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> Centrophenoxine Research, Clinical Studies
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Centrophenoxine Various Research

Gerontopsychological studies using NAI ('Nurnberger Alters-Inventar') on patients with organic psychosyndrome (DSM III, Category 1) treated with centrophenoxine in a double blind, comparative, randomized clinical trial

ARCH. GERONTOL. GERIATR. (Netherlands), 1989, 9/1 (17-30)

A double blind clinical trial was performed on 50 persons (25 men, 25 women) over the age 60 (average age: 77 years). They suffered from dementias of medium level (DSM III, Category 1, ICD No. 299), and had been residents in an old age home longer than 3 months at the start of the trial. The patients were treated first for 2 weeks by placebo tablets and their initial performance was recorded during this period by using the Nuremberg Gerontopsychological Inventory (NAI). This was then followed by a treatment for 8 weeks with the nootropic drug, centrophenoxine (CPH), the dose of which was 2 g/day distributed in 2 x 2 tablets of Helfergin500 (Promonta, Hamburg, FRG), or with placebo tablets of identical size, then the NAI test was repeated again. Verum or placebo treatment was selected randomly and the code was revealed only after having elaborated all the results of the trial. During the treatment period four drop-outs occurred for intercurrent diseases. Evaluation was based on a semi-quantitative, intra-individual comparison of the performance before and after treatment. The results obtained suggest that CPH treatment may be useful in dementias of medium level in quite old groups of patients, since 48% of the verum group displayed improvements in the memory functions against 28% of the placebo group. CPH seems to be a useful and harmless drug in the treatment and most probably also in prevention of dementias.

Clinical drug trials in Alzheimer's disease

ANN. NEW YORK ACAD. SCI. (USA), 1985, VOL. 444 (428-436)

This paper will review the drugs currently prescribed in the United States for the treatment of AD and consider a broad range of investigational drugs recently studied or currently under study in AD. Particular emphasis will be placed on recent trials with cholinergic compounds, neuropeptides, and nootropic drugs. Positive reports have appeared concerning the efficacy of the newer piracetam analogs in AD and multi-center studies with several of these drugs, as well as with CI-911, are currently underway. Any conclusion as to whether these drugs represent significant improvements over the extremely modest effects of piracetam must await the outcome of these studies. A dramatic therapeutic advance appears unlikely. Among other experimental drugs of interest in AD are 4-amino-pyridine and 3,4-diaminepyridine, compounds with multiple pharmacologic effects that facilitate oxidative metabolism; Active lipid, a compound designed to fluidize cell membranes; centrophenoxine, a stimulant also thought to deplete age-related lipofuscin accumulation; aluminum chelators, such as desferrioxamine; and alaproclate, a 5-HT reuptake inhibitor. In view of the emerging neurochemical evidence that AD involves multiple neurotransmitter systems, it may be that therapeutic strategies involving combination treatments or even an individualized 'cocktail' approach will be necessary to develop effective treatments for what may be the most tragic and dehumanizing of all mental disorders. Although clearly effective drugs have not yet been developed for treating the primary symptoms of AD, dramatic progress has been made in recent years in uncovering the neurochemical deficits in the disorder and, hence, in developing rational treatment strategies. If the pace of this progress continues, we may see the development of a truly effective compound for treating AD. Such a drug would be of inestimable personal and social value.

Centrophenoxine: Effects on aging mammalian brain

J. AM. GERIATR. SOC. (USA), 1978, 26/2 (74-81)

A study was made of the effects of centrophenoxine on the learning and memory of old mice. The results were correlated with changes in neuronal lipofuscin in the cerebral cortex and hippocampus. Old female mice (11-12 months) were treated with centrophenoxine for three months and their learning and memory were tested in a T-maze. The number of trials required to attain the criterion in the 20 treated old mice were compared with those for 20 untreated mice of the same age and for 20 younger untreated mice. The treated animals learned the task with significantly fewer trials, and also exhibited a reduction of neuronal lipofuscin pigment in both the cerebral cortex and the hippocampus. The changes in lipofuscin were demonstrated by study of the characteristic autofluorescence, and by histochemical and ultrastructural (electron microscope) observations.

Effect of centrophenoxine on the antioxidative enzymes in various regions of the aging rat brain

EXP. GERONTOL. (USA), 1983, 18/3 (185-197)

