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Current
Pharmaceutical Design
ISSN: 1381-6128
Current Pharmaceutical Design
Volume 12, Number 6, 2006
Contents
Drug Targets in Alzheimer's Disease
Executive Editors: G. Münch and G. Stuchbury
Editorial Pp. 659-660
γ-Secretase
as a Therapeutic Target for Treatment of Alzheimer's Disease
Pp. 661-670
T. Tomita and T. Iwatsubo
[Abstract]
Reduction of Aβ Levels in the Sprague Dawley
Rat After Oral Administration of the Functional γ-Secretase
Inhibitor, DAPT: A Novel Non-Transgenic Model for Aβ
Production Inhibitors Pp. 671-676
M. El Mouedden, M. Vandermeeren, T. Meert and M. Mercken
[Abstract]
Targeting the Alpha 7 Nicotinic Acetylcholine Receptor to
Reduce Amyloid Accumulation in Alzheimer’s Disease Pyramidal
Neurons Pp. 677-684
M.R. D’Andrea and R.G. Nagele
[Abstract]
Antigonadotropins: A Novel Strategy to Halt Alzheimer's
Disease Progression Pp. 685-690
C.W. Gregory, C.S. Atwood, M.A. Smith and R.L. Bowen
[Abstract]
The Cell Cycle and Hormonal Fluxes in Alzheimer Disease:
A Novel Therapeutic Target Pp. 691-697
K.M. Webber, G. Casadesus, X. Zhu, M.E. Obrenovich, C.S.
Atwood, G. Perry, R.L. Bowen and M.A. Smith
[Abstract]
Antioxidants as a Potential Therapy Against Age-Related
Neurodegenerative Diseases: Amyloid Beta Toxicity and Alzheimer’s
Disease Pp. 699-704
P. Hajieva and C. Behl
[Abstract]
Neuroprotective Therapies for Alzheimer’s Disease
Pp. 705-717
A. Huber, G. Stuchbury, A. Bürkle, J. Burnell and
G. Münch
[Abstract]
Brain Inflammation, Cholesterol, and Glutamate as
Interconnected Participants in the Pathology of Alzheimer’s
Disease Pp. 719-738
G.E. Ringheim and A.M. Szczepanik
[Abstract]
General Articles
Mitochondria: A Target for Neuroprotective Interventions
in Cerebral Ischemia-Reperfusion Pp. 739-757
M. Christophe and S. Nicolas
[Abstract]
Fatty Acid Amide Hydrolase: A Potential Target for Next Generation
Therapeutics Pp. 759-772
M. Maccarrone
[Abstract]
Abstracts
[Back
to top]
Editorial
Alzheimer's disease (AD) is the most common cause of dementia,
affecting more than 30% of the population over 85 years of
age. In 2002, the estimated cost of dementia in Western countries
was about 1% of GDP, by 2050, this is expected to increase
to about 3%. The development of neuroprotective pharmacological
strategies is an important task for the research community.
AD is characterized by two characteristic lesions, amyloid
plaques and neurofibrillary tangles, which are present in
high numbers in the grey matter of affected brain areas. Neurofibrillary
tangles are intracellular deposits formed by hyperphosphorylated
and extensively crosslinked tau protein. Tau is a microtubule-associated
protein that regulates a variety of properties of neuronal
microtubules, especially their stability and orientation.
In AD, however, tau is hyperphosphorylated and forms fibrillar
inclusions. Presumably this leads to neuronal dysfunction
by disturbing cytoskeletal functions of neurons, resulting
in abnormal axons and therefore impaired axonal transport.
Senile plaques are the second characteristic hallmark in AD
sufferers. These extracellular protein deposits are mainly
composed of beta-amyloid peptide (Aβ)
which forms β-sheeted
fibrils that become insoluble. Aβ
is derived from the β-amyloid
precursor protein (APP), an integral membrane protein that
is processed by β-
and γ-secretases.
In a variety of cell culture models, Aβ
has been shown to cause toxicity to neurons by various mechanisms,
many of which involve oxidative stress. Inflammation, as evidenced
by the activation of microglia and astroglia, is another hallmark
of AD. Inflammation, including the induction of superoxide
production (“oxidative burst”), is an important
source of oxidative stress in AD patients. The inflammatory
process occurs mainly around the amyloid plaques and is characterized
by pro-inflammatory substances released from activated microglia.
