S628 P.5.a. Dementia and neurological disorders − Dementia (basic) auranothiomalate, a specific GPx inhibitor abolished cytoprotec- tive effect of Selol. Taken together, these studies indicate that Selol stimulates endogenous antioxidant system via enhancement activity of GPx and protects cells against oxidative stress. In conclusion, these results indicate a novel direct connection between Selol and redox homeostasis and highlighted Selol as a potential candidate in therapy of neurodegenerative disorders connected with oxidative stress activation. Disclosure statement: Supported from MUW statutory funds and MMRC statutory theme 17. P.5.a.006 Flavopiridol, an inhibitor of cyclin-dependent kinase 4, reverses cognitive deficits induced by b-amyloid peptide 1-42 A. Impellizzeri 1° , G.M. Leggio 1 , R. Pellitteri 2 , M. Spatuzza 2 , D. Puzzo 3 , S. Salomone 1 , A. Navarria 1 , A. Copani 4 , M.V. Catania 2 , F. Caraci 5 , F. Drago 1 1 University of Catania, Department of Clinical and Molecular Biomedicine − Section of Pharmacology and Biochemistry, Catania, Italy; 2 National Research Council of Italy, Institute of Neurological Sciences, Catania, Italy; 3 University of Catania, Department of Biomedical Sciences − Section of Physiology, Catania, Italy; 4 University of Catania, Department of Drug Sciences, Catania, Italy; 5 University of Catania, Department of Clinical and Molecular Biomedicine − Section of Pharmacology and Biochemistry Department of Educational Sciences IRCCS Oasi Maria SS Troina (EN), Catania, Italy Purpose: Activation of cell cycle activation is an early event in the pathogenesis of Alzheimer’s disease (AD). Expression of cell cycle proteins and replicative DNA synthesis have been observed in neuronal populations fated to degenerate in the AD brain. In cultured neurons, synthetic Ab reproduces the neuronal cell cycle re-entry observed in transgenic animals and in the AD brain. The ectopic re-activation of cell cycle in AD neurons could lead to synaptic failure and ensuing cognitive deficits which precede frank neuronal death [1,2]. Cytostatic drugs that act as cyclin- dependent kinase (CDK) inhibitors, such as flavopiridol, might be studied in experimental models of AD to prevent Ab-induced toxicity. Presently no studies have conducted in vivo to explore the effects of this antineoplastic drug in animal models of AD. Aims of the present work were to examine the neuroprotective effects of flavopiridol against Ab toxicity as well as the effects of this drug on memory retention loss in CD1 mice injected intracerebroventricularly (I.C.V.) with Ab 1−42 (400 pmol/mouse). We also assessed the effects of flavopiridol on the occurrence of ectopic cell-cycle events in frontal cortex, hippocampus and amygdala of Ab-injected mice. Methods: We examined the neuroprotective activity of flavopiridol in mixed rat neuronal cultures challenged with Ab 1−42 (5mM) for 48 hours. Neuronal death was assessed by Trypan Blue staining. Ab(1−42) was administered to cell cultures in the presence of ionotropic glutamate receptor antagonists to avoid the potentiation of endogenous glutamate toxicity. Using the passive avoidance test, one of the behavioral paradigms commonly used to evaluate memory retention in rodents, we then assessed the behavioral responses of seven-week old male CD1 mice injected intracerebroventricularly (I.C.V.) with Ab 1−42 (400 pmol/mouse) to repeated administration of flavopiridol (0.5, 1 and 3 mg/kg). Flavopiridol was administered intraperitoneally (i.p.) to animals for 11 days three days after Ab injection. Results: Flavopiridol significantly prevented Ab-induced tox- icity in mixed cultures at concentrations which are known to inhibit CDK4 and Ab-induced cell cycle activation in neurons (100nM-500nM). We then examined the effect of flavopiridol on memory retention loss in CD1 mice injected I.C.V. with Ab 1−42 (400 pmol/mouse). Flavopiridol (0.5 and 1 mg/kg) reversed in the passive avoidance test the loss of memory retention induced by Ab. Using immuno-histochemical procedures we found a strong induction of cyclin A2 in NeuN positive cells of cerebral cortex, hippocampus and amygdala of Ab-injected mice compared to vehicle-treated animals. Interestingly, flavopiridol at the lowest dose of 0.5 mg/kg prevented the occurrence of ectopic cell-cycle events in cerebral cortex, hippocampus and amygdala. Conclusion: These data demonstrate that flavopiridol is neu- roprotective at nanomolar concentrations against Ab toxicity in mixed neuronal cultures and also that this antineoplastic drug prevents, at the lowest dose of 0.5 mg/kg, the occurrence of brain ectopic cell-cycle events in Ab-injected mice. These data suggest for the first time that drugs that inhibit cell cycle activation, such as flavopiridol, might prevent cognitive deficits in AD animal models. References [1] Arendt T, Br¨ uckner MK. Linking cell-cycle dysfunction in Alzheimer’s disease to a failure of synaptic plasticity. Biochim Biophys Acta 2007; 1772:413−21. [2] Copani A, et al. Mitotic signaling by beta-amyloid causes neuronal death, FASEB J. 1999; 13: 2225–2234. P.5.a.007 Extracellular oligomers of alpha- synuclein induce Parkin modifications and dopaminergic PC12 cell death A. Lenkiewicz 1° , A. Wilkaniec 1 , A. Adamczyk 1 1 Mossakowski Medical Research Centre, Department of Cellular Signalling, Warsaw, Poland a-Synuclein (ASN), the major component of Lewy bodies (LB), and parkin, a multifunctional E3 ubiquitin ligase, are implicated in the pathophysiology of Parkinson’s disease (PD). Mutations of the gene encoding ASN cause autosomal dominant forms of PD, whereas loss-of-function mutations of the gene encoding Parkin account for autosomal recessive forms of this disease. The most recent data suggested the important role of both ASN and Parkin and interplay between these proteins in sporadic PD. It was indicated that ASN binds to Parkin and they co-localize in both Parkinson’s LB and axonal spheroids, suggesting that interaction between those proteins could strongly contribute to the pathophysiology of PD. Latest reports indicate a key role of both intra- and extracellular ASN in development and pro- gression of PD. ASN can be released into extracellular space as monomers, oligomers and aggregates. Our previous data showed that extracellular oligomers of ASN might be an initial and crucial factor contributing to the neurodegeneration occurring in PD and it is suggested that Parkin overproduction could protect against ASN-dependent neurodegeneration. However, it remains unclear whether oligomers of ASN liberated into extracellular space could affect Parkin function. We addressed this issue, by investigating the role of extracellular oligomers of ASN in Parkin modifications and rat dopaminergic pheochromocytoma (PC12) cells viability. In this study we examined the effect of exogenous ASN oligomers on