Current Medicinal Chemistry – Central Nervous System Agents, Volume 2, No. 1, 2002
Neuropharmacology Activity of Alkaloids from
South American Medicinal Plants.Pp.1-15
A.
Capasso, R. Aquino, N. De Tommasi, S. Piacente, L. Rastrelli and C. Pizza
The Metabotropic Glutamate Receptor System:
G-Protein Mediated Pathways that Modulate Neuronal and Vascular Cellular Injury Pp.17-28
Shi-Hua
Lin, Zhao Zhong Chong and Kenneth Maiese
Glutamate and Schizophrenia: Pathophysiology
and Therapeutics Pp.29-44
G.J.
Marek
Beneficial Neurobiological Effects of
Melatonin Under Conditions of Increased Oxidative Stress Pp.45-58
Russel
J. Reiter, Susanne Burkhardt, Javier Cabrera and Joaquin J. Garcia
New Perspectives on the Structure and
Function of the Na+ Channel
Multigene Family Pp.59-81
Nobukuni
Ogata and Shigeru Yoshida
[Back to top] Neuropharmacology Activity of Alkaloids from
South American Medicinal Plants
A.Capasso, R. Aquino, N. De Tommasi, S. Piacente, L.
Rastrelli and C. Pizza
Higher plants, which
have served humankind as sources of biologically active molecules since its
earliest beginnings, continue to play a key role in the world health. Compounds
from higher plants are of great potential value as medicinal agents, as
"leads" or model compounds for synthetic or semisynthetic structure
modifications and optimization, as biochemical and/or pharmacological probes.
As a consequence
of the renewed interest in the search of new substances from natural sources as
potential candidates in the drug development, since 1980 our research group has
been involved in investigation of higher plants employed in Italian, Chinese,
African and South-American traditional medicine. Our primary objectives are
-
to isolate as
many secondary metabolites as possible for the phytochemical knowledge of the
plants studied
-
to identify
active principles in plants with claimed biological activity
-
to evaluate
pharmacological effects of plant extracts, fractions and pure compounds in
relationship to the parent plant material
-
to subject the
isolated compounds to biological screenings on the basis of their structural
relationship with known drugs.
One of our
approach to the study of medicinal plants is the preliminary pharmacological
screening of the plant extracts, followed by a bioassay-guided fractionation of
the extracts leading to the isolation of the pure active constituents. Such a
strategy has been used in the isolation of a number of antispasmodic alkaloids
from the extracts of South-American medicinal plants, which showed a pronounced
inhibitory activity on the electrical induced contractions of isolated
guinea-pig ileum (E.C.I.) and on morphine withdrawal.
The alkaloids
represent the group of natural products that has had the major impact
throughout history on the economic, medical, political, and social affairs of
humans. Many of these agents have potent physiological effects on mammalian
systems as well as other organisms, and as a consequence, some constitute
important therapeutic agents. In the plant kingdom, the alkaloids appear to
have a restricted distribution in certain families and genera; particularly
Apocynaceae, Papaveraceae, Ranunculaceae, Rubiaceae, Solanaceae, and
Berberidaceae are out-standing for alkaloid-yielding plants.
Alkaloids are usually
classified according to the nature of the aminoacids or their derivatives from
which they are biosynthetized.
Our interest has
been centered on alkaloids derived from the aromatic aminoacids and in
particular on isoquinoline alkaloids (biologically derived from phenylalanine)
from Argemone mexicana (Papaveraceae), Aristolochia constricta
(Aristolochiaceae) and on alkaloids with an indole nucleus (biologically
derived from tryptophane) from Sickingia williamsii and Sickingia tinctoria
(Rubiaceae).
[Back to top] The Metabotropic Glutamate Receptor System:
G-Protein Mediated Pathways that Modulate Neuronal and Vascular Cellular Injury
Shi-Hua Lin, Zhao Zhong Chong and Kenneth Maiese
During both cell
differentiation and development, the metabotropic glutamate receptor (mGluR)
system plays an important role in securing successful maturation of an
organism. Yet, the mGluR system may hold a more crucial role that involves the
prevention and reversal of cellular injury during acute and chronic
neurodegenerative disorders. As G-protein related receptors, the mGluR system
employs a host of signal transduction systems to regulate cell survival and
injury. In most circumstances, it is activation of specific mGluR subtypes that
prevent the induction of programmed cell death (PCD) along two distinct
pathways that involve the degradation of genomic DNA and the exposure of
membrane phosphatidylserine (PS) residues. To reach this end of cytoprotection,
the mGluR system modulates a selective range of cellular pathways that include
protein kinases, intracellular calcium, endonucleases, and cysteine proteases,
but excludes more “up-stream” cellular mechanisms such as mitogen-activated
protein kinases. Cytoprotection through the mGluR system is directly clinically
relevant, since immediate and delayed injury paradigms demonstrate the ability
of this system to reverse PCD in both neuronal and vascular cell populations.
Future investigations with the mGluR system will offer both a novel and robust
foundation for the development of efficacious therapeutic regimens against
cellular injury.
