Central
Nervous System Agents in Medicinal Chemistry
ISSN: 1871-5249
Current Medicinal Chemistry
- Central Nervous System Agents
Volume 5, Number 4, December 2005
Contents
Laminin and its Related Peptides for the Treatment
of Alzheimer's Disease Pp. 243-247
Akira Monji,Ken-ichiro Tashiro,Ichiro Yoshida,Sadayuki
Hashioka, Takahiro Kato and Shigenobu Kanba
[Abstract]
Neurotoxicity: The Broad Framework of Electron Transfer,
Oxidative Stress and Protection by Antioxidants Pp.
249-258
Peter Kovacic and Ratnasamy Somanathan
[Abstract]
Therapeutic Agents for Alzheimer's Disease Pp.
259-269
Won Hyuk Suh, Kenneth S. Suslick and Yoo-Hun Suh
[Abstract]
The Amyloid β-Protein Precursor and Alzheimer’s
Disease. Therapeutic Approaches Pp. 271-283
D. Del Toro, M. Coma, I. Uribesalgo, F.X. Guix and F.J.
Muñoz
[Abstract]
Targeting Protein Degradation in the Nervous System
Pp. 285-306
Jason J. Yi and Michael D. Ehlers
[Abstract]
Mechanisms of Neuroprotection by Polyphenols
Pp. 307-318
J.G. Frade, N.R. Ferreira, R.M. Barbosa and J. Laranjinha
[Abstract]
Abstracts
[Back to top]
Laminin and its Related Peptides for the Treatment
of Alzheimer's Disease
Akira Monji, Ken-ichiro Tashiro, Ichiro Yoshida, Sadayuki
Hashioka, Takahiro Kato and Shigenobu Kanba
Alzheimer's disease (AD) is one type of dementing central
nervous amyloidosis characterized by two different types of
fibrillar deposits, namely senile plaques and neurofibrillary
tangles. Amyloid-β-proteins (Aβ) are the major constituents
of senile plaques. The aggregation of soluble Aβ into
insoluble amyloid fibrils is believed to be an important step
in the pathogenesis of AD and the prevention of this process
therefore seems to be a promising strategy for the treatment
of AD. Laminin is an important extracellular matrix (ECM)
protein which has been reported to accumulate in the senile
plaques. It supports such biological activities as cell adhesion,
cell proliferation, neurite outgrowth. Recent reports have
revealed that laminin inhibits both Aβ fibril formation
and Aβ neurotoxicity in vitro. Laminin-related
peptides, which have almost the same biological activities
as laminin, have also recently been reported to inhibit Aβ
fibril formation and/or Aβ neurotoxicity. Finally, Laminin
can induce a complete disaggregation of Aβ amyloid fibrils
by disassembly into protofibrils and subsequently into an
amorphous aggregate. These results thus suggested that laminin
or its related peptides may be useful as an effective therapeutic
agent for the treatment of AD.
[Back to top]
Neurotoxicity: The Broad Framework of Electron
Transfer, Oxidative Stress and Protection by Antioxidants
Peter Kovacic and Ratnasamy Somanathan
A broad overview of neurotoxins is presented based on electron
transfer, reactive oxygen species, and oxidative stress. Although
mode of action is complex, these aspects evidently play an
important role in many cases. It is relevant that metabolites
from toxins generally possess electron transfer functionalities
which can participate in redox cycling. Much evidence exists
in support of the theoretical framework. Toxic effects at
the molecular level include lipid peroxidation, DNA attack,
adduction, enzyme inhibition, oxidative attack on the CNS,
and cell signaling. The toxins fall into many categories,
including drugs, industrial chemicals, abused drugs, reproductive
toxins, metal compounds, pesticides, and herbicides. Beneficial
effects of antioxidants are documented, which may prove clinically
useful. Knowledge of mechanisms operating in CNS insults should
prove useful in drug design.
[Back to top]
Therapeutic Agents for Alzheimer's Disease
Won Hyuk Suh,Kenneth S. Suslick and Yoo-Hun Suh
Currently, a handful of FDA approved drugs are commercially
available to treat Alzheimer's disease (AD). Among these,
Tacrine (Cognex), Donepezil (Aricept), Rivastigmine (Exelon),
Galantamine (Reminyl) and Memantine (Nemenda; Forest) are
either acetylcholinesterase or N-methyl-D-aspartate
antagonists. These are only palliative solu-tions, however,
and side effects remain an important concern. Clearly, the
search for more potent and effacious drugs for the treatment
of AD is one of the most pressing pharmacological goals, and
many more drugs are either in clinical trials or are being
tested in laboratories around the world, both in academia
and industry.
