Cognitive Enhancers: Choline and Piracetam
Anticancer Effects of Curcumin Profound effects of combining choline and piracetam on memory enhancement and cholinergic function in aged rats
Bartus RT; Dean RL 3d; Sherman KA; Friedman E; Beer B
Vitamin B12 improves cognitive disturbance in rodents fed a choline-deficient diet
Sasaki H; Matsuzaki Y; Meguro K; Ikarashi Y; Maruyama Y; Yamaguchi S; Sekizawa K
The effect of vitamin B12 on learning disturbance was tested in rats. Rats were fed a choline-enriched, choline-deficient, and choline-deficient diet with vitamin B12. Concentrations of acetylcholine in the brain were significantly lower in rats fed a choline-deficient diet than rats fed a choline-enriched diet. Passive avoidance learning shows that rats on a choline-deficient diet showed significantly impaired learning compared to rats on a choline-enriched diet. However, there was no significant difference of acetylcholine in the brain or in the passive avoidance learning between rats fed a choline-enriched and a choline-deficient with vitamin B12 diet. We, therefore, suggest that vitamin B12 potentiates learning in an acetylcholine-deprived brain.
Cognitive Enhancers: Gingko Biloba
Proof of efficacy of the ginkgo biloba special extract EGb 761 in outpatients suffering from mild to moderate primary degenerative dementia of the Alzheimer type or multi-infarct dementia
Kanowski S.; Herrmann W.M.; Stephan K.; Wierich W.; Horr R.
The efficacy of the ginkgo biloba special extract EGb 761 in outpatients with presenile and senile primary degenerative dementia of the Alzheimer type (DAT) and multi-infarct dementia (MID) according to DSM-III-R was investigated in a prospective, randomized, double-blind, placebo-controlled, multi-center study. After a 4-week run-in period, 216 patients were included in the randomized 24-week treatment period. These received either a daily oral dose of 240 mg EGb 761 or placebo. In accordance with the recommended multi-dimensional evaluation approach, three primary variables were chosen: the Clinical Global Impressions (CGI Item 2) for psychopathological assessment, the Syndrom-Kurztest (SKT) for the assessment of the patient's attention and memory, and the Nurnberger Alters-Beobachtungsskala (NAB) for behavioral assessment of activities of daily life. Clinical efficacy was assessed by means of a responder analysis, with therapy response being defined as response in at least two of the three primary variables. The data from the 156 patients who completed the study in accordance with the study protocol were taken into account in the confirmatory analysis of valid cases. The frequency of therapy responders in the two treatment groups differed significantly in favor of EGb 761, with p < 0.005 in Fisher's Exact Test. The intent-to-treat analysis of 205 patients led to similar efficacy results. Thus, the clinical efficacy of the ginkgo biloba special extract EGb 761 in dementia of the Alzheimer type and multi-infarct dementia was confirmed. The investigational drug was found to be well tolerated.
Central nervous system effects of Ginkgo biloba, a plant extract
Itil T.M.; Eralp E.; Tsambis E.; Itil K.Z.; Stein U.
Extracts of Ginkgo biloba (EGb) are among the most prescribed drugs in France and Germany. EGb is claimed to be effective in peripheral arterial disorders and in 'cerebral insufficiency.' The mechanism of action is not yet well understood. Three of the ingredients of the extract have been isolated and found to be pharmacologically active, but which one alone or in combination is responsible for clinical effects is unknown. The recommended daily dose (3 x 40 mg extract) is based more on empirical data than on clinical dose-finding studies. However, despite these, according to double-blind, placebo-controlled clinical trials, EGb has therapeutic effects, at least, on the diagnostic entity of 'cerebral insufficiency,' which is used in Europe as synonymous with early dementia. To determine whether EGb has significant pharmacological effects on the human brain, a pharmacodynamic study was conducted using the Quantitative Pharmacoelectroencephalogram (QPEEG [R]) method. It was established that the pharmacological effects (based on a predetermined 7.5-13.0-Hz alpha frequency band in a computer-analyzed electroencephalogram: CEEG [R]) of EGb on the central nervous system (CNS) are significantly different than placebo, and the high and low doses could be discriminated from each other. The 120-mg, but particularly the 240-mg, single doses showed the most consistent CNS effects with an earlier onset (1 h) and longer duration (7 h). Furthermore, it was established that the electrophysiological effects of EGb in CNS are similar to those of well- known cognitive activators such as 'nootropics' as well as tacrine, the only marketed 'antidementia' drug currently available in the United States.