Reactive oxygen species (ROS) are the most prominent molecules
in the inflammatory process, along with prostaglandins, IL-1β,
IL-6, M-CSF and TNF-α.
In light of the many pathological hallmarks of the disease,
selecting a therapeutic target and designing appropriate pharmacological
strategies appears to be a very complex and nearly impossible
task. This issue of Current Pharmaceutical Design combines
contributions from some of the world leaders in the filed
of AD therapy and presents a kaleidoscope of theories and
approaches, as well as original data mixed with expert reviews.
In the first article, Taisuke Tomita and Takeshi Iwatsubo
[1] intensively review α-secretase,
the pivotal enzyme in generating the C terminus of Aβ.
Their manuscript informs the reader on recent progress in
γ-secretase
biology, which has shed substantial light on the proteolytic
mechanism, regulation and composition of this unusual enzyme,
as well as the recent development of inhibitors of γ-secretase
activity.
In the second manuscript “Reduction of Aβ
levels in the Sprague Dawley rat after oral administration
of the functional γ-secretase
inhibitor, DAPT: a novel non-transgenic model for Aβ
production inhibitors” Mohammed El Mouedden, Marc Vandermeeren,
Theo Meert and Marc Mercken [2] introduce a very elegant and
fast non-transgenic animal model for the testing of amyloid
lowering drugs. Plaque-developing APP transgenic mice are
currently widely used as an in vivo model of choice, as these
animals produce readily measurable amounts of human Aβ.
Transgenic animals however, also require extensive, time-consuming
breeding programs and can show high inter-animal differences
in the expression level of the transgene. The authors show
that DAPT, given orally to normal Sprague Dawley rats, significantly
lowered Aβ40
and Aβ42
peptide levels in brain extract, CSF, and the plasma dose-
and time-dependently, establishing the usefulness of the wild-type
rat model for testing small-molecule inhibitors of Aβ
production.
In a further “amyloid” manuscript, “Targeting
the alpha 7 nicotinic acetylcholine receptor to reduce amyloid
accumulation in Alzheimer’s disease pyramidal neurons”,
Michael R. D’Andrea and Robert G. Nagele [3] propose
that many (if not most) amyloid plaques in the entorhinal
cortex of AD brains are actually the lysis remnants of degenerated,
Aβ42-overburdened
neurons. They point out that the most vulnerable neurons are
those that abundantly express the alpha7 nicotinic acetylcholine
receptor (α7nAChR),
and internalization of Aβ42
appears to be facilitated by the high-affinity binding of
Aβ42
to the α7nAChR
on neuronal cell surfaces, followed by endocytosis of the
resulting complex and its accumulation within the lysosomal
compartment. In view of the pathophysiological consequences
of Aβ42
binding to αnAChR
on neuronal surfaces that stem from excessive intraneuronal
Aβ42
accumulation, they suggest that the α7nAChR
could be an important therapeutic target for treatment of
AD.
A significant amount of research has been focused on the
relationship between hormones and Alzheimer’s disease.
However, the majority of this work has been on estrogen and
more recently, testosterone. Christopher W. Gregory, Craig
S. Atwood, Mark A. Smith and Richard L. Bowen [4] show in
their manuscript "Antigonadotropins: A Novel Strategy
to Halt Alzheimer's Disease Neurodegeneration" how a
serendipitous patient encounter led them to question whether
other hormones of the hypothalamic-pituitary-gonadal axis
could be playing a role in the pathogenesis of Alzheimer’s
disease. The age-related decline in reproductive function
results in a dramatic decrease in serum estrogen and testosterone
concentrations and an equally dramatic compensatory increase
in serum luteinizing hormone concentrations. In an elegant
review they put forward the “gonadotropin hypothesis”
of Alzheimer’s disease, and discuss potential therapeutic
anti-gonadotropin compounds.