This study investigated the effect (in vivo) of centrophenoxine (Lucidril) on the activity of antioxidant enzymes (glutathione peroxidase GSH-PER, glutathione reductase GSSG-RED, superoxide dismutase SOD and catalase) in subcellular fractions from the regions of the brain (cerebrum, cerebellum and brain stem) of rats aged 6, 9, and 12 months. In all age groups, normal (control) activity of GSH-PER, GSSG-RED and SOD in the three brain regions was higher in the soluble fractions than in the particulate fractions. The three regions of the brain showed different levels of the enzyme activities. Enzymes in soluble fractions (except GSSD-RED in cerebrum of rats aged 12 months) did not change with age. In particulate fractions, however, the enzymes showed age-related changes: GSH-PER decreased with age in cerebellum and brain stem, but showed an age-related increase in cerebrum, GSSG-RED and SOD increased with age in all the three brain regions. Catalase activity in all the three brain regions remained unchanged in all age groups. Six week administration of centrophenoxine (once a day in doses of 80 mg/Kg and 120 mg/Kg) to the experimental animals produced increases in the activity of SOD, GSH-PER and GSSG-RED in particulate fractions from all the three brain regions. In the soluble fractions, however, only SOD and GSH-PER activity was increased. In vitro also centrophenoxine stimulated the activity of GSH-PER. A dosage of 80 mg/Kg produced greater changes than a 120 mg/Kg dosage. The drug had no effect on the activity of catalase. Centrophenoxine also reduced lipofuscin deposits (studied both biochemically and histochemically) thus indicating that the drug inhibited lipofuscin accumulation by elevating the activity of the antioxidant enzymes. The data suggest that alleviation of senescence by centrophenoxine may, at least, partly be due to activation by it of antioxidant enzymes.

A membrane hypothesis of aging

J. THEOR. BIOL. (ENGLAND), 1978, 75/2 (189-195)

Experimental data show that cell membranes become more rigid during aging. If this involves a decrease of resting potassium permeability, the intracellular potassium concentration will increase. Such an increase is beneficial for the maintenance of cell excitability, however, it represents a drawback for the nuclear functions, since the intracellular ionic strength may reach values even above 400 mEq kgsup -sup 1 cell water, where the chromatin becomes more condensed and the activity of DNA-dependent RNA-polymerase as well as other enzymes probably decreases. This 'membrane hypothesis' of aging may explain the decreased protein synthetic activity of old cells, especially of postmitotic ones. X-ray microanalysis has revealed that potassium concentrations significantly increase in the nucleus and cytoplasm of brain and liver cells of old rats. The chromatin of old nerve cells is more condensed than that of the young ones, the rates of nucleolar and nucleoplasmic RNA-synthesis are significantly lower in the old brain cells, and also the number of perichromatin granules decreases with age. A decrease of intracellular potassium content in brain cells of old rats can be brought about by phytohemagglutinin-P and centrophenoxine. This is accompanied by a sort of rejuvenation: the chromatin becomes decondensed, the rates of nucleolar and nucleoplasmic RNA-synthesis increase together with the number of perichromatin granules, the medium life-span and the learning capacity of the animals increase. These experimental results support the 'membrane hypothesis' of aging.

Age-dependence of free radical-induced oxidative damage in ischemic-reperfused rat heart

Archives of Gerontology and Geriatrics (Ireland), 1996, 22/3 (297-309)

Oxygen free radical-induced oxidative damage is involved in both aging and ischemia-reperfusion. The purpose of this study was to determine the aging-induced oxidative alterations in rat heart as well as the age-dependence of heart injury following ischemia-reperfusion. A comparative study was performed on young and old ischemic-reperfused rat hearts. Protein oxidation and the ascorbyl radical level in heart tissue were determined in order to characterize the oxidative stress. Comparing the control conditions, old hearts have 31% more oxidized proteins as measured by protein carbonyl content, and 18% lower ascorbyl radical level as determined by ESR, than young ones. The extent of increase of protein oxidation and ascorbyl free radical depletion induced by ischemia-reperfusion is less pronounced in the old hearts (7 and 8% respectively), as compared to the young ones (55 and 21% respectively). Pre-treatment with a free radical scavenger, such as centrophenoxine, diminished the ischemia-reperfusion injury in both young and old rat hearts.

Age-related decline in multiple unit action potentials of CA3 region of rat hippocampus: Correlation with lipid peroxidation and lipofuscin concentration and the effect of centrophenoxine

NEUROBIOL. AGING (USA), 1993, 14/4 (319-330)

Changes in lipid peroxidation, lipofuscin concentration, and multiple unit activity (MUA recorded in conscious animals) in the CA3 region were studied in the hippocampus of male Wistar rats aged 4, 8, 16, and 24 months. The lipid peroxidation and lipofuscin concentration were increased with age. The MUA, however, declined with age. Correlational analyses were performed for the four age groups to determine the relationship between the age-associated decline in MUA with the age-related alterations in lipid peroxidation and lipofuscin concentrations. The age-related increase in lipid peroxidation correlated positively with the age-associated increase in lipofuscin concentration. The age-related increases in lipid peroxidation and lipofuscin concentration correlated negatively with the changes in MUA. Since lipid peroxidation may affect neuronal electrophysiology, our data suggested that age-related increase in lipid peroxidation may contribute to an age-associated decline in neuronal electrical activity. Centrophenoxine effects were studied on the three above-mentioned age-associated changes in the hippocampus. The drug had no effect on all three parameters in 4- and 8-month-old rats. In 16- and 24-month-old rats, however, the drug significantly increased the MUA but concomitantly decreased lipofuscin concentration and lipid peroxidation. Correlational analyses of the data on MUA, lipid peroxidation and lipofuscin concentration from the centrophenoxine-treated animals showed that the drug-induced diminution in both lipofuscin and lipid peroxidation was significantly correlated with the drug-induced increase in MUA. The differential effect of the drug in younger (4-8 months) and older (16-24 months) animals indicated that the stimulation of MUA was clearly associated with concomitant decrease in lipid peroxidation and lipofuscin concentration.

