P4.007 Learning-enhancing and anxiolytic effects of memantine in nontransgenic and transgenicmice over-expressing APPswe and PS1

24, Def;enerat~oe and neurological d~sorders box and a sample trial commenced (10 rain). 2,1 h later mice were subjected to one familiar and one unfamiliar object. The time spent exploring the familiar and new object was determined. Animals were also assessed for possible visual deficits. lles~ts: Significant decline in the ORT performance was observed at 6 and 7.5 months of age in the untreated A D l l mice. Memantine prevented the development of this deficit at both ages, after 1.5 and 3 months of treatment, respectively. Memantine treated mice did not perform significantly different from the wt mice. No visual deficits were recorded. Conelmio~: Memantine was well tolerated by AD11 mice at clinically relevant levels and can prevent the development of behavioural deficits observed in untreated animals at ages where a number of neurochemical changes are already known to be robustly established in the AD11 brain.

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Neuroprotective properties of memantine in different models of excitoxicity

M. Leist, C. Volbracht, J. van Beck. H-. Lundbeck A/~ Molecular

Disease Biology, Valhy, Denmark Baekgroltmd: Neuronal dysNnction in Alzheimer's disease (AD) may result, in part, from sustained elevations of glutamate levels and increased sensitivity to glutamate, leading to low-level influx of calcium into neurons, impaired neuronal homeostasis and eventmally neurodegeneration. Agents that specifically block the pathological stimulation of glutamate receptors, mainly the N-methyl-D-asparate receptor (NMDA-R) might be anticipated to restore physiological %notion of neurons and thereby have disease-modifying effects in AD. Previous attempts to use N M D A - R antagonists to retard the progression of AD have been hindered by the psychotomimetic and cardiovascular effects of these drugs. The tolerability of clinically used uncompetitNe NMDA-R antagonist memantine is highly dependent on changes in membrane potential and the drug's fast channel unblocking kinetics. Memantine blocks sustained NMDA-R activation under pathological conditions and rapidly leaves the NMDA-R channel upon transient physiological activation. Purpose: We investigated the neuroprotective properties of memantine in cellular models of different complexity. Methods: Organotypic rat hippocampal slices and routine cerebellar granule cell cultures were exposed to different direct or indirect excitotoxins. Death was measured by counting neurons with condensed nuclei. Results: First, an established model was chosen based on the known pharmacological properties of memantine, in order to find relevant concentrations for cell culture experiments. Memantine protected rat neurons in organotypic hippocampal slices from NMDA-induced excitotoxicity within micromolar range. Next, we tested memantine within the previously determined dose range in neuronal stress models, which are dependent on excitation of cells by endogenous glutamate. Memantine protected murine oerebellar granule cells from apoptosis induced by the mitochondrial toxin 1-methyl-4-phenylpyridinium (MPP+). Furthermore, neuronal apoptosis induced by the pathophysiological mediator nitric oxide (NO) released from S-nitrosoglutathione (GSNO) was inhibited by memantine. Additionally, memantine prevented apoptosis induced by oxygen-glucose deprivation (OGD), a model of cerebral ischemia, in cerebellar granule cells. C~nelmiom These findings support a beneficial effect of NMI)A-R inhibition by memantine in different apoptotic models.

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Learning-enhancing and anxiolytic effects of memantine in nontransgenic and transgenic mice over-expressing APPswe and PS1

T, Keikki 1, R. Minkeviciene 1 , P, Banerjee 2, 1Uniuers#y of Kuopio, Neuroscience and Neurology, Kuopio, Finland; 2Forest Researc~ Institute, Prediuical z~esearc~, New Jersey, rgg,A,

Background: Memantine, a low-moderate affinity, uncompetitive NMDA receptor antagonist, was approved in the U.S. in October 2003 for the treatment of moderate to severe Alzheimer's disease. Objeeti~: To determine the effects of subchronic memantine dosing on spatial memory and other behaviors in transgenic and nontranagenic mice. M.ethods: Eight-month-old male C57BL/6J mice (C, n=40), transgenic C57BL/6J mice carrying mutated human APPswe and PS1 (A246E) genes (A/P, n=45), and their nontransgenic littermates (NT, n=36) were assigned to memantine or placebo. Memantine (10, 30 and 100 mg/kg/day to the C mice, 30 mg/kg/day for the A/P and NT mice) was administered orally for 3 weeks in drinking water prior to testing. Motor and exploratory activities were assessed by an automated activity monitor with infrared detection. Social behavior was assessed by the intruder-induced aggression test and anxiety in the plus maze. Spatial loag-term memory was tested in the Morris water maze. Results: Memantine had no effect on locomotor actNity or aggressive behavior as measured by the activity and intruder tests in A/P or NT mice. In the plus maze, memantine dosedependently increased exploration of the open arm of C mice, indicating reduced anxiety. Memantine irrproved spatial learning in A/P mice and, to a lesser degree, in NT mice without affecting swimming speed. In addition, memantine dose-dependently improved acquisition of spatial learning in the water maze in C mice and reduced swimming close to the pool wall. The 10, 30 and 100 mg/kg/day doses of memantine resulted in steady-state plasma concentrations of 0.5, 1.1 and 5.5 I~M, respectively. Cenel~ien: These data indicate that memantine improves learning in transgenic mice expressing Alzheimer's diseaselike pathology. In addition, memantine was shown to exhibit anxiolytic-like activity.

~P300

as a measure for reflecting cognitive dysfunctions in patients with brain concussion

S.I. Hart, ZW. Icon. Our Lady of Mercy I-iosp#al, TI~e Cat]~olic

Unioers#y of Korea, Neuropxyciqiatry, In&con, RepuNic of Korea Although abnormal MP.I findings were not shown in patients with brain concussion by traffic accidents, it has been well known that their cognitive dysfunctions could be complained. This study was design to examine the availability of P300 as an objective measure reflecting minor brain dysfunctions. Auditory and visual "oddball" paradigms were employed in normal controls (N=12) and patients with brain concussion without MRI abnormalities (N=12). Auditory stimulus categories were defined as the standard (1000 I-Iz, 80%) and target (2000 I-Iz, 20%) with the intensity of 75 dE. Visual stimulus categories were defined as the standard (circle, 3.5 cm diameter, 80%) and target (square, 15 cm on a side, 20%). The stimuli were presented in random series, once every 2 seconds. P300 in patients with brain concussion was elicited later (F=14.4, P<0.001) and smaller (F=45.8, P<0.0001) across the both auditory and visual modalities. There were no