Along this line of research, Kate M. Webber, Gemma Casadesus,
Xiongwei Zhu, Mark E. Obrenovich, Craig S. Atwood, George
Perry, Richard L. Bowen and Mark A. Smith [5] enforce the
view that the combination of amyloid deposition, tau phosphorylation,
oxidative stress, metal ion dysregulation and inflammation
all contribute to disease pathogenesis, though none of these
mechanisms result in all the downstream changes that occur
during the course of AD. For this reason, they searched for
a causative factor that predates known features found in AD,
and that might be a fundamental initiator of the pathophysiological
cascade. In this regard, they propose that the dysregulation
of the cell cycle that occurs in neurons susceptible to degeneration
in the hippocampus during AD is a potential causative factor
that would initiate all known pathological events. As a result
of the gender bias present in AD, they suspect that postmenopausal
and andropausal hormones may be involved and, with this in
mind, their review specifically focus on the gonadotropins.
Antioxidants have also emerged as a potential therapy against
age-related neurodegenerative diseases: In their manuscript,
P. Hajieva and C. Behl [6] emphasise that although the exact
neurochemical effector mechanism of Aβ
aggregation is not yet elucidated, age-associated disturbances
of metal ion metabolism have been proposed to promote the
formation of aggregates from soluble Aβ.
Oxidative stress is postulated to be a downstream effect of
Aβ-metal
ion interactions. Therefore, the modulation of brain metal
metabolism and attenuation of oxidative stress by antioxidant
molecules are proposed as a potential therapeutic intervention
in AD. In their review, they summarize the recent literature
focused on APP/Aβ-metal
ion interactions and the use of antioxidant metal chelators
as potential therapy against AD.
In support of Behl’s hypothesis, Anke Huber, Grant
Stuchbury, Alexander Bürkle, Jim Burnell and Gerald Münch
[7] have reviewed the possible contribution of reactive oxygen
species (ROS) to AD pathogenesis. Increased levels of ROS
(also termed “oxidative stress”), produced by
normal mitochondrial activity, inflammation and excess glutamate
levels, are proposed to accelerate neurodegenerative processes
characteristic of Alzheimer’s disease. Their review
presents evidence of the importance of oxidative stress in
the pathogenesis of these diseases and explains the nature
of different types of ROS mediating neuronal damage. Furthermore,
the potential beneficial effects of neuroprotective treatments,
including antioxidants and anti - glutamatergic drugs are
discussed.
In a brilliant finish, G. E. Ringheim and A. M. Szczepanik
[8] present “Brain inflammation, Cholesterol, and Glutamate
as Interconnected Participants in the Pathology of Alzheimer’s
Disease. Reports that individuals taking anti-inflammatory
medications reduce their risk of developing AD has led to
the “inflammation hypothesis” of AD and the subsequent
testing of these drugs in the clinic. Recently, the approval
of the NMDA receptor antagonist memantine (Namenda®)
has provided clinical support for glutamatergic processes
in the disease and generated a renewed interest in the role
of excitatory amino acids in the etiology of AD. In this review,
they haven take a closer look at these three compelling areas
for addressing AD therapeutics: inflammation, cholesterol,
and glutamate. They present arguments that these components
are interconnected and mutually regulate processes involved
in AD progression. Special focus is given to inflammation
as a central feature of AD that may be acting in synergy with
cholesterol and glutamate to mediate the observed pathophysiology.
In summary, this small selection of papers proposing somewhat
different hypotheses of AD, illustrates how difficult, maybe
impossible, it is to propose a singular “hypothesis
of AD” and one type of drug that cures all the symptoms
at once. In contrast, it is very likely, that patients presenting
themselves with this multifactorial disease need to take a
cocktail of drugs which each counteract one particular pathogenic
age-related process in AD.
References
[1] Tomita T, Iwatsubo T. γ-Secretase
as a Therapeutic Target for Treatment of Alzheimer's Disease.
Curr Pharm Design 2006; 12(6): 661-670.
[2] El Mouedden M, Vandermeeren M, Meert T, Mercken M. Reduction
of Aβ
Levels in the Sprague Dawley Rat After Oral Adminis-tration
of the Functional γ-Secretase
Inhibitor, DAPT: A Novel Non-Transgenic Model for Aβ
Production Inhibitors. Curr Pharm Design 2006; 12(6): 671-676.
