Antioxidant

Antioxidant Properties of Curcumin

Unnikrishnan and Rao 8, 9 studied the antioxidative properties of curcumin and its three derivatives (demethoxycurcumin, bisdemethoxycurcumin, and diacetyl cur-cumin). The authors demonstrated that these substances provide a protection of hemoglobin from oxidation except the diacetyl curcumin, which has little effect in the inhibition of nitrite-induced oxidation of hemoglobin. The effect of curcumin on lipid peroxidation has also been studied in various models by several authors. Curcumin is a good antioxidant and inhibits lipid peroxidation in rat liver micro-somes, erythrocyte membranes, and brain homogenates. The antioxidant activity of curcumin could be mediated through antioxidant enzymes such as superoxide dis-mutase, catalase, and glutathione peroxidase. Curcumin has been shown to serve as a Michael acceptor, reacting with glutathione and thioredoxin 10 . Reaction of curcumin with these agents reduces intracellular GSH in the cells. In fact, curcumin has been found to be at...

Antioxidant Scavanger Action

The chemical structure of EGb constituents is responsible for its remarkable antioxi-dant reactive oxygen nitrogen species (RONS) scavenging activity. Its neuroprotec-tive function is based on its ability to eliminate free radicals, it acts as an antioxidant and a free-radical scavenger, and it reduces lipid peroxidation, which decreases tissue levels of ROSs and inhibits membrane lipid peroxidation. Both flavonoid and ginkgolide constituents are involved in the antioxidan free-radical-scavenging effects of EGb. The flavonoids preferentially react with hydroxyl radicals 17 and chelate pro-oxidant transition heavy metal ions 18 , which consequently inhibits the formation of new hydroxyl radicals. Significant antioxidant activity is consequently one of the most analysed protective effects of EGb on the CNS and the circulatory system. An extract can significantly eliminate free oxygen radicals (superoxide, hydrogen peroxide and hydroxyl radicals) and has also been found to be an...

Addition of Stabilizers Such as Antioxidants and Stabilization through the Use of Packaging

Often, the effect of oxygen can be eliminated by the addition of antioxidants. Oxidation of lovastatin in aqueous solution is inhibited by antioxidants such as a-tocopherol and butylated hydroxyanisole (BHA), as shown in Table 9.553 Similarly, the inhibition of the oxidation of cholecalciferol by a-tocopherol and ascorbic acid554 and the inhibition of the oxidation of NSC-629243 (an O-alkyl-N-aryl thiocarbamate see Scheme 49) by thioglycolic acid187 have been reported. The ability to inhibit oxidative photodegradation of benzaldehyde has been utilized as a measure of the antioxidant effects of polyhydric phenols.555 Pharmaceuticals are often stabilized by the utilization of packaging containing an antioxidant.556 For example, the photooxidation of cianidanol in the solid state was inhibited by lowering the concentration of oxygen with the use of an oxygen absorbent, as illustrated in Figure 132.402

Antioxidant Activity

Antioxidation is one of the most important mechanisms for preventing or delaying the onset of major degenerative diseases 2 . Active oxygen (hydroxyl, peroxy radicals, and single oxygen) is highly toxic and one of the strongest causative agents of many diseases, including cancer, heart disease, cataracts, and cognitive disorder. Antioxidants block the oxidation processes that contribute towards these chronic diseases and delay the onset of degenerative diseases of aging 17, 18 . The antioxidative activity of garlic powder has been evaluated to compare it with that of horseradish and shellfish extracts. Garlic powder showed the strongest antioxidant activity, and its activity was dose dependent (Table 4.6). Antioxidant properties in garlic extracts are mostly attributed to the presence of allicin, as antioxidant activity of allicin-free garlic extracts was much lower than that of the garlic extracts 19 . Antioxidant mechanisms are believed to exert their effects by blocking oxidative...

Antioxidants

Antioxidants are commonly described as cancer chemopreventive agents, especially in the lay press, on the basis that they scavenge free radicals and prevent damage to cellular constituents, including the genome. In particular, vitamin C (ascorbic acid) (see Structure 9.23) has been recommended for many years as a chemopre-ventive agent. However, a recent retrospective study in patients suggests that it provides no benefit. White button mushrooms, which contain the antioxidant ergot-hioneine (see Structure 9.24), are also claimed to have cancer chemopreventive properties.

Role of Inflammation in Neurodegenerative Disorders

Two types of glial cells, namely microglia and astrocytes, are the primary players of the inflammatory process in the brain (35,36). Under normal conditions, microglia serve a function of immune surveillance. Astrocytes, on the other hand, act to maintain ionic homeostasis, buffer the action of neurotransmitters, and secrete nerve growth factors. In response to immunological stimuli or injuries in the brain, glia, especially microglia, readily become activated. Traditionally, injury- and or neuronal death-induced glial activation have been called reactive gliosis with the term reactive microgliosis specifically referring to the activation of microglia. Perhaps in analogy to certain components of the immune response observed in the peripheral system, activated astrocytes and microglia which are either resident or, as some have speculated, recruited to the injury site play a key role in tissue repair through phagocytosis and secretion of various trophic factors. However, activated glia,...

Microglial Activation Part of the Etiology of PD

The hallmark of PD is the progressive degeneration of the nigrostriatal dopaminergic system involving the loss of dopaminergic neurons in the substantia nigra and their fibers in the striatum. Sufficient damage to the dopaminergic pathways, over time, eventually leads to disorders in movement regulation. It has now been recognized that microglial activation is involved in the neurodegenerative process of PD (55-58). Furthermore, epidemiological studies appear to suggest that microglial activation, as a consequence of exposure to infectious agents and environmental toxins and occurrence of early-life traumatic brain injuries, may play a role in the early stage of the pathogenetic process of PD (59-64). Some of the important clues in favor of the hypothesis that microglial activation will result in dopaminergic neurodegeneration have come from experiments with neuron-glia cultures stimulated with the bacterial endotoxin LPS. Indeed, LPS neurotoxicity requires the presence of glia, and...

Role of 5HT and Its Transporter in MDMAInduced Neurotoxicity

It can be envisioned that activation of the 5-HT transporter by MDMA renders 5-HT terminals vulnerable to further initiators of toxicity. Indeed, MDMA-induced 5-HT neurotoxicity is prevented in animals in which the 5-HT transporter is inhibited by fluoxetine (50,51). Actions of MDMA on the 5-HT transporter may be responsible for the generation of reactive oxygen species, i.e., free radicals, or for an increase in intracellular calcium concentrations (52), both of which could contribute to the process of toxicity.

Role of Oxidative and Bioenergetic Stress in MDMA Neurotoxicity

Increasing evidence suggests that MDMA-induced 5-HT neurotoxicity results from increased free radical formation and the subsequent induction of a state of oxidative stress. Support for a free radical hypothesis of MDMA toxicity is based on findings that (1) MDMA increases the formation of free radicals, (2) MDMA produces cellular damage that often accompanies free radical formation, and (3) free radical scavengers and or antioxidants attenuate MDMA-induced 5-HT neurotoxicity. Although free radicals are short-lived reactive species, in the presence salicylic acid, a stable adduct, that is, 2,3-dihydroxybenzoic acid (DHBA), is formed that can be quantified analytically. MDMA produces a rapid and sustained increase in the extracellular concentration of 2,3-DHBA in brain (43,51, There are several potential sources for free radicals generated by MDMA. Dopamine may undergo enzymatic or nonenzymatic oxidation to form superoxide radical and hydrogen peroxide. The importance of superoxide...

Grass Wheat And Barley

Effects Wheat grass is an excellent source of such antioxidant vitamins as A, B, C, and E. Both wheat grass and barley grass contain all the minerals essential for health, especially calcium, cobalt, iron, phosphorus, potassium, sulfur, and zinc. In addition to all the vitamins and minerals, they are high in chlorophyll, which according to some experts helps rid the body of toxins (including pesticides, drugs, and radiation) and discourages the growth of harmful bacteria. Barley also contains the antioxidants superoxide dismutase (SOD) and 2-0-GIV.

General Information

Calcium dobesilate is an antioxidant that has been used to treat diabetic retinopathy, in which it slows progression of the disease during long-term oral treatment by reducing microvascular permeability, leading to improved visual acuity (1). It not only acts as an antioxidant but also stimulates endothelial production of nitric oxide.

Animal and in vitro toxicology

Studies of the effects of cannabinoids on neurons in vitro have also yielded inconsistent results. Exposure of rat cortical neurons to THC shortened their survival twice as many cells were dead after exposure to THC 5 mmol l for 2 hours than in control cultures (18). Concentrations of THC as low as 0.1 mmol l had a significant effect. The effects of THC were accompanied by release of cyto-chrome c, activation of caspase-3, and DNA fragmentation, suggesting an apoptotic mechanism. All of the effects of THC could be blocked by the antagonist AM-251 or by pertussis toxin, suggesting that they were mediated through CB1 receptors. Toxic effects of THC have also been reported in hippocampal neurons in culture, with 50 cell death after exposure to THC 10 mmol l for 2 hours or 1 mmol l for 5 days (19). The antagonist rimonabant blocked these effects, but pertussis toxin did not. The authors proposed a toxic mechanism involving arachidonic acid release and the formation of free radicals. On...

