Central
Nervous System Agents in Medicinal Chemistry
ISSN: 1871-5249
Central Nervous System Agents
in Medicinal Chemistry
Volume 8, Number 1, March 2008
Contents
The Effect of Morphine on the Expression of COX-2
and iNOS Enzymes Pp. 1-9
Anna Capasso
[Abstract]
Antipsychotic Augmentation Strategies to Ameliorate
Negative and Cognitive Symptoms in Schizophrenia; Implications
for Future Research Pp. 10-25
Gerben Duisterwinkel, F.J. Bosker, A.N. Scholte-Stalenhoef,
M Vervoort and H. Knegtering
[Abstract]
Design and Evaluation of Semicarbazones and Thiosemicarbazones
as Novel Anticonvulsants Pp. 26-28
Navneet Aggarwal, Ruchi Aggarwal, Pradeep Mishra, J.S.
Jain, S.K. Bansal and K.K. Jha
[Abstract]
Neuropeptides B, S and W, Obestatin/Ghrelin-Associated
Peptide, and Others: Really New Feeding Regulatory Peptides?
Pp. 29-36
Bernard Beck, Carine Pourié and Jean-Louis Guéant
[Abstract]
Anesthesia and Postoperative Cognitive Dysfunction
(POCD) Pp. 37-47
Bettina Jungwirth, Walter Zieglgänsberger, Eberhard
Kochs and Gerhard Rammes
[Abstract]
Antioxidant Agents in Alzheimer’s Disease
Pp. 48-63
Patrizia Mecocci, E. Mariani, M.C. Polidori, K. Hensley
and D.A. Butterfield
[Abstract]
Recent Development in the Search for Effective Antidepressants
Using Traditional Chinese Medicine Pp. 64-71
Tracy H.H. Pang, F.C.F. Ip and Nancy Y. Ip
[Abstract]
Abstracts
[Back to top]
The Effect of Morphine on the Expression of COX-2 and iNOS
Enzymes
Anna Capasso
The effect of morphine on the expression on COX-2 and
iNOS was considered by evaluating:
a) the effects of COX1 and COX2 inhibitors on morphine
withdrawal in vitro. Tolmetin (selective
COX-1 inhibitor) and meloxicam (selective COX-2 inhibitor)
treatment before or after morphine were able of both preventing
and reversing the naloxone-induced contracture after exposure
to morphine in a concentration-dependent fashion.
b) the role of NF-κB
in the expression of morphine withdrawal by using the PDTC,
an inhibitor of NF-κB
activation. PDTC was able to reduce the naloxone-induced
contracture after exposure to the morphine in a concentration-dependent
fashion.
c) the role of NO in the expression of morphine withdrawal.
L-NAME was able dose dependently to reduce the nalox-one-induced
contraction after exposure to morphine whereas D-NAME at the
same concentrations did not affect it. The inhibitory effect
of L-NAME on morphine withdrawal was dose dependently reversed
by L-arginine not by D-arginine. Finally, GTN on its own significantly
increased the naloxone-induced contraction after exposure
to morphine and it was also able to reverse the inhibition
of morphine withdrawal caused by L-NAME.
d) the effect of morphine on COX-2 protein expression
in LPS-stimulated J774 macrophages. Treatment of
J774 macrophages with LPS caused an accumulation of PGs. The
addition of morphine to the cells 30 min before LPS challenge
increased significantly PGs production. The COX-2 immunofluorescence
study indicated that the control cells showed only background
staining, cell stimulated with LPS alone revealed a diffuse
accumulation of COX-2 immunostaining in the cytoplasm: this
accumulation of COX-2 immunostaining increase significantly
in cells stimulated with LPS+Morphine. This effect was reverted
by naloxone.
e) the effect of morphine on NO production by LPS-stimulated
J774 macrophages. Treatment of J774 macrophages with
LPS caused an significant increase of NO Morphine added to
the cells 0.5 h before activation with LPS, further in-creased
NO production. This effect was reverted by naloxone. Morphine
was not able to increase NO production when added after LPS
challenge.
The present paper provides a strong evidence that both PGs
and NO are involved in the development of morphine with-drawal
further indicating that during morphine withdrawal the opioid
induces the expression of the COX-2 and iNOS enzymes.
[Back to top]
Antipsychotic Augmentation Strategies to Ameliorate Negative
and Cognitive Symptoms in Schizophrenia; Implications for
Future Research
Gerben Duisterwinkel, F.J. Bosker, A.N. Scholte-Stalenhoef,
M. Vervoort and H. Knegtering
Negative and cognitive symptoms of schizophrenia remain
difficult to treat. Many add-on medications to alleviate these
symptoms have been proposed and investigated. In this inventory
the various treatment strategies published since 1990 are
being reviewed and categorised according to the pharmacological
mechanism putatively involved. Not-withstanding the problems
one experiences when comparing the applied measures for negative
and cognitive symptoms, three clear recommendations for future
research can be made viz. modulation of glutamatergic systems,
blockade of serotonin 5-HT2
receptors and modulation of histaminergic systems. Strategies
aimed at nAChR subtypes may also hold some promise.
[Back to top]
Design and Evaluation of Semicarbazones and Thiosemicarbazones
as Novel Anticonvulsants
Navneet Aggarwal, Ruchi Aggarwal, Pradeep Mishra, J.S.
Jain, S.K. Bansal and K.K. Jha
A series of semicarbazones and thiosemicarbazones were
designed and synthesized to meet the structural requirements
essential for anticonvulsant activity. All the compounds were
evaluated for anticonvulsant activity after intraperitoneal
(i.p.) administration to mice by maximal electroshock (MES)
and subcutaneous metrazol (ScMet) induced seizure methods
and minimal motor impairment was determined by rotorod test.