[3] D’Andrea MR, Nagele RG. Targeting the Alpha 7 Nicotinic
Acetylcholine Receptor to Reduce Amyloid Accumulation in Alzheimer’s
Disease Pyramidal Neurons. Curr Pharm Design 2006; 12(6):
677-684.
[4] Gregory CW, Atwood CS, Smith MA, Bowen RL. "Antigonadotropins:
A Novel Strategy to Halt Alzheimer's Disease Neurodegeneration".
Curr Pharm Design 2006; 12(6): 685-690.
[5] Webber KM, Casadesus G, Zhu X, Obrenovich ME, Atwood
CS, Perry G, Bowen RL, Smith MA. The Cell Cycle and Hormonal
Fluxes in Alzheimer Disease: A Novel Therapeutic Target. Curr
Pharm Design 2006; 12(6): 691-697.
[6] Hajieva P, Behl C. Antioxidants as a Potential Therapy
Against Age-Related Neurodegenerative Diseases: Amyloid Beta
Toxicity and Alzheimer’s Disease. Curr Pharm Design
2006; 12(6): 699-704.
[7] Huber A, Stuchbury G, Bürkle A, Burnell J, Münch
G. Neuroprotective Therapies for Alzheimer’s Disease.
Curr Pharm Design 2006; 12(6): 705-717.
[8] Ringheim GE, Szczepanik AM. Brain Inflammation, Cholesterol,
and Glutamate as Interconnected Participants in the Pathology
of Alzheimer’s Disease. Curr Pharm Design 2006; 12(6):
719-738.
Gerald Münch and Grant Stuchbury
Department of Biochemistry and Molecular Biology
James Cook University
Molecular Sciences Bld 21
Townsville 4811
Australia
gerald.muench@jcu.edu.au
OR grant.stuchbury@jcu.edu.au
[Back to top]
γ-Secretase
as a Therapeutic Target for Treatment of Alzheimer's Disease
T. Tomita and T. Iwatsubo
Alzheimer’s disease (AD) is the most common cause
of dementia with aging, that is pathologically characterized
by senile plaques that contain amyloid-β
peptides (Aβ
) and neurofibrillary tangles comprised of phosphorylated
tau. Genetic and biological studies provide evidence that
the production and deposition of Aβ
contribute to the etiology of AD. γ
-Secretase is the pivotal enzyme in generating the
C terminus of Aβ,
that determines its aggregability and pro-pensity for deposition.
Drugs that regulate the production of Aβ
by inhibiting γ-secretase
activity could provide an effec-tive therapeutics for AD,
although recent studies suggest that γ-secretase
plays important roles in novel signaling path-ways that play
essential roles in embryonic development. This review focuses
on recent progresses in the γ-secretase
bi-ology that shed substantial light on the proteolytic mechanism,
regulation and composition of this unusual enzyme. Moreover,
we review the recent development of inhibitors and provide
a direction for the effective treatment of AD through inhibition
of γ-secretase
activity.
[Back to top]
Reduction of Aβ Levels in the Sprague Dawley
Rat After Oral Administration of the Functional γ-Secretase
Inhibitor, DAPT: A Novel Non-Transgenic Model for Aβ
Production Inhibitors
M. El Mouedden, M. Vandermeeren, T. Meert and M. Mercken
Considerable effort has been made to develop drugs that
delay or prevent neurodegeneration. These include inhibitors
of Aβ -generating
proteases for the treatment of Alzheimer’s disease.
Testing the amyloid hypothesis in vivo requires molecules
that are capable of entering the CNS and that produce a substantial
reduction in brain Aβ
levels. Plaque-developing APP transgenic mice are
currently widely used as an in vivo model of choice
as these animals produce readily measurable amounts of human
Aβ .