Effects of centrophenoxine on body composition and some biochemical parameters of demented elderly people as revealed in a double-blind clinical trial

ARCH. GERONTOL. GERIATR. (Netherlands), 1990, 10/3 (239-251)

A double-blind clinical trial was performed on 50 persons (25 men, 25 women, average age 77 years) suffering from dementias of medium level (DSM III, Category 1, ICD No. 299). All subjects were residents in an old age home. The patients were treated first for 2 weeks by placebo tablets. During this period, body composition parameters were determined and these data served as controls. This was then followed by an 8-week-long treatment with the nootropic drug, centrophenoxine (CPH), 2 g/day distributed in 2 x 2 tablets of Helfergin500 (Promonta, Hamburg, FRG), or placebo tablets of identical size. After 8 weeks the laboratory tests were repeated again. The randomization code for verum or placebo treatment was revealed only after completing the trial. Four dropouts occurred during the treatment period. The total body water, extracellular water volume and exchangable Na+ were determined by means of radioisotope methods. Plasma volume (PV) was measured by indocyanine-green dilution test. Body weights were also recorded. From the above data further parameters could be calculated. Serum lipid data as well as several hormone levels were also checked in the blood samples. The main results were better performance in psychometric tests (Pek et al., 1989) and a significant increase of the average intracellular water content (2.2-2.5% by weight) in the verum-treated group. The rehydration of the intracellular mass due to CPH treatment is consistent with the OH. free radical scavenger properties of CPH and the predictions of the membrane hypothesis of aging.

On the role of intracellular physicochemistry in quantitative gene expression during aging and the effect of centrophenoxine. A review

ARCH. GERONTOL. GERIATR. (Netherlands), 1989, 9/3 (215-229)

The turnover of proteins in biological systems is due mostly to an ever-occurring damaging (cross-linking) effect of the OH. free radicals. The replacement of the damaged proteins requires a continuous gene expression. A key issue of experimental gerontology is why the gene expression maintains the fidelity but loses the speed during aging. The membrane hypothesis of aging (MHA) proposes a cellular mechanism based on the fact that the more compact cellular structures (e.g., membranes) are damaged faster than the more diluted ones (e.g., cytosol). In addition, the cell membrane is exposed also to the residual heat-induced damage deriving from a frequent discharge of its electric polarity. Therefore, one can assume that even an extremely small incompleteness of the replacement of the damaged membrane components per turnover cycle may result in an error accumulation, which may be responsible first for the inhibition of growth, then for aging of cells. In agreement with this hypothesis, neurons display a life-long, gradual loss of the passive potassium permeability of the cell membrane, resulting in a continuous dehydration of the intracellular mass, i.e., an increase of physical density. Theory and experimental models show that this latter process causes a slowing down of all enzyme functions including those realizing the gene expression and the elimination of the damaged components. Increase of the dry mass content of cells and tissues is an obligatory process for maturation; however, later on it leads to aging. The known nootropic effects of centrophenoxine (CPH) can be interpreted on the basis of the OH. radical scavenger properties of dimethylaminoethanol (DMAE) which is incorporated in the neuronal membranes of the brain in form of phosphatidyl-DMAE. The protective effects of CPH (and of similar, newly synthesized other drugs) on the membrane components can slow down the age-dependent deteriorations of the intracellular physicochemistry, in agreement with the predictions of the MHA.

Effect of centrophenoxine and BCE-001 treatment on lateral diffusion of proteins in the hepatocyte plasma membrane as revealed by fluorescence recovery after photobleaching in rat liver smears

EXP. GERONTOL. (USA), 1989, 24/4 (317-330)

The average lateral diffusion coefficient of proteins (D) in the cell membrane of hepatocytes has been measured in liver smears by fluorescence recovery after photobleaching (FRAP), based on the so-called peroxide-induced autofluorescence (PIAF) deriving from the oxidation of riboflavin bound to membrane proteins. It has been previously shown that D displays a significant negative linear age correlation. The in vivo effects of two drugs were tested on this parameter. Young (2.7 months) and old (24-26 months) male rats received centrophenoxine (CPH) or a new drug (BCE-001) by either intraperitoneal (i.p.) injection or per os through a gastric tube for 26 to 42 days. D was measured on a double-blind basis in the hepatocyte plasma membrane of treated and control groups. The CPH and BCE-001 treatments did not affect the value of D in the young rats. However, the latter drug increased their growth rate. An increase of D in old animals was induced by treatment with either drug. When the drug effects in old rats were compared, BCE-001 proved to be more efficient than CPH, and at the same time was able to significantly retard the age-dependent loss of body weight characteristic of these animals at the age of approximately 2 years. Our results are in good accord with the predictions of the membrane hypothesis of aging as regards the role of properly placed OH. free radical scavengers in the improvement of membrane and overall cell function.