Possible Mode of Action of Hp

Also relevant in this regard is the inhibitory effects of Hp on the NFkB pathway and the possible anti-oxidant effects of Hp extracts, for which there is some evidence. Antioxidants are potential inhibitors of NFkB, which is activated by reactive oxygen species generated during inflammation, and are recognised as key promoters of inflammation and inducers of pro-inflammatory genes. In vitro assessment of a water extract of Devil's Claw showed moderate antioxidant capacity (Trolox assay), which was not due to the content of iridoids, which exert minimal antioxidant activity 40 . However, the constituent acteoside has antioxidant properties, as has been shown in a number of studies. Acteoside is rarely discussed with regard to the pharmacology of Hp. It is present in Hp extracts in amounts similar to that of harpagoside 10 , which is the more characteristic and most often discussed constituent of Hp. Acteoside and acety-lated derivatives are present in many plants and have been...

Oxidative Stress A Possible Cause of METHInduced Neurotoxicity

The exact mechanisms responsible for METH-induced neurotoxicity have not been fully defined. As mentioned previously, however, a large body of work implicates oxidative stress inflicted by reactive oxygen species in damaging neurons. Although GLU plays a significant role in the destructive effects of METH,268 it is clear that excess DA is required for neurotoxicity to occur. Reactive species can form from oxidation of DA, DA auto-oxidation, and disruption of mitochon-dria.77 Pretreatment with DA-synthesis inhibitors prevents METH-induced damage in both DA and 5-HT systems and L-dopa reverses this effect.82269-271 METH administration also induces the formation of an endogenous neurotoxin 6-hydroxydopamine (6-OHDA), used experimentally to induce DA-specific lesions.272273 Further, studies in genetically modified mice have shown that the degree of damage is mediated, in part, by a number of enzymes. Mice over-expressing the reducing enzyme superoxide dismutase (SOD) show reduced...

Evaluating Qualitative Biological Activity

Bioautographic techniques work extremely well if antioxidant activity is determined using the free radical DPPH (1,1-diphenyl-2-picryl-hydrazyl) as a spray reagent (Fig. 5.2). Fig. 5.2 Antioxidant activity of acetone leaf extracts of several Combretum species determined by spraying with methanolic DPPH solution. White areas indicate the presence of antioxidant compounds in extracts. Fig. 5.2 Antioxidant activity of acetone leaf extracts of several Combretum species determined by spraying with methanolic DPPH solution. White areas indicate the presence of antioxidant compounds in extracts. tograms measuring different activities one can identify compounds with antibacterial, antifungal, and antioxidant activities.

Isolation and Biological Activity of Antibacterial Compounds from C erythrophyllum

The biological activity of five of these compounds was examined in more detail. All had good activity against Vibrio cholerae and Enterococcus faecalis, with MIC values in the range of 25-50 pg mL-1. Rhamnocitrin and quercetin-5,3'-dimethyleth-er also inhibited Micrococcus luteus and Shigella sonei at 25 pg mL-1. With the exception of 5-hydroxy-7,4'-dimethoxy-flavone, the flavonoids were not toxic towards human lymphocytes. This compound is potentially toxic to human cells and exhibited the poorest antioxidant activity whereas rhamnocitrin and rhamnazin exhibited strong antioxidant activity. Genkwanin, rhamnocitrin, quercetin-5,3'-dimethyleth-er, and rhamnazin had higher anti-inflammatory activity than the positive control mefenamic acid. Although these flavonoids are known, this is the first report of biological activity with several of these compounds.

Ethnoveterinary Research

Polyphenols in the extract were determined by the Folin-Ciocalteu method with gallic acid as standard. Qualitative antioxidant activity was screened by spraying TLCs of the extracts with 0.2 1,1-diphenyl-2-picryl hydrazyl (DPPH), and quantified with the Trolox equivalent antioxidant capacity (TEAC) assay. MIC and total antibacterial activity (TAA) values were determined by serial microplate dilution for Staphylococcus aureus, Escherichia coli, Pseudomonas aeruginosa, and Enterococcus faecalis, with gentamicin as standard and tetrazolium violet as growth indicator. Acetone and ethanol extracted the largest quantity of material. The polyphenol concentration was 49.2 in the acetone extract of the root and 3.8 in the dichlorom-ethane extract of the leaf. Antioxidant activity of at least five antioxidant compounds as measured by TEAC ranged from 1.34 (ethanol extract of the root) to 0.01 (hexane extract of the leaf). The total antibacterial activity (volume to which active compounds...

Order Myrtales Lindley 1833

The order Myrtales consists of 12 families and more than 9000 species of tropical trees, shrubs, climbers and herbs thought to have originated from the order Rosales (Appendix I). About three-fourths of the species belong to the family Melas-tomataceae (4000) and to the family Myrtaceae (3000). The medicinal properties of Myrtales are often attributed to tannins or essential oils. Tannins are astringent, antioxidant, cytotoxic, antimicrobial but may cause neoplasia. Essential oils of several plants species classified within the family Myrtaceae are of therapeutic value Eucalyptus globulus Labill. and Eugenia aromatica O. Ktze. (cloves).

Biological Effects Of

The main biological effect of ROS is the induction of oxidative stress, which can be defined as a situation of imbalance between the production of radical species and antioxidant defense systems. Oxidative stress can cause damage to all kinds of biomolecules, including lipids, proteins, and DNA. For this reason, the mechanism of action of several kinds of antitumor agents is based, at least partly, on the production of hydroxyl radicals and other ROS and the subsequent damages that they cause on biological molecules by a number of mechanisms that will be summarized in this chapter.1 Most of these mechanisms have been discovered during the course of studies on the anthracyclines.2

Reproductive system

A second unusual approach to the bleeding problem has been to give vitamin E. There is evidence that there is a poor angiogenic response in the endometrium of users of Norplant, and it has been hypothesized that this might be caused by an imbalance of pro-oxidant and antioxidant processes. A placebo-controlled study has suggested that vitamin E (200 mg day for 10 days monthly) significantly reduces the number of monthly bleeding days (42). However, there was also some reduction in bleeding days with placebo, and this approach would need further study before the results could be accepted as clinically useful.

The Role of Reactive Oxygen Species

ROS include molecules such as superoxide, H2O2, the hydroxyl radical, singlet oxygen, and hypochloric acid, and play many important physiological roles. They aid in the destruction of microbes and tumor cells, but may also alter and damage several components of normal cells, including membrane proteins lipids and DNA, and may result in cancer induction. Many ROS effects depend upon the levels of the free radicals. EGCG, like other antioxidants, decreases ROS levels at low concentrations and increases them at high concentrations 5 . Superoxide functions as a key ROS. It is converted into H2O2 by superoxide dis-mutase within cells. H2O2 is degraded into water and O2 by catalase. EGCG scavenges superoxide and elevates the activity of both protective superoxide dismutase and catalase in neurons 23, 50 . All phagocytic cells, including brain microglia, produce and release ROS. These cells also contain protective enzymes to inactivate the free radicals, including glutathione peroxidase...

Herbal Alert Green

Green tea and black teas come from the same plant. The difference is in the processing. Green tea is simply dried tea leaves, whereas black tea is fermented, giving it the dark color, the stronger flavor, and the lowest amount of tannins and polyphenols. The beneficial effects of green tea lie in the polyphenols, or flavonoids, that have antioxidant properties. Antioxidants are thought to play a major role in preventing disease (eg, colon cancer) and reducing the effects of aging. Green tea polyphenols are powerful antioxidants. The polyphenols are thought to act by inhibiting the reactions of free radicals within the body that are thought to play a role in aging. The benefits of green tea include an overall sense of well-being, cancer prevention, dental health, and maintenance of heart and liver health. Green tea taken as directed is safe and well tolerated. It contains as much as 50 mg of caffeine per cup. Decaffeinated green tea retains all of the polyphenol content. The...

Cotinus coggygria Scop

Pharmaceutical interest The medicinal properties of Cotinus coggy-gria Scop. could be attributed to the presence of fisetin, disulphuretin, sulphuretin, sulphurein, gallic acid, methyl gallate and pentagalloyl glucose, which are known to occur in this plant (Du HQ, 1983 Westenburg HE et al., 2000). The cholagogue property of Cotinus coggygria Scop. is confirmed experimentally, as syrup of the plant protects the liver against chemical damages, lowers the tension of choledochal sphincter, increases the bile flow and raises the body immunity (Shen Q etal., 1991). The tannins of Cotinus coggygria Scop. are antioxidant (Ivanova D et al., 2005).

Camellia sinensis Green tea

Green tea contains antioxidant polyphenols such as catechins and flavonols. Most of the experimental and epidemiological studies concerning green tea effects have been targeted at its possible cardiovascular, anti-inflammatory, and anticarcinogenic effects, which have been linked to the antioxidant pro-oxidant properties of its polyphenol constituents 67, 69 . Daily ingestion of tea as an antioxidant has also been reported to prevent stroke. Green tea extract orally administered to Wistar rats for 3 weeks before induction of ischemia by occlusion of middle cerebral arteries and reperfusion minimized the eicosanoid accumulation and oxidative damage in addition to the reduction of neuronal cell death 70 . Green tea extract prevented cerebral ischemia damage caused by global ischemia-reperfusion in Mongolian ger-bils 71 . (-)-EGCG has potent antioxidant properties in a green tea polyphenol and had a neuroprotective effect against neuronal damage following global ischemia in Mongolian...