Structural changes in the hippocampi of three inbred mouse strains
Barkats M.; Venault P.; Christen Y.; Cohen-Salmon C. Genetique, Neurogen./Comportement, URA 1294 CNRS, Universite de Paris V-Rene Descartes, 45 rue des Saints-Peres, 75270 Paris Cedex 16 France LIFE SCI. (USA) , 1995, 56/4 (213-222)
Female mice of the inbred strains C57BL/6J, BALB/cJ and DBA/2J were used to determine the possible existence of a genetically-based differential susceptibility to the effects of treatment with an extract of Ginkgo biloba (Gb 761). Timm's silver-sulphide staining method was used to visualize and determine changes in the areas of the hippocampal structures of aged subjects, and more specifically on the projection fields of the messy fibers which appear to decrease as a function of ageing. Experiments were begun when the animals were 15 months old. Treated animals received EGb 761 (50 mg/kg/day, p.o.) for 7 months in their drinking water. Inter-strain differences existed for the areas of the whole regio inferior, stratum pyramidale, stratum lacunosum moleculare and hilus (CA4) and for the projection field of intra- and infrapyramidal mossy fibers (iipMF) in the CA3 region of the hippocampus. Chronic treatment with EGb 761 significantly increased the projection field of iipMF and significantly reduced the area of the stratum radiatum, as compared with control mice. No differential sensitivity to EGb 761 existed among the mouse strains tested. Antioxydant properties of EGb 761 may explain its neuroprotective and neurotrophic actions on the hippocampus, and might explain certain improvements in memory and other cognitive functions in both humans and experimental animals.
Conjugated Linoleic Acid (CLA)
Conjugated linoleic acid: A powerful anticarcinogen from animal fat sources
Ip C.; Scimeca J.A.; Thompson H.J.
Conjugated linoleic acid (CLA) is a mixture of positional and geometric isomers of linoleic acid, which is found preferentially in dairy products and meat. Preliminary studies indicate that CLA is a powerful anticarcinogen in the rat mammary tumor model with an effective range of 0.1-1% in the diet. This protective effect of CLA is noted even when exposure is limited to the time of weaning to carcinogen administration. The timing of this treatment corresponds to maturation of the mammary gland to the adult stage, suggesting that CLA may have a direct effect in reducing the cancer risk of the target organ. Of the vast number of naturally occurring substances that have been demonstrated to have anticarcinogenic activity in experimental models, all but a handful of them are of plant origin. Conjugated linoleic acid is unique because it is present in food from animal sources, and its anticancer efficacy is expressed at concentrations close to human consumption levels.
Conjugated linoleic acid and atherosclerosis in rabbits
Lee K.N.; Kritchevsky D.; Pariza M.W.
Conjugated linoleic acid (CLA) consists of a series of positional and geometric dienoic isomers of linoleic acid that occur naturally in foods. CLA exhibits antioxidant activity in vitro and in vivo. To assess the effect of CLA on atherosclerosis, 12 rabbits were fed a semi-synthetic diet containing 14% fat and 0.1% cholesterol for 22 weeks. For 6 of these rabbits, the diet was augmented with CLA (0.5 g CLA/rabbit per day). Blood samples were taken monthly for lipid analysis. By 12 weeks total and LDL cholesterol and triglycerides were markedly lower in the CLA-fed group. Interestingly, the LDL cholesterol to HDL cholesterol ratio and total cholesterol to HDL cholesterol ratio were significantly reduced in CLA-fed rabbits. Examination of the aortas of CLA-fed rabbits showed less atherosclerosis.
Conjugated linoleic acid (9,11- and 10,12-octadecadienoic acid) is produced in conventional but not germ-free rats fed linoleic acid
Chin S.F.; Storkson J.M.; Liu W.; Albright K.J.; Pariza M.W.
Conjugated linoleic acid (CLA) is an anticarcinogen in several model animal systems. Conjugated linoleic acid occurs naturally in food and is present at higher concentrations in products from ruminant animals. Given that certain rumen microorganisms produce CLA from free linoleic acid, we studied the effect of feeding free or esterified linoleic acid on tissue CLA concentrations using conventional and germ-free rats. Conventional rats were fed a 5% (wt/wt) corn oil control diet alone or supplemented with 5% free linoleic acid or 8.63% corn oil (equivalent to 5% linoleic acid in triglyceride). Germ-free rats were fed autoclavable nonpurified diet alone or supplemented with 5% free linoleic acid. Analyses of CLA concentrations were performed on lipids extracted from liver, lung, kidney, skeletal muscle and abdominal adipose tissue, and on liver phospholipid and neutral lipid fractions. Tissue CLA concentrations were higher in conventional rats fed free linoleic acid (the major isomers were cis-9, trans-11 and trans-9, cis-11) than in control animals. Conjugated linoleic acid concentrations in free linoleic acid-fed rats were maximal at 4 wk, and levels were 5-10 times higher than those of controls. Elevated CLA concentrations were also observed in liver phospholipid and neutral lipid fractions. In contrast, CLA concentrations in the tissues of germ-free rats were not affected by diet. Feeding the corn oil-fortified diet to conventional rats did not increase CLA concentration in the tissues. We conclude that the intestinal bacterial flora of rats is capable of converting free linoleic acid (but not linoleic acid esterified in triglycerides) to cis-9, trans-11 and trans-9, cis-11 CLA isomers.