Age-related change in the multiple unit acitvity of the rat brain parietal cortex and the effect of centrophenoxine

EXP. GERONTOL. (USA), 1988, 23/3 (161-174)

In this study, spontaneous multiple unit activity (MUA, action potentials derived simultaneously from a number of neurons in a given brain region) was recorded through electrodes chronically implanted in the parietal cerebral cortex of the rats of 1, 3, 6, 9, 12, and 26 months of age (cross-sectional study). Electrophysiological recordings were obtained from unrestrained conscious rats using standard techniques. The results indicated that multiple unit activity was decreased with aging (senescence). Maximum firing rate (MUA counts) was found at the age of 3 months. At 6 months of age, the MUA was decreased by about 30%, while during 6 to 12 months of age the activity seemed to remain unchanged. At 26 months of age the firing rate was, however, further decreased (about 40%). Centrophenoxine administration led to an increase in MUA in the rats of 12 and 26 months of age. The results, thus, further showed that centrophenoxine, a nootropic drug known for its antiaging effects in experimental animals as well as in humans, also manifested beneficial effects electrophysiologically. The data presented in this work are new and significant, since although age effects on gross electrophysiological signals (EEG, evoked potentials, etc.) are known, the aging changes in cellular level electrophysiological signals (action potentials) have not been generally studied particularly in conscious animals.

Studies on the effect of iron overload on rat cortex synaptosomal membranes

BIOCHIM. BIOPHYS. ACTA (NETHERLANDS), 1985, 820/2 (216-222)

Iron as ferrous ammonium sulfate was injected into the cerebral spinal fluid of rats. After three consecutive days of injection of 4 mumol of iron, the total iron content of brain cortex synaptosomes from the iron-treated animals was 2-fold higher than that from control animals receiving the saline vehicle only. Spin label studies of the synaptosomal membranes demonstrated that the lipid region of the membranes became more rigid and, in addition, the mobility of labeled SH groups of membrane proteins decreased after the iron treatment. The cholesterol content was significantly higher in iron-treated animals as compared to controls. Centrophenoxine pretreatment (100 mg/kg body weight daily for 6 weeks) diminished the iron effects. Synaptosomal membrane alterations observed after iron treatment were similar to changes observed previously during aging. This lends support to the notion that free-radical induced damage occurs in brain membranes with increasing age.

Alterations in the molecular weight distribution of proteins in rat brains synaptosomes during aging and centrophenoxine treatment of old rats

MECH. AGEING DEV. (IRELAND), 1984, 28/2-3 (171-176)

Properly prepared membrane proteins of brain synaptosomes of 2-, 12- and 24-month-old CFY female rats were filtrated on a Sepharose 2 B gel. The molecular weight distribution showed an age-dependence: there was a clear shift toward the higher molecular weights in the adult and old rats. The observed alterations reflect an increased cross-linking of the proteins during aging due most probably to the OH free radical damage of the cell components. Centrophenoxine treatment for 2 months reversed this phenomenon in the old animals: the high molecular weight fractions decreased and the lower ones increased in the treated animals as compared to the old, untreated rats. The results support the membrane hypothesis of aging and contribute to a better understanding of the biological effects of centrophenoxine.

Cytochemical interaction of nucleolus and cytoplasm in the Purkinje cells of senile white rats under the influence of centrophenoxine

EXP. GERONTOL. (USA), 1984, 19/4 (241-251)

Senile white rats were treated with centrophenoxine at a dosage of 100 mg/Kg body weight/day for 60 days intraperitoneally. Sections of variously fixed and embedded cerebella were studied cytochemically to note the effect of the drug on the senile Purkinje neurons. The nucleolus was found to be hyper-active, as evidenced by the processes of budding and extrusion. A frank regeneration of the Nissl patches along with an increase in alpha-esterase and decrease in the activity of acid phosphatase and simple esterase was noted in the Purkinje cells after 60 days' treatment. It is suggested that the drug exerts its positive effects by regenerating the general cytoplasm and by revitalizing the nucleocytoplasmic interactions in the senile Purkinje cells.