Pharmaceutical interest

Anti-inflammatory properties The anti-inflammatory property of Impatiens balsamina L. is confirmed in vitro and involves anthocyanidins, coumarins and quinones. An ethanolic extract of flowers of Impatiens balsamina L. shows, in vivo, antianaphylactic, antipruritic and antihistaminic properties (Fukomo H et al., 1995 Ishiguno K etal., 1992). The aerial parts and especially the flowers and stems of Impatiens balsamina L. contain pelargonidine, delphinidine, cyanidine or malvidine, which are well-known to decrease capillary permeability and fragility and are therefore used to treat edema. These anthocyanidins are probably effective due to their ability to scavenge free radicals. It is also thought to be due to the collagen of the vascular wall in the control of the permeability of that wall, which may involve an inhibition of the proteolytic degradation enzymes (elastase, collagenase).This vitamin P property led to the use of anthocyaninin-containing drugs for the symptomatic treatment...

Drug Resistant Gram Negative Bacteria

Table 10.2 summarizes the literature data on the activity of plant extracts and plant-derived products against drug-resistant Gram-negative bacteria. Plant materials with activity specifically targeted against antibiotic-resistant strains and with other biological activities that could potentiate their therapeutic role provide examples of natural products that are worthy of further investigation. In this context, we studied propolis and Zingiber officinale extracts with multiple biological properties such as anti-inflammatory, antioxidant, hepatoprotective, antitumoral, and antimicrobial activities. Propolis and Z. officinale have shown specific antibacterial activity against rifabutine-, tinidazole-, and clarithromycin-resistant H. pylori strains (isolates from antral mucosal biopsies of patients with chronic gastritis or duodenal ulcer) with MIC values equal to 0.075-0.3 and 0.075-0.6 mg mL-1 respectively 105 . Equally interesting are plants that have activity against bacteria...

Paeonia suffruticosa P lactiflora

The root bark of Paeonia suffruticosa Andrews (Ranunculaceae) is a drug used in TEM as both an analgesic and an anti-inflammatory agent 118 , and it is prescribed in various TEM preparations for the treatment of blood stagnation. It has been reported to have strong superoxide and hydroxyl radical scavenging activity 119 . Its antioxidative effects are due to enhancing activities of SOD, CAT, and GPX 120 . Paeonol (Fig. 16.1) inhibits cerebral ischemic injury by blocking increases in Ca2+, decreases in SOD activity and the content of MDA, and improved Ca2+-ATPase activity in ischemic brain tissue 121, 122 . a-benzoyloxypaeoniflorin, an antioxidant monoterpene glycoside, from P. suffruticosa has potent radical-scavenging activity on the DPPH radical 123 .

Contributions of Elementology to Potential Treatments for Hepatic Disorders

Cascales and coworkers investigated altered liver function induced by chronic administration of thioacetamide (TAA), which was partially restored by rhodium complex 79 . Schwartz reported the importance of selenium in the treatment of liver necrosis 80 . The biochemical role of selenium as a component of glutathione peroxidase was studied by Rotruck et al. 81 . The antioxidant activity of this enzyme serves to maintain the integrity of cellular and subcellular structures. Selenium is a natural antioxidant and appears to preserve tissue elasticity by delaying the oxidation of polyunsaturated fatty acids. Selenium participates in the lipooxyge-nase pathway along with catalase, superoxide dismutase, vitamin E, vitamin C, ca-rotenoids etc., whose principal function is to eliminate the free radicals involved in the pathogenesis of liver disorders 82 . Zinc, as a component of metalloenzymes, protects against hydroxyl radicals and inhibits apoptosis induced by glucocorti-coids. It is also...

Other Alternatives in Liver Therapy

Apart from the use of herbal medicines and trace metal elements to treat liver disorders there are other alternative approaches currently in use. Some of these therapies are effective in treating liver diseases, as has been shown from a few cases reported in reviews. For example thymosin therapy involves using hormones normally secreted by the thymus gland, such as thymosin, thymopoietin, and serum thymic factor. These hormones appear to stimulate the body's production of interferon. People with low levels of these hormones are susceptible to infections of the liver. Replenishment of hormone level according to biological demand might explain the disease alleviation that has been noted in these types of cases 95 . Metabolic therapies involve the use of very high doses of vitamins and restricted diets, the latter to relieve the liver from extra toiling. Megadose vitamin therapy is based on the theory that the higher the dose of vitamins, the faster the cure. However, a consistent low...

Huanglianjiedu Decoction

Chronic oral pre- and post-HLD prevented cholinergic synaptic dysfunction and serotonergic presynaptic hyperactivity induced by transient ischemia 196 . Pre-treatment with oral administration of HLD protected against the impairment of learning and memory induced by transient cerebral ischemia and prevented a decrease in the ACh content of the mouse brain 197 . HLD also protected against transient forebrain ischemia induced by occlusion of both common carotid arteries in C57BL 6 mice by increasing the expression of Cu Zn-SOD and reducing the exposure of hippocampal neurons to oxidative stress 198 . HLD extract reduced ischemia-reperfusion brain injury and neutrophil infiltration in MCAo rats 62 . The neuroprotective effect of HLD can be explained by multiple mechanisms, the anti-inflammatory and antioxidant activity of Scutellariae Radix, Coptidis Rhizoma, and Gardiniae Fructus, and inhibition of ACh release by Coptidis Rhizoma and Phel-lodendri Cortex.

Buyanghuanwu Decoction

Buyanghuanwu decoction (BYHWD), a traditional Chinese herbal prescription, has been used clinically for hundreds of years to treat stroke with a yang-tonic effect. The component herbs of BYHWD are Astragalis Radix, Lumbricus, Angelicae Sinensis Radix, Ligustici Chuanxiong Rhizoma, Paeoniae Radix Rubra, Persicae Semen, and Carthami Flos. BYHWD shows an antioxidant effect by raising the decline of superoxide dismutase and GPX activities in a rat model induced by pertussis vaccine 199 . BYHWD improves recovery of neurological function, reduces infarction volume, stimulates neural proliferation, and modulates VEGF and Flk1 expression in transient focal cerebral ischaemic rat brains 200 . BYHWD protects neurons from hypoxia-induced apoptosis, the mechanism of which may lie in the elimination of NO and oxygen free radicals produced during hypoxia, and also by up-regulation of Bcl-2 expression 201 , and down-regulation of p53 and p21 gene expression 202 .

Plants as Protective Agents Against DNA Damage

Similarly, crude extracts of propolis, a natural composite balsam produced by honeybees from gum of various plants, have been used as folk medicine. Recently, these extracts have gained popularity both as a medicine with antibacterial, antiviral, anti-inflammatory, and antioxidant properties, and as a food to improve health and prevent disease 16-18 . Analyses of chemical composition have identified at

Degenerators of cells

Aydos et al.478 underlined the particularly detrimental effects of nicotine on germ cells, peritubular structures and Sertoli cells. The germ cells were degenerated, and spermatids retained excess cytoplasm and accumulated electron-dense lipid droplets in the cytoplasm. Moreover, the results of Aydos et al.478 proved that the acrosomes in rats exposed to nicotine were irregular and abnormally configured. It is not difficult to interpret these results as evidence of active nicotine toxicity. Moreover, this chronic toxicity is reported also by Sener et al.479, who have studied aqueous garlic extract as an antioxidant. In this research, male Wistar albino rats were injected with nicotine, which led to increased collagen contents in tissues. Although Sener et al.479 reported the aqueous garlic extract was a protector of rat tissues, there is evidence of nicotine-induced oxidative damage. Nicotine toxicity has been studies also on None of these studies question the symptoms of acute and...

Treatment of Cerebral Ischemia

Numerous studies on the effects of EGb on cerebral ischemia have been conducted over the course of many years. EGb has extensive protective effects on the central nervous system (CNS) and cerebrovascular system. It functions as a neuroprotective agent in its ability to eliminate free radicals, acts as an antioxidant and free-radical scavenger, reduces lipid peroxidation, and is a membrane stabilizer and inhibitor of platelet-activating factor via the terpene ginkgolide B 8 . Different pathological models of cerebral ischemia were used to evaluate its effects, and measurements were taken at both the cellular and molecular levels to determine its mechanisms of action, which depend on a direct effect on neuronal cells and an indirect effect on brain circulation. In experimental models with different paradigms such as focal and global ischemia, administrated before or after the insult and given oraly or intraperitoneally 9-12 , in oedema and hypoxia, it was mostly shown that EGb reduced...

Family Buddlejaceae Wilhelm 1910 nom conserv the Butterfly bush Family

Pharmaceutical interest The largest genus of Buddlejaceae is the genus Buddleja (butterfly-bush) with 100 plant species in both the Old and New World, some of them cultivated a plant garden. To date, the state of knowledge on the pharmacology of Buddlejaceae is vestigial. Caffeoyl phenylethanoid glycosides, such as verbascoside isolated from Buddleja officinalis Maxim., might hold some potential as antioxidant. Note that a number of Buddleja species are used as topical antiseptic and diuretic. In the Asia-Pacific, Buddleja asiatica Lour., Buddleja lindleyana Fortune (Buddleja curviflora sensu Stuart, non H. & A., Buddleja jap nica sensu read, non Hemsl.), Buddleja officinalis Maxim. and Buddleja albiflora Hemsl. are medicinal. It would be interesting to learn whether a more intensive study on this family discloses any molecules of therapeutic interest.

Family Gesneriaceae Dumortier 1822 nom conserv the Gesneriad Family

Pharmaceutical interest A number of plants classified within the genera Gloxinia, Achimenes, Sinningia and Streptocarpus are cultivated for decorative purposes. Little is actually known of the therapeutic potential of this large family. Caffeoyl phenylethanoid glycosides might hold some antioxidant potentials. Approximately twenty plants classified within the family Gesneriaceae are of medicinal purposes in the Asia-Pacific. These are often used to counteract the putrefaction of the skin, to combat fever and to resolve inflammation.

