Symposium 13 Monday Sept. 24th 1.30 pm–3.00 pm; Room: Lecture Hall 1
Asian-Pacific-European-Symposium: Chairpersons: Colombo G (Italy), Tateno M (Japan)
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Presentation S13-1
The effect of 12-week open-label memantine treatment on cognitive function improvement in patients with alcohol-related dementia
Kim D, Park J, Cheon Y (Republic of Korea)
Aims. There is compelling evidence that alcohol-induced neurotoxicity is related to glutamate excitotoxicity. It is hypothesized that the low affinity NMDA receptor antagonist memantine would improve the cognitive function of patients with alcoholic dementia. The aim of this study was to test this hypothesis and to evaluate the effect of memantine on the cognitive improvement of patients with alcohol-related dementia (ARD).
Methods. The study was designed as a 12-week open-label study investigating the efficacy of 20 mg memantine, a low-affinity NMDA receptor antagonist, as a treatment for cognitive and neurobiological problems in 19 patients with probable ARD according to the criteria for ARD proposed by Oslin et al. The CERAD-K and several clinical assessment scales were completed before and after the 12-week memantine treatment period.
Results. Significant improvements in the mean scores from baseline to final assessment were observed in the Global Deterioration Scale (GDS) (p< 0.05), Brief Psychiatric Rating Scale (BPRS) (p < 0.01), Geriatric Quality of Life—Dementia (GQOL-D) scale (p < 0.01) and Neuropsychiatric Inventory (NPI) (p < 0.01) at the end of week 12. The CERAD-K subscales of word list recall (p < 0.05), word list recognition (p < 0.05), time orientation (p < 0.01), drawing an interlocking pentagon (p < 0.05), and the total MMSE-K scores (p < 0.01) of the patients all showed significant improvement following the memantine trial.
Conclusions. In this open-label study, patients with alcohol-related dementia treated with 20 mg/day memantine for 12 weeks showed cognitive function improvement. The result of this study suggests the possible usefulness of memantine for the treatment of alcohol-related dementia.
Presentation S13-2
Ethanol-induced neuronal damage and stem cell implantation
Yoshinaga T, Ishii T, Ukai W, Hashimoto E, Saito T (Japan)
Aims. Heavy alcohol consumption during pregnancy can cause various neurodevelopment deficits known as fetal alcohol syndrome (FAS). We previously demonstrated that immature cells were susceptible to ethanol toxicity even at a physiological concentration in the experimental condition using neural stem cells (NSCs) prepared from rat embryos. Our main research concerns are the investigation of the pathophysiology of ethanol-induced neuronal damage and the development of therapeutic approaches for the sufferer of prenatal ethanol exposure.
Methods. For the in vitro study, NSCs were prepared from E-13.5 rat embryos in a monolayer culture. Cultured cells were exposed to ethanol at various concentrations and the effect of ethanol was assessed at each stage of cell mature process such as proliferation, differentiation and survival. As for in vivo study, pregnant rats were given ethanol (3 g/kg/dose) or physiological saline via a catheter every 12 hours for 4 days (gestational day 10 to 13). Rats were divided into four groups, i.e. control, fetal alcohol effect (FAE) group, control with transplantation and FAE with transplantation. NSCs were stained with fluorescein-based dye to chase their migration and labeled with [35S]-methionine for quantification. Then, cells were transplanted to newborn rats of 30 days-old by injection through tail vein followed by immunosuppressive treatment. After the completion of behavioral tests, brain tissues were investigated microscopically.
Results. In vitro studies revealed that ethanol suppressed the differentiation of NSCs into neurons at concentrations that did not affect the survival of cells. The inhibitory effect was increased as the concentration of ethanol became higher. Both ethanol and MEK inhibitor U0126 enhanced neuron-restrictive silencer factor (NRSF) binding activity and decreased neuronal differentiation in a concentration dependent manner. These results suggest that MAP kinase cascade might be involved in the mechanism of decreased neurogenesis in which NRSF might play an important role. In the in vivo study, transplanted cells could be detected in various areas of the brain. The brains of FAE group had more transplanted-cells than those of control group. NSC transplantation ameliorated behavioral abnormalities in FAE group.
Conclusions. Ethanol decreased neuronal differentiation of stem cells without affecting survival of the cells. The evidence that physiological concentration of ethanol could suppress the generation of new neurons suggests that disrupted cell differentiation might be a mechanism of ethanol-induced neuronal damage. Cell transplantation might be able to become a new strategy to treat developmental and learning abnormalities observed in offspring of a mother with heavy alcohol consumption during pregnancy.
Presentation S13-3
Taste preferences and the risk of alcohol dependence: from animal to human studies
Bienkowski P (Poland)
Aims. The aim of this presentation will be to summarise results of animal and human studies on the relationship between hedonic responses to basic tastes and alcohol abuse.
Results of an ongoing study on reactivity to sucrose solutions in families (trios) of alcoholic patients will be presented.
Methods. Preference or avoidance of a certain taste by laboratory animals may be assessed in a series of two-bottle tests and/or in the taste reactivity procedure. In humans, hedonic responses to basic tastes may be examined with the aid of the sip-and-spit method and likert or visual analogue scales.
Results. Mice and rats with a high preference for saccharin and sucrose solutions tend to consume more ethyl alcohol than animals with a low sweet preference. The above association has been shown for both selectively-bred alcohol preferring lines and outbreed strains of rats. Sweet component of ethanol taste may provide partial explanation for these findings. In humans, alcohol dependence by itself is not associated with altered responses to sweet solutions. However, sweet liking may be a phenotypic marker of alcoholics with a family history of alcoholism. It has been reported that avoidance of salty solutions is another characteristic of alcohol preferring rats. In line with the above, children of alcoholics tend to rate salty solutions as more unpleasant as compared to children of non-alcoholic parents.
Conclusions. More studies are needed to show whether altered hedonic responses to sweet and salty solutions correlate with heritable subtypes of alcoholism and/or predict therapeutic effects of anti-alcohol drugs.
Presentation S13-4
Treatment targets in pharmacological anti-craving therapy of alcoholism: An overview
Kiefer F (Germany)
Aims. Addiction is a chronic disorder that develops on a genetic, psychosocial and environmental background. Whereas withdrawal treatment is widely accepted as a pharmacotherapeutic domain, anti-craving and relapse prevention treatment in clinical practice up to now is mainly based on psychosocial and psychotherapeutic interventions.
Methods. New therapies have been developed due to the knowledge of the biological mechanisms of alcohol dependence.
Results. Especially co-morbid depressive- and anxiety disorders seem to require a rational pharmacotherapeutic treatment regime.
Conclusions. The presentation will focus on the neurobiological background of addiction treatment, will interpret very recent data from clinical trials and will translate these results into relevant information for clinical ‘bedside’ treatment.