They are very useful in the testing of a variety of amyloid-lowering
approaches but their use for compound screening is often limited
by their cost. Transgenic animals also require extensive,
time-consuming breeding programs and can show high inter-animal
differences in the expression level of the transgene. Hence,
we considered it important to develop and characterize a new
and simple non-transgenic animal model for testing Aβ
modulation. For this purpose, Wild-type adult Sprague
Dawley rats were treated with DAPT, a functional γ
-secretase inhibitor, and the Aβ40
and Aβ42
levels in brain-tissue and body fluids were assessed. We showed
that DAPT, given orally, significantly lowered Aβ40
and Aβ42
peptide levels in brain extract, CSF, and the plasma dose-
and time-dependently. We can conclude that our data establish
the usefulness of the wild-type rat model for testing small-molecule
inhibitors of Aβ
production.
[Back to top]
Targeting the Alpha 7 Nicotinic Acetylcholine
Receptor to Reduce Amyloid Accumulation in Alzheimer’s
Disease Pyramidal Neurons
M.R. D’Andrea and R.G. Nagele
Although there is still no known effective preventative
treatment or cure for Alzheimer’s disease (AD), the
development of new drugs that target pathological features
that appear early in the course of this disease and alleviate
some of the early cognitive and memory symptoms is a laudable
goal that may be one step closer. To date, the acetylcholinesterase
inhibitors have been the most widely used AD drugs and have
been somewhat successful in slowing loss of cognition. In
the last few years, a number of studies have demonstrated
that amyloid beta (1-42) (Aβ42),
the predominant Aβ
peptide species in amyloid plaques, first accumulates in vulnerable
neurons prior to plaque formation. Recently, we have shown
that many (if not most) amyloid plaques in the entorhinal
cortex of AD brains are actually the lysis remnants of degenerated,
Aβ42-overburdened
neurons. Furthermore, the most vulnerable neurons appear to
be those that abundantly express the alpha7 nicotinic acetylcholine
receptor (α7nAChR),
and internalization of Aβ42
appears to be facilitated by the high-affinity binding of
Aβ42
to the α7nAChR
on neuronal cell surfaces, followed by endocytosis of the
resulting complex and its accumulation within the lysosomal
compartment. This mechanism provides a reasonable explanation
for the selective vulnerability of cholinergic and cholinoceptive
neurons in AD brains and for the fact that Aβ42
is the dominant Aβ
peptide species in both intraneuronal accumulations and amyloid
plaques. In view of the pathophysiological consequences of
Aβ42
binding to α7nAChR
on neuronal surfaces that stem from excessive intraneu-ronal
Aβ42
accumulation, the α7nAChR
could be an important therapeutic target for treatment of
AD. In addition, it further emphasizes the potential merits
of new and effective therapeutic strategies pointed towards
the goal of lowering of Aβ42
levels in the blood and cerebrospinal fluid as well as blocking
Aβ42
in the blood from penetrating the blood-brain barrier and
entering into the brain parenchyma.
[Back to top]
Antigonadotropins: A Novel Strategy to Halt Alzheimer's
Disease Progression
C.W. Gregory, C.S. Atwood, M.A. Smith and R.L. Bowen
A significant amount of research has been focused on the
relationship between hormones and Alzheimer’s disease.
However, the majority of this work has been on estrogen and
more recently testosterone. A serendipitous patient encounter
led one of us (RLB) to question whether other hormones of
the hypothalamic-pituitary-gonadal axis could be playing a
role in the pathogenesis of Alzheimer’s disease. The
age-related decline in reproductive function results in a
dramatic decrease in serum estrogen and testosterone concentrations
and an equally dramatic compensatory increase in serum luteinizing
hormone concentrations. Indeed, there is growing evidence
that the gonadotropin, luteinizing hormone, which regulates
serum estrogen and testosterone concentrations, could be an
important causative factor in the development of Alzheimer's
disease. This review provides information supporting the “gonadotropin
hypothesis, ” puts forth a novel mechanism of how changes
in serum luteinizing hormone concentrations could contribute
to the pathogene-sis of Alzheimer’s disease, and discusses
potential therapeutic anti-gonadotropin compounds.
[Back to top]
The Cell Cycle and Hormonal Fluxes in Alzheimer Disease:
A Novel Therapeutic Target
K.M. Webber, G. Casadesus, X. Zhu, M.E. Obrenovich, C.S.
