Current Medicinal Chemistry - Central Nervous System Agents - Volume 2, Issue 1, 2002

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).

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.

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.

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

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).