Other Anti Ischemic Effects

Recent studies using gerbils, mice and rats have provided some insight into the beneficial action of EGb. In experimentally induced cerebral ischemia, a 7-d treatment reduced the degree of CNS damage induced by middle cerebral artery liga-tion 46,47 . In a similar ischemia paradigm, other investigators found that EGb protected against neuronal death in the hippocampal CA1 area of the gerbil brain 15 a follow-up study revealed that the protection extended to cells in the frontal lobe 47 . In addition, using an Alzheimer's mutant mouse model (Tg2576), EGb treatment for 6 months markedly improved spatial cognitive performance, without affecting central P-amyloid concentrations 48 . It was found that EGb could increase the rat cerebral blood flow 49 and improved ischemic memory impairment in mice 50 . Several lines of evidence suggest that EGb alleviates the subcellular damage of cerebral ischemia 51 and allows mitochondria to maintain their respiratory activity under ischemic conditions...

Engineered Plants to Modulate Vitamin E Composition

Overexpression of VTE1 in Arabidopsis leaves resulted in up to a sevenfold increase in tocopherols and a dramatic shift in tocopherol composition from a-tocopherol (16.5 ) to Y-tocopherol (80.5 ), which indicated that both VTE1 and Y-TMT are limiting factors for tocopherol biosynthesis 102 . This differs from previous work, in which overexpression of y-TMT and HPT, singly or in combination, clearly demonstrated that y-TMT was not a limiting factor for tocopherol biosynthesis in Arabidopsis leaves in the absence of stress but became a limiting factor under abiotic stress 29, 93, 104 . Accumulation of tocopherol in VTE1 overexpressing plants led to a 60 and 40 decrease in ascorbate and glutathione, two key water-soluble antioxidants, respectively 102 . It is unclear why increased VTE1 activity would lead to a reduction in ascorbate and glutathione, indicating that there is still much to be learned on the regulation of tocochromanol synthesis in plants.

Postnatal Development

Nursing infants receive complete nutrition and protection from environmental pathogens from their mother's milk (Newman, 1995 Kelly and Coutts, 2000 Korhonen et al., 2000). Human, bovine, and goat milk contain 2-AG, 2-PG, 2-linoleoyl glycerol (2-LG), oleamide, AEA, PEA, and OEA (Fride et al., 2001 Schuel et al., 2002b). 2-AG is present in milk at much higher concentrations than AEA, whereas 2-PG and 2-LG are present at the highest levels (Fride et al., 2001). OEA is the most abundant NEA in human milk, whereas AEA is present at lower levels than OEA and PEA (Schuel et al., 2002b). OEA reduces feeding in rats (Rodriguez de Fonseca et al., 2001). PEA also produces anorexic effects but is less potent than OEA. The inhibitory effect of OEA on feeding is not blocked by CBj- and CB2-specific antagonists (SR141716 and SR144528, respectively), suggesting that OEA does not act via currently known CBRs. PEA and OEA are potent anti-inflammatory, antioxidant, and antimicrobial agents (Schmid et...

Chemopreventive Agents

Various mechanisms have been proposed to explain the action of chemopreven-tive agents, which has given rise to two main categories anti-initiators (or blocking) and anti-promotional (or suppressing) agents. Anti-initiators are claimed to selectively enhance the metabolism of some carcinogens, thus reducing the body's exposure to them. In particular, they may block DNA damage resulting from carcinogens (or resulting free radicals) by detoxifying the carcinogens via induction of Phase 1 and 2 enzymes. Alternatively, they may inhibit the metabolic activation of certain carcinogens that require this form of activation by selectively inhibiting Phase I enzymes. Anti-initiators may also work by increasing the expression of cytoprotec-tive genes in human cells, including those that produce drug-metabolizing enzymes such as glutathione (GSH) transferase and NAD(P)H quinone oxidoreductase 1 (NQO1) as well as antioxidant genes such as glutamate cysteine ligase modifier (GCLM) subunits and...

Clinical Trials in Humans

A placebo-controlled double blind pilot study on 30 HCV patients with a phenol-rich antioxidant grain food showed that antioxidant food considerably improved defense. In 11 of the 15 patients (who received 6 g food powder three times daily for three months) liver enzymes were decreased and the viral load remained unchanged, compared to placebo (15 patients who received an herbal extract with no antioxidant). After three months of treatment a sustained response was observed in 5 of 9 antiox-idant-pretreated patients when they received interferon and ribavirin treatment even six months after discontinuation of the 12-month antioxidant therapy 134 .

Ascorbic Acid Vitamin C

An authoritative analysis published in The Lancet in 2004 concluded that there is no evidence that vitamins (including vitamin C) help prevent the occurrence of common gastro-intestinal (GI) cancers. (see Structure 9.23)The study included more than 170,000 people at high risk for GI cancers and pooled 20 years of research data. However, despite this result, some experts still believe that antioxidants play a role in chemoprevention in certain individuals, and other studies are still ongoing. Ergothioneine, a constituent of white button mushrooms, the type most commonly consumed in the U.S. and Europe, has been proposed as an antioxidant vitamin with cancer chemopreventive and cardiovascular properties (Structure 9.24). White mushrooms are the best known source of ergothioneine, containing about 4 times more than chicken liver (previously considered the best source) and about 12 times more than wheat germ, also a good source of the nutrient. Even exotic mushrooms such as shiitake,...

Biological Intervention

Interventions with cytoprotective efficacy, such as the antioxidants mentioned for early radiation effects, are considered to be similarly effective for late effects, if given at the time of irradiation. This, however, is only true if the protection occurs at the cellular level, and not through interaction with, for example, repopulation processes. This has, for example, been demonstrated for amelioration of CNS changes by amifostine (Nieder et al. 2004), possibly resulting from a reduction of the vascular component of the radiation effect however, no evidence from conclusive clinical results is available.

Influence ofKinetin on Animals

In experiments using animal cells and other organisms it was shown that kinetin influences many processes, regulates proliferation, and has antiaging and antioxidant properties. Kinetin's antioxidant and scavenger activity was confirmed in vivo and in vitro. It could act in a few different ways as a donor of hydrogen, as an enzyme, or as an activator of enzyme activity 37-40 . Because of these properties kinetin prevents damage to DNA, proteins, and other macromolecules, avoiding the accumulation of abnormal particles in organs, tissues, and cells. The antiaging properties of kinetin were shown using in vitro cell cultures, in vivo on skin, and fruit flies. The fruit fly Zaprionus, with its diet supplemented with 125 to 625 M kinetin, prolonged life span due to a reduction in the age-specific death rates, slowed down development, and delayed maturation of insects in the larval and pupal stages. Delayed aging is reached at the cost of decreased reproductive activity and egg-laying...

Convolvulus pleuricaulis

Curcuma longa is a perennial rhizomatous plant growing all over India. Curcumin or C. longa extract shows strong antioxidant activity. -amyloid-induced oxida-tive stress appears to be an important pathway of neuronal cell death in AD. The methanolic extract of turmeric led to the isolation of Calebin-A and the curcum-ins, which effectively protects neuronal cells against -amyloid deposition. In another study, curcumin, on oral administration to alcohol-fed rats, caused a significant An extract prepared from green leaves (EGB761) was identified as therapeutically useful for the treatment of peripheral circulatory disturbances, as it is a vasodilator. Results showed that EGB761 is not a vasodilator in the classical sense, but it is a CNS function modulating and neuroprotective agent, sustainable for the therapy of patients with cerebrovascular disorders or cerebral insufficiencies. Ginkgo is widely used in Europe for treating dementia. It improves blood flow in the brain and contains...

Diospyros argentea Griff

Secondly, the quinone moiety generates highly reactive free radicals (Lown JW, 1979). Thirdly, naphthoquinones are planar, and intercalate with DNA. An example of a naphthoquinone of therapeutic interest is atovaquone, which is used to treat malaria and Pneumocystis carinii infection. Examples of cytotoxic naphthoquinones are plumbagin, isodiospyrin and 8 -hydroxyisodiospyrin which inhibit significantly the proliferation of Hepa, KB, Colo-205 and HeLa cell-lines cultured in vitro (Kuo YH et al., 1997).

Phenolics and Polyphenols

Quinones have aromatic rings with two ketone substitutions (Fig. 15.6), and are highly reactive. These colored compounds are responsible for the browning reaction in cut or injured fruits and vegetables, dying of henna and are an intermediate of the melanin synthesis pathway 57 . The switch between diphenol (or hydroqui-none) and diketone (or quinone) occurs easily through oxido-reduction reactions and hence, the individual redox potential of a particular quinone-hydroquinone pair is very important in biological systems. Quinones provide a source of stable free radicals, and also irreversibly bind with nucleophilic amino acids in proteins 58 leading to the inactivation and loss of protein function. Hence, the range of antiviral effects of quinone is considerable, and the probable target of quinones is the virus attachment site and some viral enzymes (Table 15.2). The nonspecific anti-HIV-1 activity of (-)-epigallocatechin 3-O-gallate is due to its ability to disrupt post-adsorption...

Enantioselective Cannabinergic Ligands

HU210 is one of the most potent cannabinoids known. It acts through CB1 and CB2 receptors and is a potent inhibitor of forskolin-stimulated cyclic adenosine monophosphate (cAMP) production. Both the affinity and potency of HU210 are much higher than those of its synthetic (+)-S, S-enantiomer HU211 (also called dexanabinol). HU-211 is devoid of cannabinoid activity but has other interesting in vivo properties, including its action as an NMDA (N-methyl-D-aspartate) antagonist, antioxidant, and inhibitor of the synthesis of tumor-necrosis factor (TNF). It has found utility as a potential neuroprotective agent, and after favorable results in animal models (Shohami and Mechoulam 2000), it is now undergoing phase III clinical trials in Europe and Israel for traumatic brain injury (Knoller et al. 2002 Agranat et al. 2002).