Centrophenoxine increases the rates of total and mRNA synthesis in the brain cortex of old rats: An explanation of its action in terms of the membrane hypothesis of aging

EXP. GERONTOL. (USA), 1984, 19/3 (171-178)

The rates of total and polyA sup +RNA (mRNA) synthesis were measured by radioisotope technique in the brain cortex of female CFY rats. There was practically no significant difference between the young (1.5 months) and adult (13 months) rats; however, the old group (26 months) displayed a considerable decrease of the rates of synthesis of both classes of RNA studied. Centrophenoxine treatment (100 mg per kg body weight per day, for 2 months) reversed this tendency, and increased significantly the synthesis rates of old rats almost to the adult level. The results are interpreted in terms of the membrane hypothesis of aging, attributing a free-radical scavenger function of the dimethylamino-ethanol incorporated into the nerve cell membrane from the centrophenoxine.

Alterations of the synaptosomal membrane 'microviscosity' in the brain cortex of rats during aging and centrophenoxine treatment


Synaptosomal and myelin fractions were isolated from the brain cortex of young, adult and old male CFY rats (2, 12, and 24 mth, respectively). The purity of the fraction was tested by transmission electron microscopy and marker enzyme assays. The cholesterol content of the fractions was also determined. Samples of the fractions were labelled with diphenylhexatriene (DPH) and the fluorescence anisotropy ® of the label was measured at various optical densities. The values of r extrapolated to zero optical density were compared in the age groups and used for calculating the 'microviscosity' of the membranes. The 'microviscosity' of synaptosomal membranes displayed a significant age-dependent increase: from 2.3 + or - 0.02 (SD) in the young group it increased to 2.6 + or - 0.03 poise by the age of 24 mth at 37degr.C. Most of this increase occurred between the adult and old age. The cholesterol content of the synaptosomes also increased significantly during aging. Centrophenoxine (CPH)-treatment with 100 mg/kg body weight daily dose for 2 mth was able to reverse the age-dependent alterations of both the membrane 'microviscosity' and the cholesterol content in the synaptosomes: the values returned nearly to the adult level. The result obtained are interpreted in terms of the membrane hypothesis of aging attributing a primary role to the free-radical induced membrane damage in cellular aging.

Effects of centrophenoxine on lipofuscin in the retinal pigment epithelium of old mice

NEUROBIOL. AGING (USA), 1983, 4/1 (89-95)

The effects of centrophenoxine on the retinal pigment epithelium (RPE) of 17 month old female mice have been studied. Animals were injected subcutaneously for 3 months (60 injections) with the drug (0.1 mg/g of body wt) daily in 0.1 M phosphate buffered saline at pH 7.0. The morphological changes in the pigment layers of the retina of both eyes were studied by light and electron microscopy and the lipofuscin pigment was demonstrated by its autofluorescence and ultrastructural characteristics. There was a significant reduction of the lipofuscin pigment in the treated animals, but the melanin pigment remained unchanged. The lipofuscin granules also appeared less osmiophilic and showed a greater preponderance of membranes and vacuoles. Although the precise mechanism of action of the drug is not clear, an increased protective function of the pigment epithelium by the drug has been suggested.

The effect of acute and chronic centrophenoxine treatment on the synaptic plasticity of old rats


The cerebellar glomerulus was studied by electron microscopic morphometry in female Wistar rats. Age-dependent alterations have been revealed from 3 to 28 mth of age, and the effect of centrophenoxine (CPH) was analyzed in two different patterns of administration. First, 27-mth-old rats were treated daily for 6 wk (acute treatment), and second, 18-mth-old rats were treated 3 times per week for 5 months (chronic treatment). The dose was 100 mg CPH/kg body weight, injected intraperitoneally. The surface density (S(v)), the numerical density (N(v)) and the average length ((bar)L) of the synaptic junctions were calculated from data obtained on ethanol-phosphotungstic acid stained ultrathin sections. An age-dependent reduction of S(v) and N(v) of the synaptic contact zones was found, and the (bar)L increased in the oldest animals. CPH-treatment resulted in a marked increase of S(v) in both types of application, whereas the other two parameters behaved differently in the two groups. The chronic treatment resulted in a significant slowing down of the decrease of N(v), whereas (bar)L remained invariate. On the contrary, the acute treatment increased (bar)L but did not alter significantly N(v). The results and the differences between the treatment types are discussed in terms of synaptic plasticity and are interpreted as different manifestations of the same reactive synaptogenetic process.

Meclofenoxate-induced increase in cell metabolic activities in normal diploid human glia cells in a stationary cell culture system


Quantitative biochemical studies were undertaken in order to examine the influence of the accumulation of lipofuscin in secondary lysosomes on cell metabolic activities of normal diploid human glia cells in a stationary cell culture system. Glia cells accumulate lipofuscin as a function of the duration of the stationary cultivation in vitro. The accumulation of lipofuscin can be decreased by the long-term treatment with the pharmacon meclofenoxate (centrophenoxine, Helfergin(Reg.trademark)). Concomitant with the reduction of the accumulated lipofuscin, meclofenoxate-treated glia cells show enhanced rates of RNA synthesis, protein synthesis and glucose uptake. Most likely, in meclofenoxate-treated normal diploid human glia cells in vitro, the utilisation of glucose is shifted from glycolysis to the pentose phosphate pathway. The data suggest that the meclofenoxate-induced reduction of lipofuscin accumulation has a positive effect on cell metabolic functions and causes a delay of the cellular aging of the human glia cells in vitro.