Atwood, G. Perry, R.L. Bowen and M.A. Smith
Several hypotheses have been proposed attempting to explain
the pathogenesis of Alzheimer disease (AD) including theories
involving amyloid deposition, tau phosphorylation, oxidative
stress, metal ion dysregulation and inflammation. Strong evidence
suggests that each one contributes to disease pathogenesis,
though none of these mechanisms result in all the downstream
changes that occur during the course of AD. For this reason,
we and others have begun the search for a causative factor
that predates known features found in AD, and that might be
a fundamental initiator of the pathophysiological cascade.
In this regard, we propose that the dysregulation of the cell
cycle that occurs in neurons susceptible to degeneration in
the hippocampus during AD is a potential causative factor
that would initiate all known pathological events. Neuronal
changes supporting alterations in cell cycle control in the
etiology of AD include the ectopic expression of markers of
the cell cycle, organelle kinesis and cytoskeletal alterations
including tau phosphorylation. Given the early and presumably
devastating consequences of cell cycle re-entry, we have made
a concerted effort to elucidate the initiating factor that
drives aberrant mitotic re-entry in AD. As a result of the
gender bias present in AD, we suspect that postmenopausal
and andropausal hormones may be involved and, with this in
mind, in this review we specifically focus on the gonadotropins.
Therapeutic interventions targeted at gonadotropins, if they
are indeed the driving mitogenic force, could both prevent
disease in those patients currently asymptomatic or halt,
and even reverse, disease in those currently afflicted.
[Back to top]
Antioxidants as a Potential Therapy Against Age-Related
Neurodegenerative Diseases: Amyloid Beta Toxicity and Alzheimer’s
Disease
P. Hajieva and C. Behl
Alzheimer’s disease (AD) is a progressive age-related
neurodegenerative disorder with distinct neuropathological
features. Extracellular plaques, consisting of aggregated
amyloid peptides of 39-43 amino acids are one of the most
prominent pathological hallmarks of this disease. Although
the exact neurochemical effector mechanism of Aβ
aggregation is not yet elucidated, age-associated disturbances
of metal ion metabolism have been proposed to promote the
formation of aggregates from soluble Aβ.
Oxidative stress is postulated to be a downstream effect of
Aβ-metal
ion inter-actions. Therefore, the modulation of brain metal
metabolism and attenuation of oxidative stress by antioxidant
mole-cules are proposed as a potential therapeutic intervention
in AD.
Here, we summarize the recent literature focused on APP/A?-metal
ion interactions and the use of antioxidant metal chelators
as potential therapy against AD.
[Back to top]
Neuroprotective Therapies for Alzheimer’s Disease
A. Huber, G. Stuchbury, A. Bürkle, J. Burnell and
G. Münch
One of the major age-related damaging agents are reactive
oxygen species (ROS). The brain is more vulnerable to oxidative
stress than other organs as concomitant low activity and capacity
of antioxidative protection systems allow for increased exposure
of target molecules to ROS. Since neurons are postmitotic
cells, they have to live with cellular damage accumulated
over many decades. Increased levels of ROS (also termed “oxidative
stress”), produced by normal mitochondrial activity,
inflammation and excess glutamate levels, are proposed to
accelerate neurodegenerative processes characteristic of Alzheimer’s
disease. This review presents evidence of the importance of
oxidative stress in the pathogenesis of these diseases and
explains the nature of different types of ROS mediating neuronal
damage. Furthermore, the potential beneficial effects of neuroprotective
treatments, including antioxidants and anti - glutamatergic
drugs are discussed.