[Back to top] Glutamate and Schizophrenia: Pathophysiology
and Therapeutics
G.J. Marek
Since the 1950’s,
the major thrust of antipsychotic drugs development has been centered around
the monoamine dopamine since all antipsychotic drugs potently block dopamine
receptors. However, in the last fifteen years increasing attention has been
focused on serotonin (5-HT), and 5-HT2A receptors in particular as the atypical
antipsychotic drugs (e.g., clozapine, olanzepine, risperidone) potently block
this receptor. These atypical antipsychotic drugs, in addition to having a
decreased incidence of motor side effects, also improve particular symptoms
(negative symptoms and cognitive dysfunction) upon which typical antipsychotic
drugs exert little effect. However, even these atypical antipsychotic drugs
have limited efficacy for many patients. Current neuroimaging studies have
implicated cortical-striatal-thalamic circuits and interactions of these
circuits with areas such as the hippocampus, pontine nuclei and the cerebellum.
Within the thalamocortical pathways, clear abnormalities appear to be present
within the glutamate system. In addition, the psychotomimetic effects of drugs
which induce psychosis may be dependent upon interactions between the
monoamines and glutamate. Therefore, current strategies are directed toward the
discovery of novel antipsychotic drugs that act directly on the glutamate
system. The largest unresolved answer facing the field is whether the critical
problem in schizophrenia is a “hypoglutamatergic” or a “hyperglutamatergic”
state. One of the dangers facing the strategy of enhancing glutamatergic
transmission is that overactivation of ionotropic NMDA and AMPA receptors can
lead to neurotoxicity. Thus directions being pursued involve more subtly
modulating regulatory sites on these ionotropic receptors or directing agents
to the modulatory G-protein coupled metabotropic glutamate (mGlu) receptors.
[Back to top] Beneficial Neurobiological Effects of
Melatonin Under Conditions of Increased Oxidative Stress
Russel J. Reiter, Susanne Burkhardt, Javier Cabrera and
Joaquin J. Garcia
Aerobic organisms
consistently sustain molecular abuse because of oxidative stress. Oxidative
stress is a consequence of oxygen (O2) being converted to semi-reduced toxic
species including the superoxide anion radical (O2-·), hydrogen
peroxide (H2O2) and the hydroxyl radical (·OH). Besides
these oxygen-based reactive species, the O2-· also rapidly combines with nitric oxide
(NO·) to produce the peroxynitrite anion (ONOO- ), an agent with
well defined neurotoxic actions. Furthermore, ONOO- is converted to
peroxynitrous acid (ONOOH) which can degrade into the ·OH or an agent with
similar toxicity.
How much of the O2
used by aerobes is actually converted to reactive species is unknown, but the
general consensus is on the order of 2-4% of the total O2
inhaled. Once formed the toxic species may or may not be neutralized by a
complex antioxidative defense system. Those that are not detoxified can
mutilate essential macromolecules within brain cells, thereby diminishing their
functional efficiency, or , in extreme cases, killing the cells via either
necrosis or apoptosis .
Despite its
importance for essential organismal functions as well as for survival, the
central nervous system is unexpectedly highly susceptible to oxidative insults.
One reason for this is that the brain, although constituting roughly 2% of the
body weight in humans, utilizes 20% of the total O2
inhaled. Thus, proportionally it generates a large number to toxic radicals.
Other reasons for the brain's high susceptibility to free radical damage
include the fact that it contains large quantities of polyunsatu rated fatty
acids (PUFA) which are easily damaged (oxidized) by reactive species and,
regionally at least, the nervous system contains high levels of iron and
ascorbic acid both of which, under the some circumstances, can be strongly
prooxidant. Thus, the brain, perhaps more than any other organ, is subjected to
excessive oxidative damage over the course of a life time. This persistent
bludgeoning of essential molecules in brain cells is believed to contribute to
a variety of neurodegenerative diseases. This review briefly describes the role
of free radicals in several models of neurodegeneration and summarizes the
actions of a newly discovered antioxidant, melatonin, in reducing the damage
done by toxic oxygen and nitrogen derivatives.
[Back to top] New Perspectives on the Structure and
Function of the Na+ Channel
Multigene Family
Nobukuni Ogata and Shigeru Yoshida
Recent studies on
the voltage-gated Na+ channel (VGSC) have revealed several
excellent discoveries regarding its structure and function. This article
summarizes recent findings on VGSCs, and presents our views on the subject.
Based on the
multi-pore 3D model of the VGSC, we propose a “twist-sprinkler” model: (i) twisting
and untwisting of the central cavity corresponds to the closed and open states
of the channel, and (ii) cytoplasmic outlet pores sprinkle Na+
ions laterally over the inner surface of the plasma membrane to effect a rapid
depolarization.
VGSCs can be
classified into two major categories. Category-I isoforms currently comprise
nine highly homologous clones (NaV1.1- NaV1.9), most of
which have been functionally expressed. In contrast, the category-II isoform
consists of one clone (NaX), which has not been successfully expressed
in an exogenous system. It is considerably different from the category-I
isoforms, especially in the S4 segment, and shows little voltage
dependence.
The main function
of the category-I isoforms is to form an action potential upstroke. However, NaV1.6
can also influence subthreshold electrical activity in neurons through the
“persistent” and “resurgent” Na+ currents, indicating that the VGSC itself
can modulate overall neuronal firing behavior. NaV1.8
and NaV1.9 are preferentially expressed in
peripheral nociceptive neurons and contain a structure common to tetrodotoxin
(TTX)-resistant Na+ channels. Both NaV1.8
and NaV1.9 play a pivotal role in pain sensation.
The category-II
isoform NaX (x = unknown function) is a
“concentration-sensitive” but not “voltage-sensitive” Na+
channel. It is involved in regulation of salt intake behavior by sensing an
increase in [Na+]o, and it should be renamed as NaC (c =
concentration).