Changes in the characteristics of collagen of young male garden lizards following centrophenoxine and lysine treatment

EXP. GERONTOL. (ENGLAND), 1982, 17/5 (399-405)

Both centrophenoxine and lysine appear to stimulate the deposition of collagen as evident from the values of total content in skin and tendon. The solubilities of collagen in salt and acid media and the soluble/insoluble collagen ratio increased in almost all the three tissues of treated lizards though differing to some extent in the degree of response. It is suggested that both the chemicals possibly prevent cross-link formation thus retarding the aging of collagen in lizard tissues.

Alterations in total content and solubility characteristics of proteins in rat brain and liver during ageing and centrophenoxine treatment

EXP. GERONTOL. (ENGLAND), 1981, 16/3 (229-240)

The cerebral cortex and liver tissues of young, adult and old (1-4, 15 and 25-30 months of age, respectively) CFY rats of both sexes were investigated. Water-soluble (WSP) and water-insoluble (WIP) protein fractions were separated after homogenization of 10 mg tissue per 1 ml of distilled water, by centrifugation at 500 g. The WSP and WIP fractions were analyzed by electron microscopy and their protein contents were determined by a modified Folin phenol reaction. Electron microscopy revealed a complete destruction of the cell organelles due to the strong osmotic shock. Total protein contents of both tissues increased significantly in the old rats and also the WIP contents were much higher in aged animals than in the young and adult ones. Mild heat treatment (64degr.C, 10 min) or 3 M urea were able to resolubilize a considerable portion of the WIP in the young animals, however, in adults and olds their effect was strongly reduced. Protease inhibitors displayed only very limited influences on the WIP. The conclusion was reached that a considerable portion of WIP of the old animals may be covalently cross-linked. Certain methodical problems of protein determination are also discussed. In vivo application of centrophenoxine (100 mg/kg body weight) for 4 weeks significantly reduced the WIP content in 25-month-old females, and the total protein content also displaced a decreasing tendency. The results are discussed in terms of the membrane hypothesis of ageing.

Morphometric studies on synapses of the cerebellar glomerulus: The effect of centrophenoxine treatment in old rats

MECH. AGEING DEV. (SWITZERLAND), 1980, 14/1-2 (265-271)

Young, adult and old female Wistar rats (3, 18 and 28 months of age, respectively), were studied using electron-microscopic stereology. Synaptic parameters of the cerebellar glomerulus were calculated and compared with similar data obtained from old Wistar rats of the same breed treated with centrophenoxine (CPH; Helfergin, Promonta, Hamburg) in the form of intraperitoneal injections (100 mg/kg body weight) for 40 days. This treatment resulted in a sort of 'rejuvenation' of synaptic structures. Namely, the surface density and the total length of synaptic contact zones were markedly reduced in the untreated old group, but in the treated animals these parameters returned to the values found in the young and adult animals. At the same time the numerical density of synapses remained unaltered in the treated group, while the average synaptic length displayed some further increase. The results are interpreted in terms of the age-dependent decrease in reactive synaptogenesis, suggesting that CPH stimulates the metabolism of the nervous elements persisting in old brain. The possible mechanism of CPH effect is also discussed.

On the role fo cross-linking of cellular proteins in aging

MECH. AGEING DEV. (SWITZERLAND), 1980, 14/1-2 (245-251)

Water-insoluble protein fractions increase in the brain cortical tissue and liver of rats during aging in both sexes. This suggests a possible increase in the cross-linking of proteins which may be due to the formation of, for example, hydroxyl free radicals during several metabolic processes. In vivo application of centrophenoxine causes a reversal of this phenomenon in old rats. In vitro experiments show that the generation of hydroxyl free radicals by chemical systems like homolysis of Hsub 2Osub 2 by redox coupling with Fesup 2sup +- >Fesup 3sup + conversion, results in the cross-linking of bovine serum albumin and the mixed proteins of liver or brain homogenates of young rats. The cross-linked proteins have a very much increased molecular weight, they become mostly insoluble even in 6 M urea. Dimethylaminoethanol, the effective part of centrophenoxine molecule, is able to diminish the extent of cross-linking, acting most probably as a free-radical scavenger. The results are discussed in terms of the 'membrane hypothesis of aging'. A molecular basis is proposed for the anti-aging effect of centrophenoxine.