Semicarbazones and thiosemicarbazones of lipophillic carbonyl
groups (citral and carvone) showed excellent activity while
semicarbazone and thiosemicarbazone of levulinic acid were
found to be inactive. Results of the present study show that
lipophilic aryl ring could be replaced with non-cyclic lipophillic
groups but could not be replaced with hydrophilic substituents.
[Back to top]
Neuropeptides B, S and W, Obestatin/Ghrelin-Associated Peptide,
and Others: Really New Feeding Regulatory Peptides?
Bernard Beck, Carine Pourié and Jean-Louis Guéant
The last 20 years of the twentieth century witnessed
a dramatic increase in research aimed at determining the mechanisms
that regulate feeding behavior. Researchers, prompted by the
alarming increase in the prevalence of obesity have identified
many brain neuropeptides, especially in the hypothalamus that
promote or inhibit food intake. How the complex interactions
of these peptides leads to obesity has been clarified somewhat;
unfortunately, this has not led to major advances in anti-obesity
drug discovery. Continued effort during the first years of
the new millennium has led to the discovery of new peptides
mainly through inverse pharmacology techniques. In this article,
we update information on obestatin, a closely related companion
of ghrelin, on neuropeptide S, neuropeptide W, and others.
These peptides use both classical and independent regulatory
pathways to modulate feeding but often have additional biological
activities. Strong arguments support a role in feeding regulation
for some peptides. For others, this role remains controversial
and further research is needed to clarify their exact effects.
[Back to top]
Anesthesia and Postoperative Cognitive Dysfunction (POCD)
Bettina Jungwirth, Walter Zieglgänsberger, Eberhard
Kochs and Gerhard Rammes
Postoperative cognitive dysfunction (POCD) describes
a decline in cognitive function for weeks or months after
surgery with a prevalence in the elderly patient. Numerous
methodological limitations make the interpretation of this
clinical syndrome, based on the available literature on POCD,
difficult, particularly the different definitions of POCD,
the lack of control groups and the relative inconsistency
in the occurrence of memory deficits. Several theories have
been advanced to explain these observations, but although
there is general agreement that POCD is likely to be multifactorial,
whether its occurrence is a result of the effects of surgery
or general anesthesia remains unclear. This review provides
a synopsis of the available clinical and preclinical data
and summarizes recent research relevant to the occurrence
of POCD and possible pharmacologic algorithms for its prevention
and treatment. The effects of volatile and intravenous anesthetics
on synaptic transmission and synaptic plasticity, which might
be related to cognitive dysfunction in the postoperative period,
will be discussed. Unraveling these mechanisms should provide
helpful indices for the identification, synthesis and development
of new chemical entities suitable for therapeutic use.
[Back to top]
Antioxidant Agents in Alzheimer’s Disease
Patrizia Mecocci, E. Mariani, M.C. Polidori, K. Hensley
and D.A. Butterfield
Understanding the molecular mechanisms of neurodegeneration
represents a scientific priority as it will allow scientists
to more specifically target and simultaneously interrupt the
multiple pathologic mechanisms that contribute to the progression
of dementia in Alzheimer’s disease (AD). Oxidative stress
represents one of the key processes in AD pathogenesis, related
to formation of both amyloid plaques and neurofibrillary tangles
as well as to alteration of many biomolecules. For this reason
several antioxidant molecules have been tested in in vitro
and in vivo studies in order to detect more efficacious
treatments. Dietary antioxidants seem also to have an important
role in AD prevention, as shown by several epidemiological
studies. Ongoing clinical trials to assess whether antioxidant
supplementation has a role in primary prevention of AD or
in delaying the progression of disease in individuals with
Mild Cognitive Impairment (MCI), are in progress or planned.
Thus, research involving new antioxidants and their potential
clinical applications will provide new insights into the molecular
basis of neuroprotective mechanisms that may be relevant to
AD and other age-related neurodegenerative disorders.
[Back to top]
Recent Development in the Search for Effective Antidepressants
Using Traditional Chinese Medicine
Tracy H.H. Pang, F.C.F. Ip and Nancy Y. Ip
Depressive disorder is a common illness that affects
millions of people worldwide and the patients often suffer
from symptoms such as depressed mood, sleep disturbances,
and suicidal ideation. Since the approval of fluoxetine in
the United States nearly 20 years ago, the annual prescription
of antidepressants has increased rapidly. However, despite
the increasing number of new antidepressants introduced to
the clinic, the quality of treatment still remains poor due
to the delayed response or low efficacy often associated with
these synthetic antidepressants. Thus, there have been a growing
number of patients turning to alternative medicine treatments
for a more effective cure. To date, one of the most frequently
used and well-studied herbal preparation for mild and moderate
depression is the extract of St John’s wort. However,
recent report has indicated that drug interaction of this
herb with other antidepressants may result in severe clinical
consequences. Traditional Chinese medicine (TCM) has a long
history of use in China with a proven record of high efficacy
and low toxicity. It is also an excellent source of diverse
and complex chemicals that possess a wide variety of biological
activities. In recent years, TCM has received growing attention
as an alternative or adjuvant therapy to Western medicine
treatments and a large volume of efforts have been directed
towards the identification of potential antidepressive phytomedicine
from TCM. Potential TCM-derived therapeutics including herbal
formulations, extracts, and individual active constituents
have been evaluated with behavioral animal models and clinical
studies. This article will review the recent development in
the search for effective antidepressive therapeutics using
TCM. Literatures published in Chinese will also be reviewed
to include the recent advances in this area. Moreover, our
group has been using a knowledge-based approach to identify
active ingredients for the treatment of neurological disorders.
The workflow of our approach will also be discussed.
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