Buddleja asiatica Lour

Pharmaceutical interest To date, the pharmacological properties of Buddleja asiatica Lour. remain unexplored. Note that the invigorating and aborting properties mentioned above, might be owing to bitter iridoids or antioxidant verbas-coside like compounds and saponins respectively. Antioxidant flavonoids and caffeic acid derivatives characterized from Buddleja globosa protect fibroblast against hydrogen peroxide (Mensah AY et al., 2001). Are the dermatological potentials of Buddleja asiatica Lour. a result of antioxidant principles

Combinations of Hypoxia Targeting Compounds and Radiation Activated Prodrugs with Ionizing Radiation

Diagram Egfr Under Hypoxic Conditions

In the 1960s Adams and Cooke (1969) proposed that electron-affinic drugs might act like O2, a potent electron-affinic molecule, to sensitize hypoxic tumor cells. These agents (hypoxia-selective radi-osensitizers (HSR) mimic O2 by reacting with the short-lived DNA free radicals generated by ionizing radiation however, unlike O2, HSR are not rapidly metabolized by the cells through which they penetrate and are thus able to reach areas beyond the O2 diffusion distance. Some examples of HSR are discussed below. Anderson RF, Shinde SS, Hay MP, Gamage SA, Denny WA (2003) Activation of 3-amino-1,2,4-benzotriazine 1,4-diox-ide antitumor agents to oxidizing species following their one-electron reduction. J Am Chem Soc 125 748-756 Anlezark GM, Melton RG, Sherwood RF, Wilson WR, Denny WA, Palmer BD, Knox RJ, Friedlos F, Williams A (1995) Bio-activation of dinitrobenzamide mustards by an E. coli B nitroreductase. Biochem Pharmacol 50 609-618 Bachur NR, Gordon SL, Gee MV (1978) A general mechanism...

Cumulative index of special reviews Annuals 1625

25. 183 drowsiness, 23.171 sedation, 21.170 Antihypertensive drugs, 19.209 fixed-dose combinations, 22.224 individualizing therapy, 17.246 Antimalarial drugs, 17.325, 20.257 adjunctive treatments, 24. 330 prophylaxis, 23.304 Antioxidant vitamins, 20.363 Antiprotozoal drugs

Herbal Medicines Potential Therapeutic Agents with Minimal Side Effects

Although some herbal medicines are effective in the treatment of diseases against which modern medicines are inefficient, very often these drugs are unscientifically exploited and improperly used. Numerous plants and polyherbal formulations are used for the treatment of liver diseases. However, in most of the severe cases, the treatments are not satisfactory. Experimental evaluation in most cases has been incomplete and insufficient and the therapeutic values have been tested against chemically induced subclinical levels of damage in rodents. Even common dietary antioxidant and micronutrients such as tocopherol 44 , ascorbic acid 45 , beta-carotene 45 , glutathione, uric acid, and bilirubin, and proteins such as ceru-loplasmin can provide protection from liver damage. The synergistic action of various ingredients of a polyherbal formulation for holistic and long-lasting cure of hepatic disorder might help in regulating the metabolism, which is one of the factors responsible for...

Cyrtandra cupulata Ridl

Pharmaceutical interest It would be interesting to know whether the medicinal properties mentioned above could be confirmed experimentally. Note that a crude methanolic extract of the leaves of Cyrtandra cupulata Ridl. inhibits moderately both estrogens-dependent CaOV-3 and MCF-7 cell-lines cultured in vitro and exhibits antioxidant capacity. Does the plant contain phytoestrogens

Pharmacological Inhibition Of Jaks

Autoimmune Jak

Inhibition of JAKs has also been observed with the serine threonine kinase inhibitor staurosporine at high concentrations, the immunosuppres-sive drug leflunomide, and octylamino-undecyl-dimethylxanthine derivatives (153-156). Piceatannol, a resveratrol analog, is a natural stilbene byproduct from the seeds of Euphorbia lagascae and reported to inhibit the p72Syk kinase (157). Recent studies showed inhibition of STAT3 and STAT5 activation by piceatannol (158). An IL-10-dependent AIDS-related B-NHL cell line was sensitized by the compound to chemotherapeutic drug-induced apoptosis through inhibition of JAK1 STAT3 activation and Bcl-2 expression (125). Curcumin (diferuloylmethane) is a plant product known for its antioxidant, antitumor, and anti-inflammatory activities (159). In T-cells, curcumin has

Pyrrolobenzodiazepine PBD Monomers

A number of PBD monomers were evaluated in the clinic in the 1960s and 1970s. Anthramycin itself was demonstrated to have antitumor activity but could not be developed due to a serious dose-limiting cardiotoxicity. This was later shown to be caused by the phenolic hydroxyl group at C9, which was being converted to quinone species that produced free radicals capable of damaging heart muscle. Other side effects included bone-marrow suppression and tissue necrosis at the injection

Coppercontaining intrauterine contraceptive devices

Copper-containing intrauterine contraceptive devices (10-12) became popular because local inflammatory reactions in the endometrium are more marked and the contraceptive effect is thus more pronounced (SEDA-21, 234) (13). In addition, copper ions released from intrauterine contraceptive devices reach concentrations in the luminal fluids of the genital tract that are toxic to spermatozoa and embryos. The ability of copper to induce the generation of free radicals and the formation of malonaldehyde may be involved in its contraceptive effect.

Safety factors that govern the choice of antianginal drug

The roles of these modifiable risks have thus become more important, and other risks interventions, such as dietary antioxidants (32) and physical activity (33), have also been highlighted. In addition, observational studies have implicated hyperhomocysteinemia as a powerful risk The roles of other modifiable susceptibility factors have become more important, and other interventions, such as dietary antioxidants (32) and physical activity (33), have also been highlighted in the past. However, a meta-analysis of the effect of vitamin E supplements has suggested that doses over 400 IU day can increase the risk of death from any cause (43).

Toxification Detoxification

Figure 15.11 Possible scheme for the formation of free radicals from the metabolism of dopamine. Normally hydrogen peroxide formed from the deamination of DA is detoxified to H20 along with the production of oxidised glutathione (GSSG) from its reduced form (GSH), by glutathione peroxidase. This reaction is restricted in the brain, however, because of low levels of the peroxidase. By contrast the formation of the reactive OH-radical (toxification) is enhanced in the substantia nigra because of its high levels of active iron and the low concentration of transferin to bind it. This potential toxic process could be enhanced by extra DA formed from levodopa in the therapy of PD (see Olanow 1993 and Olanow et al. 1998)

Antimicrobial Bioactive Phytocompounds from Extraction to Identification Process Standardization

Medicinal Plant Work Flow Chart

The activities of essential oils cover a broad spectrum. Various essential oils produce pharmacological effects, demonstrating anti-inflammatory, antioxidant, and anticancerogenic properties 17-19 . Others are biocides against a broad range of organisms such as bacteria, fungi, protozoa, insects, plants, and viruses 20-22 .

Marijuana Use In Cell Survival Neurogenesis And Apoptosis

Marijuana use and the effects of exogenous synthetic cannabinoid administration, including the activation of endocannabinoids and multiple signaling capabilities, have been shown to control cell survival and death by inhibiting or stimulating cell growth. Thus, cannabinoids induce growth arrest or apoptosis in a number of transformed neural and nonneural cells in culture (Guzman et al., 2002). Cannabinoids of all classes also have the ability to protect neurons from a variety of insults that are believed to underlie delayed neuronal death after traumatic brain injury, including excito-toxicity, calcium influx, free radical formation, neurodegeneration, and neuroinflammation (Biegon, 2004). Specifically, an important physiological role of cannabinoids is neuroprotection, and in animal studies, inhibition of calcium influx into cells, antioxidant properties that reduce damage caused by oxygen radicals, and modulation of vascular tone has been shown (Grotenhermen, 2004). It has been...

Orophea polycarpa A DC

Pharmaceutical interest The antiinflammatory property of Orophea poly-carpa A. DC is still not confirmed yet. A dichloromethane extract of leaves of Orophea enneandra displays antifungal, antioxidant and radical scavenging properties on account of lig-nans (-)-phylligenin, (-)-eudesmin, (-)-epieudesmine, tocopherol derivative polycerasoidol and a polyacetylene oropheic acid (Cavin A et al., 1998). Aristolactams enterocarpam I and II are known to occur in Orophea enterocarpa (Kamalia M et al., 1986). Enterocarpam II has been synthesized (Couture A et al., 1998).

Bacopa monniera Wettst

Bacopa monniera Wettst. (Scrophulariaceae), known by the common name 'brahmi', has been used in Ayurvedic medicine for almost 3000 years as a nerve tonic and to improve intellect and memory 128 . Various investigations have attempted to substantiate and identify a scientific basis for the reputed effects. A number of in vivo studies have shown B. monniera extracts to improve cognitive function 128-130 . The mode of action to explain these effects has yet to be fully elucidated. Some studies suggest that the antioxidant effects of B. monniera may protect the CNS from oxidative damage. Extracts of B. monniera have been reported to induce a dose-related increase in superoxide dismutase, catalase and glutathione peroxidase activities in the rat frontal cortex, striatum and hippocampus 131 , to dose-dependently inhibit nitric oxide (NO)-related toxicity (DNA damage) in cultured rat astrocytes 132 and to inhibit aluminium-induced neurotoxicity in the rat brain 133 . The antioxidant effects...