Effects of centrophenoxine on the monovalent electrolyte contents of the large brain cortical cells of old rats

GERONTOLOGY (SWITZERLAND), 1979, 25/2 (94-102)

The effect of centrophenoxine has been studied on the monovalent electrolyte contents of the brain cortical cells of old female Wistar rats by means of energy dispersive x-ray microanalysis. The drug was administered in form of an intraperitoneal injection of 100 mg/kg body weight for 20 days. The treatment decreased the potassium content in both the nucleus and cytoplasm in terms of dry mass fraction, whereas the sodium concentration remained unchanged. The Nasup +/Ksup + ratio increased significantly in both cell compartments. The chloride content of the nuclei decreased slightly. If one supposes just 1-2% rehydration of the old cytoplasm, the decrease of the total ionic strength may be of considerable extent, it may even reach the values obtained in young adult animals. The results are interpreted in terms of a recently developed 'membrane hypothesis' of aging.

Effects of centrophenoxine on the nematode caenorhabditis briggsae

AGE (USA), 1978, 1/1 (17-20)

Concentrations below 13.6 mM centrophenoxine in the culture medium had no inhibitory effect on several developmental parameters of Caenorhabditis briggsae: specifically growth, fecundity and longevity. The effects on two parameters which characterize senescence in this nematode, increased osmotic fragility and increased specific gravity, were also evaluated. Above 6.8 mM old nematodes showed significantly less osmotic fragility and reduced specific gravity. Evaluation of the effects on negative charge of the cuticle surface membrane showed that neither 6.8 mM nor 17 mM affected negative surface charge density. Electron microscope studies showed that age-pigment accumulation was significantly retarded by a concentration of 6.8 mM centrophenoxine. It is suggested that the specific gravity effect is correlated with the retardation of lipofuscin accumulation with age. If this proves correct, then specific gravity will be another parameter for measuring the effects of centrophenoxine on aging tissues. This study also demonstrated that the effects of drugs on the retardation of age pigment formation can be visualized in three weeks by utilizing C. briggsae as a model.

Further studies on the effects of centrophenoxine on lipofuscin pigment in neuroblastoma cells in culture: an electron microscopic study

EXP. GERONTOL. (ENGLAND), 1978, 13/5 (311-322)

Previous studies, using light microscopy, indicated that lipofuscin is formed in aging neuroblastoma cells in culture and that the addition of centrophenoxine to the culture media reduced cellular pigment formation. The present study, using electron microscopic methods, confirms the gradual accumulation of lipofuscin pigment as well as the ability of centrophenoxine to reduce lipofuscin accumulation in neuroblastoma cells.

Ultrastructure of lipofuscin in rat brain. Studies on topographical differences and centrophenoxine induced changes of the lipofuscin (Japanese)

J.KANSAI MED.UNIV. (JAPAN), 1975, 27/2 (349-371)

The ultrastructure of lipofuscin granules in rat brain was investigated. Various regions of the brains of young and old animals were studied. According to the aging process, lipofuscin structures varied remarkably, i.e. from small, round or oval, lysosomal structures with fine dense granules to more complicated structures, characterized by an internal lamellar or granular structure with or without vacuoles. Lipofuscin first appeared in 1 mth old rats in the nerve cells of the cerebral cortex, spinal cord and thalamus. In this stage it was characterized by small, oval and homogeneous structures with fine granules. Even in 3 mth old rats, lipofuscin in the cerebral cortex cells was exceptionally irregular in shape, the cells containing remarkably large vacuoles. In aged rats, the topographic differences of the lipofuscin granules were more marked. In the cerebral cortex, the granules were large and irregular in shape, some having a coarse aspect. In the thalamus lipofuscin had a homogeneous appearance with fine granules and few vacuolar structures were found in these cells. Intermediate types of lipofuscin were noted in the nerve cells of the cerebellar cortex and ventral horn of the spinal cord. The lipofuscin in these regions was essentially similar to that of the cerebral cortex, although vacuoles were smaller and showed oval or round contours. The dorsal ganglion cells contained a characteristic type of lipofuscin, i.e. invariably oval or round in shape and containing 1 or 2 relatively large vacuoles. Lamellar structures were occasionally found in the dense portions of the lipofuscin. Dense and vacuolated bodies were also noted in the perikarya of the satellite cells of the dorsal ganglia. In animals treated with centrophenoxine, the most marked changes were noted in the nerve cells and satellite cells of the dorsal ganglia. Although no decrease in the amount of lipofuscin was demonstrated, the size of the lipofuscin vacuoles became much larger and vacuolization of the dense bodies was noted in the satellite cells of the dorsal ganglia.