Nitric oxide scavenging by curcuminoids
Sreejayan; Rao M.N.A., India
Because curcumin, a compound with anti-inflammatory and anticancer activity, inhibits induction of nitric oxide synthase in activated macrophages and has been shown to be a potent scavenger of free radicals we have investigated whether it can scavenge nitric oxide directly. Curcumin reduced the amount of nitrite formed by the reaction between oxygen and nitric oxide generated from sodium nitroprusside. Other related compounds, e.g. demethoxycurcumin, bisdemethoxycurcumin and diacetylcurcumin were as active as curcumin, indicating that the methoxy and the phenolic groups are not essential for the scavenging activity. The results indicate curcumin to be a scavenger of nitric oxide. Because this compound is implicated in inflammation and cancer, the therapeutic properties of curcumin against these conditions might be at least partly explained by its free-radical scavenging properties, including those toward nitric oxide.
Curcumin, an antioxidant and anti-tumor promoter, induces apoptosis in human leukemia cells
Kuo M.-L.; Huang T.-S.; Lin J.-K.
Curcumin, widely used as a spice and coloring agent in food, possesses potent antioxidant, anti-inflammatory and anti-tumor promoting activities. In the present study, curcumin was found to induce apoptotic cell death in promyelocytic leukemia HL-60 cells at concentrations as low as 3.5 microg/ml. The apoptosis-inducing activity of curcumin appeared in a dose- and time-dependent manner. Flow cytometric analysis showed that the hypodiploid DNA peak of propidium iodide-stained nuclei appeared at 4 h after 7 microg/ml curcumin treatment. The apoptosis-inducing activity of curcumin was not affected by cycloheximide, actinomycin D, EGTA, W; (calmodulin inhibitor), sodium orthovanadate, or genistein. By contrast, an endonuclease inhibitor ZnSO4 and proteinase inhibitor N-tosyl-L-lysine chloro-methyl ketone (TLCK) could markedly abrogate apoptosis induced by curcumin, whereas 12-O-tetradecanoylphorbol-13-acetate (TPA) had a partial effect. The antioxidants, N-acetyI-L-cysteine (NAC), L-ascorbic acid, alpha-tocopherol, catalase and superoxide dismutase, all effectively prevented curcumin-induced apoptosis. This result suggested that curcumin-induced cell death was mediated by reactive oxygen species. Immunoblot analysis showed that the level of the antiapoptotic protein Bcl-2 was decreased to 30% after 6 h treatment with curcumin, and was subsequently reduced to 20% by a further 6 h treatment. Furthermore, overexpression of bcl-2 in HL-60 cells resulted in a delay of curcumin-treated cells entering into apoptosis, suggesting that bcl-2 plays a crucial role in the early stage of curcumin-triggered apoptotic cell death.
Antimutagenic and anticarcinogenic activity of natural and synthetic curcuminoids
Anto R.J.; George J.; Dinesh Babu K.V.; Rajasekharan K.N.; Kuttan R.
Five synthetic curcuminoids and three natural curcuminoids were investigated for their antimutagenic and anti-promotional activity. The natural curcuminoids, curcumin I (diferuloylmethane), curcumin II (feruloyl-p-hydroxycinnamoylmethane) and curcumin III (bis-(p-hydroxycinnamoyl) methane) isolated from Curcuma longa were found to be potent inhibitors of mutagenesis and crotean oil-induced tumour promotion. Curcumin III produced 87.6% inhibition to 2-acetamidofluorene (2-AAF) induced mutagenesis, at a concentration of 100 microg/plate, curcumin II and curcumin I produced 70.5% and 68.3% inhibition at the same concentration. All the synthetic curcuminoids were found to inhibit 2-AAF-induced mutagenicity among which salicyl- and anisylcurcuminoids were the most active. Curcumin III was the most effective anti-promotor among natural curcuminoids. While 90% of the control animals were having papillomas on the 10th week of tumour initiation, only 10% of the curcumin III-treated animals, 20% of the curcumin II-treated animals, and 40% of the curcumin I-treated animals were having papillomas. Salicylcurcuminoid, which was causing no papillomas by the 10th week, was the most potent anti-carcinogen among the synthetic curcuminoids. Piperonal curcuminoid also exhibited anti-promotional activity.