Singlet Oxygen And Its Reactivity

Amines generally are capable of quenching singlet oxygen via a charge-transfer process, but may react chemically as well. The primary process is envisaged as formation of a complex between the electron-donating quencher and the electron-deficient oxygen species the quenching rate constants correlate with the amine ionization potential. The resulting triplet complex dissociates with loss of energy by vibrational relaxation or forms oxidation products. Formation of products requires an abstractable hydrogen a to the nitrogen N-methyl groups are particularly susceptible. Diazabicyclo-octane (DABCO) is unable to react chemically, presumably on steric grounds, but is an efficient physical quencher. Some phenols are also able to quench singlet oxygen by a mixture of physical and chemical processes, e.g., the 2,4,6-trisubstituted phenols used as antioxidants, BHT, and a-tocopherol.

The Acute and Subacute Mouse MPTP Model

Readily absorbed and crosses the blood-brain barrier. The toxin is converted to an active toxic metabolite, 1-methyl-4-phenylpyridinium (MPP+), by the monoamine oxidase type B enzyme located in the astroglial cells (54). The produced MPP+ is taken up into the nigrostriatal DA nerve terminals selectively by the DA uptake transporter (DAT) (55). The elevated cytoplasmic MPP+ level may in turn cause the release and accumulation of the excitatory amino acid transmitter glutamate and Ca2+ within the afflicted neurons, resulting in an inhibition of complex I of the mitochondrial electron transport chain system and a production of free radicals (56,57). Impairment of respiration and oxidative damage of the mitochondria may lead to the depletion of cellular ATP and eventual neuronal death (58). Subacute MPTP injections and MPP+ production may induce apoptosis in dopaminergic neurons (59) and that could serve to initiate neuronal degeneration. On the other hand, subacute MPTP treatment causes...

Aetiology And Prevention

In 1982 there was a small outbreak of PD among Californian heroin addicts taking what was thought to be a methadone substitute, but due to a mistake in synthesis turned out to be a piperidine derivative MPTP (1-methyl-4-phenyl-1,2,3,6-tetra hydro-pyridine). By any route, even cutaneous or inspired, this causes a specific degeneration of nigral DA neurons in humans and primates but not in rodents, which may indicate some link with melanin (not found in rodents). MPTP itself is not the active factor but requires deamination by mitochondrial MAOB to a charged pyridium MPP+ which is taken up specifically by DA neurons. MAOB inhibitors such as selegiline prevent MPTP-induced PD in primates. The production of MPP+ generates free radicals as does the oxidation of DA itself. Free radicals and peroxides are highly reactive substances and can damage DNA, membrane lipid and cell protein and initiate lipid peroxidation to destroy all membranes. Hydrogen peroxide (H2O2) can actually be produced by...

Cordia dichotoma Forst f

Cordia Dichotoma Forst

Anti-inflammatory properties One might set the hypothesis that the antiinflammatory property is on the account of flavonoids, flavonols, quinones or other phenolic compounds, which are known to inhibit the enzymatic activity of lipo-oxygenase, cyclo-oxygenase, and to scavenge free radicals. Note that the fruit of Cordia myxa inhibits acetic acid-induced colitis in rats via antioxidant effects (Al-Awadi FM et al, 2001). Artemetin, or characterized from Cordia verbenacea DC. protects rats against carrageenan-induced paw edema (102.6 mg Kg-153.9 mg Kg), similar to calcium phenylbutazone (50 mg Kg Sertie JA etal., 1990). Oral administration of a lyophilized extract of leaves of Cordia verbenacea DC. (1.24 mg Kg) inhibits nystatin-induced edema in rodent. Topically, this extract (0.09 mg ear

Health Supplement Alert Melatonin

Melatonin is a hormone produced by the pineal gland in the brain. The use of melatonin obtained from animal pineal tissue is not recommended because of the risk of contamination. The synthetic form of melatonin does not carry this risk. However, melatonin is an over-the-counter dietary supplement and has not been evaluated for safety, effectiveness, and purity by the FDA. All of the potential risks and benefits may not be known. Supplements should be purchased from a reliable source to minimize the risk of contamination. Melatonin has been used in treating insomnia, overcoming jet lag, improving the effectiveness of the immune system, and as an antioxidant. The most significant use is for the short-term treatment of insomnia at low doses. Individuals wishing to use melatonin should consult with their primary health care provider or a pharmacist before using the supplement. Possible adverse reactions include headache and depression. Drowsiness may occur within 30 minutes after taking...

Glucocorticoids and inhibitors of their biosynthesis as antitumor agents

Antitumor Agents

Adrenal tissue is capable of metabolizing mitotane by action of a novel, non-steroidogenic P450-type enzyme that catalyzes hydroxylation at the position adjacent to the two chlorine atoms. Subsequent dehydrohalogenation of this intermediate leads to a highly electrophilic acyl chloride, which has been shown to react with proteins, leading to direct necrosis and atrophy of the adrenal cortex and hence inhibition of glucocorticoid synthesis (Fig. 3.28). Another possible mechanism is oxidative damage through the production of free radicals.50

Mechanisms of Action of Sunscreens

It has been suggested that sunscreens augment the defense mechanism against oxida-tive damage by UV-generated free radicals. This defense mechanism is mediated by thio-redoxin reductase in the human keratocytes, which reduces superoxide anion radicals through hydrogen peroxide to water (295). However, the oxygen radicals concentrations generated by UVA and UVB radiations, even below the minimal erythemal dose, are high enough to cause considerable deactivation of thioredoxin reductase. Sunscreens have been shown to protect the thioredoxin reductase against both UVA and UVB in human skin of types I and II. The same sunscreen, however,

Photochemotherapy and fumaric acid

Fumaric acid is used as an antioxidant, in small amounts, in the food industry. With increasing dosages, it is prescribed as therapy in cases of psoriasis (several hundred milligrams daily) leukopenia and lymphopenia may occur as adverse reactions. There is no information about effects on the unborn. However, one of the current authors (C.S.) has documented data on 15 pregnancies treated during the first trimester for psoriasis with numeric acid. No embryotoxic or teratogenic effects were found (there was one spontaneous abortion and one stillbirth).

Ilexpubescens Hook

Antioxidant antiradical properties Hyperoside, rutoside and chlorogenic acid characterized from Ilex aquifolium L. inhibit non-enzymatic lipid peroxydation in model membrane (Muller K etal., 1998). The intraperitonneal injection of an aqueous extract of Ilexparaguariensis inhibits dose-dependently the oxidation of low density lipoproteins (Gugliucci A etal., 1995). The same aqueous extract given to healthy humans who fasted, inhibits copper-induced autoxidation of low density lipoproteins in the whole plasma (Guggliucci A, 1996). This aqueous extract inhibits the contraction caused by methoxamine in a mesenteric arterial bed, and this effect is reversed by N-(G)-nitro-L-arginine methyl ester suggesting the involvement of nitrous oxide of endothelial reserve (Mucillo-Baisch AL etal., 1998).

Chromium And Chromium Picolinate

Effects Chromium assists in the breakdown and distribution of proteins and carbohydrates in the body. It is also essential for the production of an enzyme-like substance called Glucose Tolerance Factor or GTF (chromium combined with nicotinic acid and amino acids), which aids in the making and proper utilization of insulin this insulin, in turn, takes carbohydrates from the blood and gets them to the brain cells, which use them for energy. It is believed that sufficient amounts keep the blood sugar on a consistent level, preventing mood swings, depression, and adultonset diabetes, and providing energy throughout the day. Chromium picolinate is a scientifically developed form which appears to be more efficient than regular chromium it may also have a mild muscle-building effect on people with a regular exercise program. Chromium picolinate, as well as chromium polynicotinate and chromium chloride, can inhibit sugar-induced high blood pressure. The picolinate and polynicotinate forms...

Biological Activity of Ginkgo

Abstract The extract of Ginkgo biloba (Egb) contains more than 60 active substances with a high bioavailability. EGb has extensive protective effects on the central nervous system and cerebrovascular system. As neuroprotective agent it eliminates free radicals, acts as an antioxidant and a free-radical scavenger, reduces lipid peroxidation, and is a membrane stabilizer and an inhibitor of platelet-activating factor via the terpene ginkgolide. The anti-ischemic neuropro-tective effects of Egb have been proved in cerebral and spinal cord ischemic models in animals, the action possibly being related to a functional state of mitochondria and apoptosis. However, high-quality and large-scale randomized controlled trials are needed to test its efficacy for the treatment of human stroke.

Mosquito Transcriptome and Proteome

Oxidative stress (Kumar et al. 2003). The difference between genetic lines was manifested after an uninfected bloodmeal, with little additional effect of malaria parasite infection. This is reminiscent of the increased encapsulation of negatively charged beads after a normal bloodmeal (Chun et al. 1995). The induced gene set was enriched for genes of the mitochondrial genome, particularly those involved in mitochondrial respiration, and several nuclear genes including thioredoxin reductase, mitochondrial thioredoxin, and xanthine dehydrogenase. Basal expression of catalase, a gene involved in the clearance of oxidative free radicals, is higher in the susceptible than the resistant line. The catalase gene is near the Pen3 QTL involved in parasite encapsulation, which was a minor locus for P cynomolgi B but a major effect locus for P. cynomolgi Ceylon.