[Back to top]
Brain Inflammation, Cholesterol, and Glutamate as
Interconnected Participants in the Pathology of Alzheimer’s
Disease
G.E. Ringheim and A.M. Szczepanik
Alzheimer’s disease (AD) represents one of the most
common ailments afflicting the rapidly growing elderly segment
of today’s population. Despite the vast amount of effort
expended in developing a cure, currently approved drugs address
only cognitive symptoms that, although important for improving
a patient’s daily living standard, do not provide a
significant delay or halt to disease progression. Early reports
that individuals taking anti-inflammatory medications reduce
their risk of developing AD has led to the “inflammation
hypothesis” of AD and the subsequent testing of these
drugs in the clinic. Tests of a select few of these medications
in AD clinical trials have, however, yielded disappointing
results. Reports of statin-based medications reducing the
risk of AD have also led to the testing of this class of drugs
in the clinic. Recently, the approval of the NMDA receptor
antagonist memantine (Namenda®)
has provided clinical support for glutamatergic processes
in the disease and generated a renewed interest in the role
of excitatory amino acids in the etiology of AD. In this review,
we take a closer look at these three compelling areas for
addressing AD therapeutics: inflammation, cholesterol, and
glutamate. We present arguments that these components are
interconnected and mutually regulate processes involved in
AD progression. Special focus is given to inflammation as
a central feature of AD that may be acting in synergy with
cholesterol and glutamate to mediate the observed pathophysiology.
[Back to top]
Mitochondria: A Target for Neuroprotective Interventions
in Cerebral Ischemia-Reperfusion
M. Christophe and S. Nicolas
Evidence obtained over the past two decades shows that reactive
oxygen species (ROS) are involved in brain lesions, including
those due to cerebral ischemia-reperfusion. The mitochondria
are the primary intracellular source of ROS, as they generate
huge numbers of oxidative-reduction reactions and use massive
amounts of oxygen. When anoxia is followed promptly by reperfusion,
the resulting increase in oxygen supply leads to overproduction
of ROS. In ischemic tissues, numerous studies have established
a direct role for ROS in oxidative damage to lipids, proteins,
and nucleic acids. Thus, mitochondria are both the initiator
and the first target of oxidative stress. Mitochondrial damage
can lead to cell death, given the role for mitochondria in
energy metabolism and calcium homeostasis, as well as the
ability of mitochondria to release pro-apoptotic factors such
as cytochrome C and apoptosis-inducing factor (AIF).
This review discusses possible mitochondrion-targeted strategies
for preventing ROS-induced injury during reperfusion. The
sequence of events that follow oxidative damage provides the
outline for the review: thus, we will discuss protection of
oxidative phosphorylation, mitochondrial membrane integrity
and fluidity, and antioxidant or mild-uncoupling strategies
for diminishing ROS production. Among mechanisms of action,
we will describe the modulation of mitochon-drial permeability
transition pore (MPTP) opening, which may not only operate
as a physiological Ca2+ release mechanism, but
also contribute to mitochondrial deenergization, release of
pro-apoptotic proteins, and protection by ischemic preconditioning
(IPC). Finally, we will review genetic strategies for controlling
apoptotic protein expression, stimulating mitochondrial oxidative
defences, and increasing mitochondrial proliferation.
[Back to top]
Fatty Acid Amide Hydrolase: A Potential Target for Next
Generation Therapeutics
M. Maccarrone
Endocannabinoids are amides, esters and ethers of long chain
polyunsaturated fatty acids, which act as new lipid mediators.
Anandamide (N-arachidonoylethanolamine; AEA) and
2-arachidonoylglycerol are the main endogenous agonists of
cannabinoid receptors, able to mimic several pharmacological
effects of Δ9-tetrahydrocannabinol, the active
principle of Cannabis sativa preparations like hashish
and marijuana. The activity of AEA at its receptors is limited
by cellular uptake through a specific membrane transporter,
followed by intracellular degradation by a fatty acid amide
hy-drolase (FAAH). Growing evidence demonstrates that FAAH
is the critical regulator of the endogenous levels of AEA,
suggesting that it may serve as an attractive therapeutic
target for the treatment of human disorders. In particular,
FAAH inhibitors may be next generation therapeutic drugs of
potential value for the treatment of pathologies in the central
nervous system and in the periphery. Here, the potential applications
of these inhibitors for human disease will be re-viewed, with
an emphasis on the properties of hydro(pero)xy-anandamides.
In fact, these oxygenated derivatives of AEA are the most
powerful inhibitors of FAAH of natural origin as yet discovered.
In addition, new insights into the promoter region of FAAH
gene will be presented, and the therapeutic potential of mimetics
of transcription factors of this gene in the management of
human infertility will be discussed.
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