Resveratrol (RVT) is a naturally occurring trihydroxy stilbene that displays a wide spectrum of physiological activity. Its ability to behave therapeutically as a component of red wine has attracted ...wide attention. The phenol acts as a protective agent involving various body constituents. Most attention has been given to beneficial effects in insults involving cancer, aging, cardiovascular system, inflammation and the central nervous system. One of the principal modes of action appears to be as antioxidant. Other mechanistic pathways entail cell signaling, apoptosis and gene expression. There is an intriguing dichotomy in relation to pro-oxidant property. Also discussed are metabolism, receptor binding, rationale for safety and suggestions for future work. This is the first comprehensive review of RVT based on a broad, unifying mechanism.
This report presents in four main parts a novel approach based on electrochemistry, receptors and cell signaling. In Part A, there is limited correlation between dipole moments (DMs), associated ...electrostatic fields (EFs), and odor. For Part B, binding of the odorant to the receptor results in interaction of the ligand EF with those of the protein receptor, resulting in alteration. Part C addresses passage of the message by the altered EF to the olfactory neurons. Part D represents the final step in which the electrical signal is converted to perceived odor in the cerebral olfactory cortex.
Dizocilpine (MK-801), an extensively investigated drug possessing secondary amine and benzenoid functions, displays a wide array of biological properties, including anticonvulsant and anesthetic. ...There is scant discussion of biomechanism. A relevant, important finding is formation of oxidative metabolites in the hydroxylamine and phenolic categories. Analogy to cocaine metabolites suggests participation of redox entities, such as, hydroxylamine, nitroxide and nitrosonium, which can lead to electron transfer and radical formation. There is also similarity to metabolism by 3,3'-iminodipropionitrile and phencyclidine. Alternatively, the phenolic metabolites are well-known precursors of ET quinones. The review documents various physiological effects, mainly involving the central nervous system. Also of interest are the pro- and ant-oxidant properties. Considerable attention has been paid to MK-801 as an antagonist of the N-methyl-D-aspartate receptor in the glutamate category. This aspect is often associated with effects on the central nervous system. The review also provides recent literature dealing with MK-801/NMDA receptor in various areas of bioactivity. Studies were made of MK-801 involvement in working memory processing. Deficits in behavior were noted after administration of the drug. Treatment of mice with dizocilpine induced learning impairment. The influence of MK-801 on fear has been investigated. The substance is known to exert an analgesic effect in pain control. A number of reports deal with anesthetic properties.
Evidence indicates that nerve gas toxins operate in ways in addition to inhibition of acetylcholine esterase. Alternative bioactivities are discussed with focus on electron transfer. The main class, ...including pralidoxime (2-PAM), incorporates conjugated iminium and oxime moieties that are electron affinic. Various physiological properties of iminium and oxime species are reviewed. The organophosphates encompass both nerve gases and insecticides, possessing similar properties, but different activities. Toxic manifestations are apparently due, in part, to oxidative stress. Alkylation of DNA takes place which may lead to generation of reactive oxygen species. Structure-activity relationships are examined, including reduction potentials and the captodative effect.
Cocaine is one of the principal drugs of abuse. Although impressive advances have been made, unanswered questions remain concerning mechanism of toxicity and addiction. Discussion of action mode ...usually centers on receptor binding and enzyme inhibition, with limited attention to events at the molecular level. This review provides extensive evidence in support of the hypothesis that oxidative metabolites play important roles comprising oxidative stress (OS), reactive oxygen species (ROS), and electron transfer (ET). The metabolites include norcocaine and norcocaine derivatives: nitroxide radical,
N-hydroxy, nitrosonium, plus cocaine iminium and formaldehyde. Observed formation of ROS is rationalized by redox cycling involving several possible ET agents. Three potential ones are present in the form of oxidative metabolites, namely, nitroxide, nitrosonium, and iminium. Most attention has been devoted to the nitroxide–hydroxylamine couple which has been designated by various investigators as the principal source of ROS. The proximate ester substituent is deemed important for intramolecular stabilization of reactive intermediates. Reduction potential of nitroxide is in accord with plausibility of ET in the biological milieu. Toxicity by cocaine, with evidence for participation of OS, is demonstrated for many body components, including liver, central nervous system, cardiovascular system, reproductive system, kidney, mitochondria, urine, and immune system. Other adverse effects associated with ROS comprise teratogenesis and apoptosis. Examples of ROS generated are lipid peroxides and hydroxyl radical. Often observed were depletion of antioxidant defenses, and protection by added antioxidants, such as, thiol, salicylate, and deferoxamine. Considerable evidence supports the contention that oxidative ET metabolites of cocaine are responsible for much of the observed OS. Quite significantly, the pro-oxidant, toxic effects, including generation of superoxide and lipid peroxyl radicals, plus depletion of glutathione, elicited by nitroxide or the hydroxylamine derivative, were greater than for the parent drug. The formaldehyde metabolite also appears to play a role. Mechanistic similarity to the action of neurotoxin 3,3′-iminodipropionitrile is pointed out.
A number of literature strategies for treatment of addiction are addressed. However, no effective interventions are currently available. An hypothesis for addiction is offered based on ET and ROS at low concentrations. Radicals may aid in cell signaling entailing redox processes which influence ion transport, neuromodulation, and transcription.
Ideas are suggested for future work dealing with health promotion. These include use of AOs, both dietary and supplemental, trapping of the norcocaine metabolite by non-toxic complexing agents, and use of nitrones for capturing harmful radical species.
Extensive evidence supports involvement of electron transfer (ET), reactive oxygen species (ROS) and oxidative stress (OS) in the mechanism of many anticancer drugs. The common ET functionalities, ...usually present in the drug metabolites, are quinones (or precursors), metal complexes (or complexors), hydroxylamine and nitroso from ArNO2 or ArNH2, and conjugated imines (or iminium species). The ET agents function catalytically in redox cycling with formation of ROS from oxygen. Electrochemical data add support to the mechanistic viewpoint. The generated metabolites generally possess reduction potentials amenable to ET in vivo, thus giving rise to ROS. The resulting OS is a participant in destruction of the cancer cell. The action has been termed phagomimetic based on similarity to phagocytosis. It is important to recognize that drug action is often multipronged. The various modes of action are summarized.
Gossypol, a constituent of cottonseeds, displays various drug properties, including antifertility and anticancer. Toxicity is shown against the reproductive system, heart, liver, and membranes. The ...compound exhibits pro- and anti-oxidant behavior. Electron transfer (ET) functionalities, present in gossypol and its metabolites, comprise conjugated dicarbonyl, a quinone derivative, Shiff bases, and metal complexes. The parent possesses a reduction potential favorable for in vivo ET. Considerable evidence points to oxidative stress (OS), formation of reactive oxygen species (ROS), and DNA scission, characteristics of redox cycling by ET in biosystems. Mechanistic aspects are addressed with OS-ROS-ET as the guiding theme, in addition to other modes of action resulting in a multifaceted scenario.
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