Photosensitized Reactions

Any photochemical process in which there is a transfer of reactivity to a species other than that absorbing the radiation initially is called a photosensitization reaction. As a result of the long lifetime and the biradical nature with unpaired electron spins, the excited triplet states can mediate photosensitized reactions, the most common of which are photosensitized oxidations. Due to the triplet spin nature of its ground state, oxygen is spin matched with the drug triplet state and also is a very good scavenger of free radicals. These characteristics lead to two distinct mechanisms of photo-oxidation, as shown in Scheme 2.1 using AH to refer to an oxidizable substrate. This sequence may be thought of as a chain reaction because the radical activity is continually transferred and kept alive. Except in very unusual structures, free radicals are considered high reactivity species, but a suitable donor or acceptor in the near vicinity is needed. Secondary alcohols are examples of...

Approaches To Stabilization Of Formulations Against Photodegradation

When photoreactions proceed through a type I or type II photosensitization mechanism, the possibility of adding quenchers to the formulation can be considered. If they can be clearly shown to be nontoxic and not to affect the therapeutic action, this is perhaps an option. The major contenders would be substances such as ascorbic acid, a-tocopherol, and BHT, which are capable of acting as free radical scavengers and weak singlet oxygen quenchers. They are already in use as food additive antioxidants. Beta-carotene is the only major singlet oxygen quencher that may be regarded as a possible food additive, but the trace concentration that can be used may not be effective. In view of the present regulatory environment, the use of these and other quenchers would involve a considerable amount of development work.

Active Forms Of Oxygen And Oxidant Species

As noted previously, formation of free radicals or singlet oxygen is very often accompanied by the generation of various other short-lived species (such as hydroxyl radicals, superoxide radicals, and peroxyl radicals) that, together with singlet oxygen, are termed reactive oxygen species (Pryor, 1986). For example, superoxide radicals can be generated following photoionization (Equation 2.4) from singlet oxygen by electron transfer between O2 and the ground state sensitizer (Equation 2.18) or the appropriate substrates (Equation 2.19). In some cases, the subsequent reactions may result in formation of toxic hydrogen peroxide (Equation 2.20), which in turn decomposes to produce hydroxyl radicals (Equation 2.21) (Proctor and Reynolds, 1984).

In vivo properties of putative aberrant oxidative metabolites of 5ht and da

Intracerebroventricular injections of T-4,5-D into rat brain have been claimed to evoke long-lasting decreases in 5-HT levels in the hippocampus, striatum, and cortex reduced activity of tryptophan hydroxylase (Chen et al. 1992) and degeneration of nerve terminals (Crino et al. 1989). 7-S-Glu-T-4,5-D is also lethal (median lethal dose (LD50) 21 g) when administered into mouse brain, evoking extreme excitation and hyperactivity for about 30 minutes (Wong et al. 1993). During this period, 7- -Glu-T-4,5-D evokes statistically significant declines of whole brain levels of norepinephrine, DA, and 5-HT and elevation of the metabolites of these neurotransmitters (Wong et al. 1993). This might suggest that 7-S-Glu-T-4,5-D potentiates the release and elevated turnover of the monoamines although its influence on the release of other neurotransmitters, especially glutamate, remains to be determined. 7-S-Glu-T-4,5-D also redox cycles in the presence of cellular antioxidants reductants and...

Vitamin E Metabolic Modulation in Plants

Abstract Tocopherols, the lipid-soluble antioxidants known collectively as vitamin E, are synthesized only by photosynthetic organisms. These compounds play vital roles in human nutrition and health. During the past decade, the genes involved in the vitamin E synthesis pathway in plants have been isolated. Therefore, it is becoming important to manipulate these vitamin E synthesis genes to improve vitamin E content for human needs by metabolic engineering in plants. In this chapter, we summarize recent progress in the metabolic engineering of vitamin E in plants and put forward the prospect of altering vitamin E metabolic flux in the future.

Effects of longterm exposure to cannabis

Studies of the effects of cannabinoids on neurons in vitro have also yielded inconsistent results. Exposure of rat cortical neurons to THC shortened their survival twice as many cells were dead after exposure to THC 5 imol l for 2 h than in control cultures (51E). Concentrations of THC as low as 0.1 mol l had a significant effect. The effects of THC were accompanied by release of cytochrome c, activation of caspase-3, and DNA fragmentation, suggesting an apoptotic mechanism. All of the effects of THC could be blocked by the antagonist AM-251 or by pertussis toxin, suggesting that they were mediated through CB1 receptors. Toxic effects of THC have also been reported in hippocampal neurons in culture, with 50 cell death after exposure to THC 10 mol l for 2 h or 1 mol l for 5 days (52E). The antagonist rimonabant blocked these effects, but pertussis toxin did not. The authors proposed a toxic mechanism involving arachidonic acid release and the formation of free radicals. On the other...

Cymbopogon citratus DC Stapf

Antitumor properties There is an expanding body of evidence to suggest that citral prevents the formation of tumors. Lemon Grass oil protects 344 male Fischer rats partially hepatectomized against diethylnitrosamine-induced (intraperitoneal doses of 100 mg Kg body weight) early phase hepatocarcinogenesis (Puatanachokchai R et al., 2001). Note that citral (3, 7-dimethyl-2, 6-octadienal) isolated from a methanol extract of lemon-grass induces glutathione S-transferase activity (that detoxifies polycyclic aromatic hydrocarbons) in rat normal liver epithelial cell-line, RL34 cells cultured in vitro (NakamuraY et al, 2003). Extracts of lemon grass significantly inhibit the formation of aberrant crypt foci in the colon mucosa, inhibits fecal p-glucuronidase competitively and displays antioxidant property (Suaeyun R etal., 1997).

The Role of Oxidative Stress in MDMA Neurotoxicity

Free radicals are highly reactive chemicals that contain one or more unpaired electrons. Free radicals can damage neural molecules through reactions called reduction and oxidation and thereby alter the ability of these molecules to carry out their normal cellular function. Neurotoxic regimens of MDMA increase oxidative stress in the brain. In this chapter, the term oxidative stress is used to refer to both the increase in reactive chemicals, including free radicals, and the burden they place on cellular functioning. There is strong evidence that oxidative stress plays a part in MDMA neurotoxicity. Antioxidants are substances that inactivate free radicals the antioxidants ascorbate and cysteine each reduce MDMA neurotoxicity in rats without altering levels of MDMA or MDMA-stimulated dopamine release, which suggests that the nontoxic effects of MDMA are not being altered by the addition of antioxidants (Schmidt and Kehne 1990 Gudelsky 1996). The free radical scavenger...

Traditional Medicine for Memory Enhancement

Abstract In traditional practices of medicine, numerous plants have been used to alleviate memory impairment both in healthy individuals and those with disease states which are now recognised as specific cognitive disorders such as Alzheimer's disease (AD). An ethnopharmacological approach has provided leads to identify plants and their compounds that may have potential to modulate cognitive abilities by different modes of action. A variety of therapeutic targets have been identified as relevant in the treatment of cognitive disorders, including modulation of the cholinergic system, which may be achieved by the inhibition of acetyl-cholinesterase (AChE), and neuroprotection against glutamate-induced overstimulation of N-methyl-d-aspartate (NMDA) receptors, by the use of NMDA receptor modulators. Other activities considered to be relevant in the alleviation of cognitive impairment include anti-inflammatory, antioxidant and estrogenic activities. Two of the currently licensed drugs used...

Janus Carcinogens and Mutagens

Fahrig 90 showed that three substances, testosterone, p-estradiol, and diethyl-stilbestrol, were antimutagens and co-recombinogens in yeast in the absence of S9 but became co-mutagenic and anti-recombinogenic in the presence of rat liver S9. Also, vanillin, which was antimutagenic in mice in vivo, was co-mutagenic in yeast in vitro in the absence of S9. The antioxidant ascorbic acid, which is not mutagenic in the Drosophila wing spot test, has been reported to be clastogenic in mammalian cells 91, 92 . Indeed, many authors reporting on the antimutagenicity of a substance, failed to cite articles showing the mutagenicity and or carcinogenicity of the same substance. It is evident from available literature searches that the majority of these protective substances have not been tested adequately, or tested at all, for mutagenicity or carcinogenicity.

Quality Efficacy and Safety Considerations

For example, flavonoids exhibit a range of biological activities and have the ability to modulate several enzymes or cell receptors, mainly as a result of their antioxidant properties. By comparison, synthetic drugs usually contain single chemical entities so that drug-drug interactions are less likely 61 . This highlights the need to identify and purify active components from medicinal plant preparations as the potential for adverse interactions with purified compounds is less likely.

Radical Reactions in Combinatorial Chemistry

Radical Cyclizations

Organic synthesis is dominated by polar transformations, in which an electron-rich center reacts with an electron-deficient center. By contrast, homolytic processes involving organic radicals were largely unexploited for many years. The general belief was that such ''free radicals'' would be undisciplined in their reactions, and prone to undesirable pathways such as premature radical-radical recombination or hydrogen atom abstraction from the solvent. Even under successful chain-propagating conditions, the chemistry seemed best suited to polymerization. More recently, a deeper understanding of the kinetics of radical reactions has enabled 1 the orchestration of a complicated series of elementary steps, and there is now a vast number of synthetically useful radical reactions which are complementary to traditional polar processes. For example, the reaction conditions are relatively mild, avoiding strongly acidic or basic reagents, and many functional groups are tolerated without...