Autofluorescent studies of the lipofuscin in the rat brain (Japanese)

J.KANSAI MED.UNIV. (JAPAN), 1975, 27/2 (330-348)

The autofluorescent method for lipofuscin is advantageous for investigating its distribution in the cytoplasm of the nerve cells, because the bright, yellowish gold autofluorescence is easy to recognize. In the nerve cells, the types of distribution are classified as follows: a coarse granular distribution with clump formation near the nucleus (clump type); a fine granular structure, distributed diffusely in the cytoplasm (diffuse); and an intermediate type. In young and infant rats, lipofuscin is distributed diffusely in the cytoplasm in fine granules. As the aging advances, the clump type of distribution is more frequent. In the neuropil, particularly in the neuropil of the spinal cord, autofluorescent granules were first seen in 1 mth old rats. The granules appeared in a variable form, the particles having different sizes and being very fine, showing a green yellow autofluorescence. In 3 mth old rats, lipofuscin was noted as fine granules, diffuse but not yet clumping and having an orange yellow fluorescence in the cytoplasm of the anterior column cells. At this age, lipofuscin was rare in the dorsal roots or in the thalamus, and, if found, not in the cytoplasm. In 6 mth old animals, lipofuscin granules increased in number and were found in the nerve cells of the cerebral cortex, hippocampus, caudate nucleus, thalamus, brain stem and spinal cord. In 12 mth old animals, lipofuscin accumulation was much more advanced and distributed densely in the cytoplasm of perikarya of the cerebral cortex, hippocampus, basal ganglia, thalamus, brain stem, spinal cord and dorsal ganglia. The distribution as observed by fluorescent studies corresponded well with the histochemical findings (PAS and Sudan III staining). A decrease of lipofuscin in nerve cells of the spinal cord, cerebral cortex, cerebellar cortex and dorsal ganglia was well demonstrated by the fluorescent method in rats administered centrophenoxine.

Electron microscopical assessment of ageing at ultrastructural level, influenced by chemical means

AKTUEL.GERONTOL. (GERMANY, WEST), 1975, 5/3 (145-156)

This survey deals with the ultrastructural changes in the life cycle of postmitotic cells, the neuron and the myocardial cell. The most characteristic changes for both cells is the transformation of ageing mitochondria into lipofuscin. This appears to be an important factor in ageing, leading to a progressive accumulation of lipofuscin. Centrophenoxine (meclophenoxate) causes the breakdown of lipofuscin within the cell, and its transportation to the capillary wall. The removal of lipofuscin due to Centrophenoxine seen in the experimental material (tissue culture, rats and guinea pigs) supports from a morphological point of view, a treatment of ageing organs with Centrophenoxine.

The effects of dimethylaminoethyl p chlorophenoxyacetate on spinal ganglia neurons and satellite cells in culture. Mitochondrial changes in the aging neurons. An electron microscope study

MECH.AGE DEVELOPM. (--), 1974, 3/2 (131-155)

The formation and distribution of old age pigment in neurons and satellite cells of spinal ganglia in culture were studied electron microscopically, following daily application of the cultures, for 2-3 wk, with dimethylaminoethyl p chlorophenoxyacetate and compared with cultures of the same age. The relation of the aging pigment to the mitochondria has been reinvestigated. In the EM sections a fading out as well as conspicuous vacuolation of the pigment could be observed at the beginning of drug application. This was followed by disintegration and replacement of the pigment by fine osmiophilic granules leading to a diminution in the total amount of pigment present. Cytoplasmic processes and satellite cells transported thepigment to the interneural space. Further removal of the pigment occurred by means of phagocytes and proliferating endothelial cells of residual capillaries. The possible mitochondrial genesis of age pigment is discussed.

Antagonic-Stress superiority versus meclofenoxate in gerontopsychiatry (Alzheimer type dementia)
ARCH. GERONTOL. GERIATR. (Ireland), 1994, 18/SUPPL. 4 (197-206)

A double blind, comparative, parallel and randomized clinical trial was used for evaluation of two nootropics with anti-aging actions: Meclofenoxate (MF) and Antagonic-Stress (AS). Sixty-three old persons divided Into 2 groups (average age: 68.6 and 70.8 years, respectively) with senile dementia of Alzheimer type (SDAT), of mild to moderate intensity (criteria of DSM-III-R, APA, 1987; and ICD-10, WHO, 1990) were treated with one of these nootropica. Baseline and final psychogeriatric symptomatology after three months of treatments were multiply assessed: psychogeriatric by Sandoz Clinical Assessment-Geriatric scale, Self-Assessment Scale-Geriatric and their subscales; psychometric by Wechsler Memory Scale and Wechsler Adult Intelligence Scale. Prolonged treatments with MF and AS significantly decreased the psychogeriatric scores in scales and subscales, improved the cognitive performance (attention, concentration, memory, performance IQ, full IQ) and diminshed the deterioration Index (ANOVA). Therapeutical effects of AS (a neurometabolic complex containing MF) were significantly superior against MF alone (ANCOVA). MF and AS actions are discussed in connection with the brain cholinergic system, lipid peroxidation and free radical scavengers, deceleration of the aging rate, brain and erythrocyte lipofuscinolysis, multiple anti-oxidant formula, multivitamin and multimineral supplementation and with the superiority of multitherapy versus monotherapy in senile dementia and for improving the IQ and the maladaptative behavior.

Electron spin resonance spectroscopic demonstration of the hydroxyl free radical scavenger properties of dimethylaminoethanol in spin trapping experiments confirming the molecular basis for the biological effects of centrophenoxine



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