In this review, we will compare the aforementioned five drugs
with several other molecules that are currently in clinical
trials or are ready to go into clinical trials. These will
include antioxidants, metal chelators, monoamine oxidase inhibi-tors,
anti-inflammatory drugs, as well as other AChE and NMDA inhibitors.
In addition, medicinal chemistry ap-proaches toward designing
better pharmaceuticals will be discussed.
[Back to top]
The Amyloid β-Protein Precursor and Alzheimer’s
Disease. Therapeutic Approaches
D. Del Toro, M. Coma, I. Uribesalgo, F.X. Guix and F.J.
Muñoz
Alzheimer’s disease (AD) is triggered by the pathophysiological
cleavage of a single transmembrane glycoprotein denominated
amyloid β-protein precursor (AβPP) rendering amyloid
β-peptide (Aβ) that aggregates in β-sheets
forming the neuritic plaques. Since AβPP is playing a
key role in AD development, this review will be focused in
the structure, proteolytic processing, related secretases,
mutations, localization and physiological role of AβPP
protein. AβPP is present in several tissues and can be
spliced at different exons rendering up to ten AβPP isoforms.
The most abundant isoforms are AβPP770, AβPP751
and AβPP695, being the last one the predominant
isoform in neurons. Mutations in the AβPP sequence or
in the secretases that cleavage AβPP determinate an early
onset of AD. AβPP and the secretase activities involve
in the non amyloidogenic and the amyloidogenic pathways are
putative therapeutic targets in AD, but their relationships
with other physiological functions can produce controversial
results.
[Back to top]
Targeting Protein Degradation in the Nervous System
Jason J. Yi and Michael D. Ehlers
The life cycle of a protein consists of highly regulated
stages of synthesis, maturation, activity, and degradation.
The last stage of this cycle frequently occurs through the
ubiquitin-proteasome system, which tags and destroys proteins
in the cell. Work in recent years regarding the ubiquitin-proteasome
system has extended into the field of neurobiology, where
the system is critical for proper neuronal function. In this
review, we summarize existing knowledge regarding the ubiquitin-proteasome
pathway and recount recent studies that frame its importance
in neuronal development and synaptic plasticity. Furthermore,
we discuss the evidence for protein degradation in neuropathologies,
concentrating on neurodegenerative disorders characterized
by ubiquitin-rich protein aggregates. We conclude by surveying
ongoing drug discovery efforts directed at the ubiquitin-proteasome
pathway. Although the current focus of potential proteasomal
drugs is on cancer, the prevalence of this pathway in neuronal
function makes it a tantalizing target for future central
nervous system therapeutics.
[Back to top]
Mechanisms of Neuroprotection by Polyphenols
J.G. Frade, N.R. Ferreira, R.M. Barbosa and J. Laranjinha
Several lines of evidence suggest a role for oxidative cascades
of events leading to neurodegeneration associated with Parkinson’s,
Alzheimer, Huntington diseases, and amyotrophic lateral sclerosis.
In agreement with the notion of oxidative/nitrosative involvement
in these chronic diseases, in vivo models of disease
as well as biochemical and epi-demiological evidence suggest
a neuroprotective role for natural antioxidant polyphenols
in neurodegenerative diseases. However, the molecular mechanisms
for neuroprotection do not merely rely on a direct radical
scavenging/antioxidant activity. Rather, polyphenols may function
at several cellular levels, including direct interaction and
modulation of en-zymatic activities and the regulation of
signaling pathways with implications for cell survival and
death. Nitric oxide is a paradigmatic example. In view of
the wide collection of activities of nitric oxide in the brain,
ranging from synaptic plasticity to excitotoxicity, the regulation
of its rate and pattern of production and decay in tissues
by polyphenols is of obvious physiological relevance. Thus,
the elucidation of polyphenol activities at the molecular
level may lay the foun-dations for new pharmacological approaches
in relation to neurodegeneration. In this review, the molecular
mechanisms underlying the potential health promoting effects
of natural polyphenols in connection with neurodegenerative
diseases are discussed. Additionally, we provide evidence
for a modulatory effect of hydroxycinnamic phenol caffeic
acid on glu-tamate NMDA receptor/nitric oxide pathway in hippocampal
slices.
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