over years, not the minutes of classically
defined apoptosis, and neurons show both responses of apoptosis
and regeneration, evidenced by accumulated oxidative insult
and attempts at cell cycle re-entry. There is recent evidence
suggesting that several known gene mutations in causing familial
AD (amyloid β
protein precursor, presenilin-1, or presenilin-2 gene) and
familial PD (Parkin, PINK-1, or DJ-1 gene) are associated
with increased oxidative stress. Also, several known genetic
(e.g. Apolipoprotein Eε4
variant) and environmental (e.g. metals or pesticides exposure)
risk factors of sporadic AD and/or PD are associated with
increased oxidative stress. In concord, patients at the preclinical
stages of AD and PD as well as cellular and animal models
of the diseases provide consistent evidence that oxidative
insult is a significant early event in the pathological cascade
of AD and PD. In contrast to the general aspects of the pathological
hallmarks, aggregation of the disease-specific proteins such
as amyloid-β,
tau, and α-synuclein
may act as a compensatory (survival) response against the
oxidative insult via the mechanism that the disease-specific
structures sequester redox-active metals. Expanding knowledge
of the molecular mechanisms of organism longevity indicates
that pro-longevity gene products such as forkhead transcription
factors and sirtuins are involved in the insulin-like signaling
pathway and oxidative stress resistance against aging. An
enhancement of the pro-longevity signaling (e.g. caloric restriction)
may be a promising approach as anti-oxidative strategy against
age-associated neurodegenerative diseases.
[Back to top]
The Pathogenic Mechanisms of Prion Diseases
U. Unterberger and T. Voigtländer
Prion diseases are rare fatal neurodegenerative disorders
that may either occur sporadically, or be inherited or infectiously
acquired in humans. Irrespective of etiology, they can be
transmitted to other individuals, this fact being responsible
for the public attention prion diseases have received especially
since the nineteen nineties, when a new variant of Creutzfeldt-Jakob
disease linked to the consumption of prion contaminated beef
occurred for the first time in Great Britain. The infectious
particle, termed prion, is presumably composed exclusively
of a misfolded, partially protease-resistant conformer (PrPsc)
of a normal cell surface protein, the cellular prion protein
(PrPc). The pathogenesis
of prion diseases comprises entry, spread, and amplification
of infectivity in the body periphery in infectiously acquired
forms, as well as mechanisms of neuronal cell death in the
central nervous system in all disease subtypes. Most experimental
therapeutic approaches are either targeted to PrPc
or PrPsc, or to the process
of conversion from PrPc to
PrPsc. Neuroprotective strategies
aiming at an interruption of central nervous system pathogenesis
have also been tested, albeit with only moderate success.
In this review, we discuss actual and potential drug targets
in the context of the pathogenic mechanisms of prion diseases.
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