Retinol Vitamin A Family

Carotenes are promoted commercially for their antioxidant activity rather than as a source of the retinol group. Nevertheless, the carotenes are the source of the vitamin in yellow vegetables. There are many carotenes, of which three are shown in Fig. 8.2. Only j3-car-otene is symmetrical (note the dashed line)

Long Term Serotonergic Changes with MDMA

The term neurotoxicity is more difficult to define. Although no universal definition exists, most definitions are broad enough to encompass both short-term alcohol-induced headaches and the permanent nerve cell damage caused by the drug MPTP. A more useful approach to the question of whether MDMA is neurotoxic is to describe the nature and mechanisms of action of the long-term changes it can cause. Using this approach, it becomes evident that some neurotoxic MDMA regimens cause both changes in the serotonin-containing nerve cells and acute damage to the brain by free radicals (reactive chemicals that can damage cells) and thereby precipitate loss of nerve cell axons. This suggests that MDMA neurotoxicity is a type of drug-induced damage, even though the consequences of this damage are unknown.

Radiosensitizing Agents

Misonidazole and pimonidazole work, at least in vitro, by virtue of their high electron affinity. This induces the formation of free radicals and depletes radioprotective thiols, thereby sensitizing hypoxic cells to the cytotoxic effects of ionizing radiation. This allows single-strand breaks in DNA to occur, with subsequent inhibition of DNA synthesis followed by cell death. However, despite the promising in vitro results, the combination of misonidazole and radiation in several clinical trials (including a number of Phase III trials) since 1978 has failed to demonstrate improved survival. Furthermore, the clinical usefulness of misonidazole and a close analog (desmethylmisonidazole) was limited by severe but reversible toxicities, including nausea and vomiting and, more seriously, neurotoxicity (peripheral neuropathy).

Neuroprotective Herbs for Stroke

Abstract In recent years, many attempts have been made to document research data from extracts of composite formulas, single herbs, or single compounds from traditional Eastern medicine (TEM) herbs, according to orthodox pharmacological actions. Basic and clinical research in TEM constitutes an abundant source of new drug discovery and development with the integration of TEM and Western pharmacology. This article reviews herbs that have been documented to have a neuropro-tective effect in in vitro and in vivo ischemic model systems and the neuroprotective compounds isolated from them. The neuroprotective mechanisms of herbs and single compounds relevant to the treatment of brain ischemia, including antioxidant, antiexcitotoxic, and anti-inflammatory effects were also discussed. This chapter reviews herbs and prescriptions that have been screened for neuroprotective effects in in vitro and in vivo ischemic model systems and the neu-roprotective compounds isolated from them....

Current and Future Trends

Alternative approaches for photodamage repair and protection is an emerging trend in sun protection. Antioxidants (particularly vitamin E) are common ingredients in commercially available sunscreens. It has been previously shown that topical application of vitamin E inhibits UVR-induced cellular damage, edema, and erythema (317). In the past few years, there has been rising interest in scientific research to prove the efficacy of an-tioxidants as chemopreventive agents (318, 319). Recent work demonstrated evidence of DNA photoprotection of a-tocopherol (a vitamin E compound) (317). I n 2001, an oral antioxidant (astaxanthin) was promoted as sun protectant pill (320). The FDA approved the marketing of astaxanthin as dietary supplement in 1999, but the product did not undergo the review for sun protection claims. Astaxan-thin is a carotenoid obtained from micro algae and is over 500 times more potent antioxidant than vitamin E. Other natural products that gained considerable attention...

Biological Activities of Kinetin

Abstract Kinetin (N6-furfuryladenine) is a cytokinin growth factor with several biological effects observed for human cells and fruit flies. It was given the name kinetin because of its ability to induce cell division. Kinetin is often used in plant cell and tissue culture for induction of callus formation (in conjunction with auxin) and to regenerate shoots from callus (with lower auxin concentration). Kinetin exists naturally in the DNA of almost all organisms tested so far, including human cells, and various plants. The mechanism of kinetin synthesis in DNA is thought to be via the production of furfural, an oxidative damage product of DNA deoxyribose, and it is quenched by the adenine base converting it into N6-furfuryladenine. Since 1994 kinetin has been thoroughly tested for its powerful antiaging effects in human skin cells and other systems. At present, kinetin is one of the most widely used components in numerous skin care cosmetics and cosmeceuticals. There are some reports...

Longterm Effects Of Mdma 731 Long Term Effects of MDMA on 5HT Neurons

The findings in Table 7.2 have been replicated by many investigators, and the spectrum of decrements produced by MDMA administration is typically described as 5-HT neurotoxicity. Possible mechanisms underlying MDMA-induced 5-HT deficits are not completely understood, but evidence suggests the involvement of free radicals, oxidative damage, and metabolic stress.75-77 As noted above, there are increasing data to support a role for toxic MDMA metabolites in mediating the long-term serotonergic effects of the drug.60,62 Most studies examining MDMA neurotoxicity in rats have employed intraperitoneal (i.p.) or subcutaneous (s.c.) injections of 10 mg kg or higher, either as single or repeated treatments. Such MDMA dosing regimens are known to produce significant hyperthermia, which exacerbates 5-HT deficits.78,79

Cannabinoids effects on vomiting and nausea in animal models

Smoking marijuana may represent a more efficient and rapid route of administration. However, it is also possible that as marijuana contains over 60 other compounds, some of these additional consitutents may contribute to the anti-emetic anti-nausea effect. Another major cannabinoid found in marijuana is cannabidiol (CBD) however, unlike A9-THC, CBD does not produce psy-chomimetic effects 61 . CBD, unlike A9-THC, does not bind to the known cannabinoid receptors. It may act by blocking the reuptake of anandamide (an endogenous cannabinoid), or by inhibiting enzymatic hydrolysis of anan-damide, or bind with some as-yet-unknown cannabinoid receptor 61-63 . In mice, CBD is a highly effective anti-inflammatory agent 63 , as well as a neu-roprotective antioxidant 64 . In shrews, CBD inhibits cisplatin-induced 32 and lithium-induced 31 emesis and in rats CBD inhibits nausea 38 . These effects are described more fully below.

The Beginning

Drug abuse has been part of our society for centuries, but the technology to test body fluids for drugs has only been available for less than 50 yr. Testing for illicit drugs first began in Vietnam (1). In the late 1960s, an unusually large number of soldiers began returning home from Southeast Asia as heroin addicts. Identifying these GIs proved difficult. The unpopularity of the Vietnam War was already a public relations disaster for the Nixon administration, and sending our soldiers home as heroin addicts was another war tragedy that the Administration did not want. White House staffers began to look for tools that could be used to rapidly screen thousands of GIs before they returned to the United States. The search ended in 1970, when SYVA Company, a small research organization located in Palo Alto, California, developed a rapid test system capable of detecting opiates in urine. The system used an innovative homogeneous methodology based on the tumbling action of free radicals in...

Bilberry

It is used in Europe to treat varicose veins, problems with blood circulation to the brain, and a variety of eye problems, including night blindness, photophobia, glaucoma, diabetic retinopathy, and in combination with vitamin E cortical cataracts. Also used as an antiseptic, astringent, and antidiarrhea medication. Eating the fresh berries can reportedly regulate bowel action, stimulate the appetite, and reduce intestinal gas. As a tea, it is said to treat coughs, vomiting, stomach cramps, and catarrhal enteritis.

Radioactivity

Malignancies have also been linked to exposure to a or p particles (and y- or X-rays see Section 1.6.2.5 ), which are known to damage DNA by fragmentation through the formation of free radicals. A link between nuclear fallout and cancer was firmly established after atomic bombs were dropped on the cities of Hiroshima and Nagasaki, Japan, in 1945 at the end of World War II. It has also been postulated that children living close to nuclear power stations are at increased risk for developing certain forms of leukemia as well as brain tumors, although statistical analyses of these data remain controversial. However, the risk of escape of radioactive materials from nuclear reactors was highlighted by the Chernobyl incident in the Ukrainian republic of the Union of Soviet Socialist Republics in 1986. The accident caused widespread contamination of the food chain and led to a variety of different cancers in populations exposed to the radiation. It is also known that a buildup of radon gas...

Radiotherapy

A significant proportion of tumor cells are hypoxic (i.e., have a low oxygen level) and are thus less sensitive to damage by irradiation, which works through the formation of DNA-damaging oxygen-free radicals. Therefore, prior to and during radiation therapy, oxygen is sometimes administered to sensitize the tumor cells. In addition, radiosensitizing drugs such as metronidazole (normally used as an anti-protozoal antibacterial agent) have been coadministered experimentally prior to treatment in an attempt to improve therapeutic outcomes (Structure 1.2). However, such agents can also sensitize healthy tissues thus leading to no net improvement in therapeutic index.

Dandelion

Effects A good source of lecithin and choline, both of which are beneficial to memory, plus the antioxidant carotenoids lutein and violaxanthin. It may be helpful in treating constipation, fever, gout, hepatitis, insomnia, stiff joints, liver disorders, and chronic rheumatism.

Summary

Hypothetical model of the mechanism of MDMA-induced 5-HT neurotoxicity. The convergence of oxidative stress and energetic stress in the mechanism of MDMA neurotoxicity is depicted in which (1) MDMA (or a toxic metabolite)-induced activation of the 5-HT transporter facilitates free radical formation and energy depletion which act in concert to (2) promote mitochondrial impairment and (3) further generate free radicals and the cellular toxicity associated with these processes. Fig. 3. Hypothetical model of the mechanism of MDMA-induced 5-HT neurotoxicity. The convergence of oxidative stress and energetic stress in the mechanism of MDMA neurotoxicity is depicted in which (1) MDMA (or a toxic metabolite)-induced activation of the 5-HT transporter facilitates free radical formation and energy depletion which act in concert to (2) promote mitochondrial impairment and (3) further generate free radicals and the cellular toxicity associated with these processes.