Poster Abstracts Wednesday, November 9, 2005 $355

Aim: To investigate the protective effect of Pituitary adenylate cyclase activating polypeptide27 (PACAP27) on rotenone-induced cytotoxi- city in PC12 cells. MeillOdS: PC12 cells differentiated by nerve growth factor as dopaminergic neurons were treated by different concentrations of rotenone; Cell viability was assessed with MTT and cell apoptosis was detected by Annexin-V staining and flow cytometry; m R N A of PACI receptor was analyzed by RT-PCR. Results: The expression of the m R N A for PACAP receptor (dominant PAC1 receptor) in PC12 cells was demonstrated by RT-PCR; The cell viability was declining with the concentration of rotenone increasing and this neurotoxicity demonstrated dose-dependent manners; PAC.AP27 (10-7--10 -~a mol.L -1) showed significant neuroprotective effects against rotenone-indued toxicity; A decrease in the occurrence of late apoptotic features was found by double staining with Annexin-V and propidium iodide (PI) in rotenone+PACAP27 groups, compared with rotenone group; Flow cytometry results showed PACAP27 could improve the cell viability by decreasing the numbers of apoptotic cells, but this effects can be reversed by PAC.APs 27, a kind of PACAP receptor antagonist. Conclusion: These results suggest that PACAP may exert a protective effect against rotenone-induced neurotoxicity by PAC1 receptor in PC12 cells.

1004 Genetic variation in IL-10 influences the progression of Parkinson's disease

Huang, Y~, Rowe, D 2, Cook, NL ~, Halliday, GM ~. 1Prince of t~les Medical Research Institute and The University of New South Wales, Sydney, Australia; 2Royal North Shore Hospital and The University of Sydney, Sydney, Australia

Background: Microglial activation and inflammation are common salient features accompanying the specific, neurodegeneration of Parkinson's disease (PD). Reducing inflammation slows disease progression in clinical trials and animal models ofPD. Gene expression is critical for the inflanmmtory response and polsanorphisms in the promoter region of tumor necrosis factor 7 (TNFcz), interferon 7 (IFN~, and interleukin (IL)-10 genes (regulate tissue levels o f these inflammation-related molecules. We have investigated the genetic association between the progression of PD and these polsanorphisms. MeillOdS: Patients with PD (IN - 134) were recruited, assessed using the Unified Parkinson's Disease Rating Scale (UPDRS) and symptom duration established by history taking at the time of venepuncture. Disease progression was estimated by dividing the UPDRS score by duration of probable disease [1]. Genomic D N A was extracted and sequence-specific primer-polymerase chain reactions (SSP-PCR) used for the polsanorphic IFNy+874 and IL-10-819 loci and P C R restriction of fiagment length used for the polymovphic TNF~-308 locus. Genotype influences (high, intermediate and low expressors) on disease progression were analysed using SPSS-ANOVA. Results: Disease progression was influenced by IL-10-819 genotype (p < 0.05), but not TNFT-308 or IFNy+874 genotypes. Patients with the low expressing IL-10-819 T/T genotype have a more rapidly progressive PD. No s?a~ergistic effects were observed between genotypes (p > 0.05). Conclusions: The IL-10 haplotype with low IL-10 expression levels influences the progression of PD. Patients with alleles predisposing to low expression levels have an accelerated disease process. 1. Gelb DJ et al. Diagnostic criteria for Parkinson's disease. Arch Neurol 1999; 56:33-9.

1005 Inflamlafion-related genes affect age at onset of Parkinson's disease

Cook, NL ~, Huang, Y~, Gartner, C 2, Mellick, G 2, Mastaglia, F 3, Garlepp, M 4, Silburn, p2, Rowe, D 5, Halliday, GM 1. 2Prince of Wales

Medical Research Institute and The University of New South Wales, Sydney, Australia; 2Princess Alexandra Hospital and The School of Medicine, University of Queensland, Brisbane, Australia; 3Centre for Neuromuscular arid Neurological Disorders, University of Western Australia, Perth, Australia; 4Western Australian Biomedical Research Institute arid School of Pharmacy, Curtin University of Technology, Perth, Australia; 5Royal North A~ore Hospital and The University of Sydney, Sydney, Australia

Background: Neuro-inflanmmtion is a prominent feature in the progressive cell death associated with Parkinson's disease (PD). Genetic influences on multiple cytokines participating in inflanmmtion may work in concert to modify PD. In this study we evaluated polymorphisms regulating expression levels of interferon y (IFN% tumor necrosis factor) 7 (TNFT) and interleukin (IL)-I0 genes to determine their impact on age at onset of PD. MeillOdS: PD cases (N - 354) were recruited from three cohorts (Western Australia, New South Wales and Queensland), genomic DNA extracted and sequence-specific primer-polymerase chain reac- tions (SSP-PCR) used for the polymorphic IFNy + 874, IL-10-819 and IL-10-1082 loci and PCR-restriction of fragment length used for the polymorphic TNF c~-308 locus. Genotype influence (high, intermediate and low expressors) on age at disease onset was analysed using SPSS- ANOVA. Results: There was no association between age at onset and TNFcz-308 polymorphisms (iJ -- 0.8). Associations were found between age at onset of PD and IL-10 (-819 p -- 0.004; -1082 p -- 0.08; IL-10 haplotype p -- 0.02) and IFN'?'+874 (p - 0.06) loci. Low expressors of IL-10 (two T alleles) delay PD onset by 7 years compared with high expressors (two C alleles, p -- 0.002). However, in high IL-10 expressors, IFNy + 874 genotype (!figh expressors) rescues age at onset by 3 years (iJ - 0.05). Conehisions: The IL-10 haplotype reflects IL-10 expression levels influencing the onset age of PD: patients with alleles predisposing to higher expression levels have an earlier age of onset of PD. The IFN? + 874 genotype further influences age at onset in people carrying the IL-10-819 C/C genotype.

1006 Levetixacetam in tile treatment of levodopa induced dyskines i~a pilot study

Coulthard, E, Nasinmdeen, A, Wu, K, Cowen, Z, Nemnan, PK. ,,tames Cook University Hospital, Ivliddlesbrough

Background: Dyskinesia is a common, disabling consequence of prolonged treatment with levodopa or dopmnine agonists. Conven- tional drug treatments have only limited benefit. Methods: We carried out a randomized, double-blind, cross-over study investigating the novel antiepilepfic agent levetiracetam as a potential treatment for levodopa induced dyskinesia in patients with Parkinson's disease (PD). Five patients with moderate PD and significant dyskinesia resistant to optimal medical treatment completed dyskinesia diaries and had regular UPDRS assessments over a ten week period. During tiffs time, they were randomised to 2 × 4 week treatment periods (separated by a washout period) with gradually increasing doses of either levetiracetam or placebo. Results: Three patients completed the study and two withdrew with incidental medical problems early in the trial. None of the three complained of significant side effects when taking levetiracetam up to a dose of 1.5g twice daily. Two of the three subjects showed improvement in dyskinesia during the active ann of the trial although this did not reach significance. These two subjects did show a significant reduction of dyskinesia in the week when levetiracetam was taken at high dose compared with the placebo period (p < 0.05). However, the time spent partially or fully 'off ' recorded in the dyskinesia diary was also significantly increased during the active arm of the study in one subject.