パーキンソン病 Perkinson's disease
O1-9-6-1 ドーパミンD2受容体アゴニストであるカベルゴリンの発揮する神経保護作用 Protective effect of cabergoline, a dopamine D2 receptor agonist, on cultured neurons ○小高陽樹1,2, 沼川忠広2,3, 安達直樹2,3, 大島淑子2, 井上貴文1, 功刀浩2,3 ○Haruki Odaka1,2, Tadahiro Numakawa2,3, Naoki Adachi2,3, Yoshiko Ooshima2, Takafumi Inoue1, Hiroshi Kunugi2,3 早稲田大学　先進理工学部生命医科学科1, 国立精神・神経医療研究センター, 神経研究所, 疾病研究第三部2, 戦略的創造研究推進事業、科学技術振興機構3 Dept Life Sci Medl Biosci, Univ of Waseda, Tokyo, Japan1, Department of Mental Disorder Research, National Institute of Neuroscience, National Center of Neurology and Psychiatry, Tokyo, Japan2, CREST, JST, Saitama, Japan3 Cabergoline, a selective D2 receptor agonist, is useful as an agent for neurodegenerative diseases. Although Parkinson's disease is assumed to be caused by loss of dopaminergic function (including a contribution of D2 receptor-mediated function) in striatum, an expression of D2 receptor is also observed in cerebral cortex. Previous studies show cabergoline has a protective effect against oxidative stress in SH-SY5Y cells and striatal neurons, however, possible influence in cortical neurons were still unknown. Here, we found that cabergoline prevented hydrogen peroxide-induced cell death in cultured cortical neurons. We investigated molecular mechanism underlying the neuroprotection, and found that cabergoline suppressed hydrogen peroxide-induced activation of ERK, one of the intracellular signalings. Furthremore, we confirmed that ERK pathway inhibitor, U0126, selectively abolished levels of pERK and suppressed neuronal cell death, suggesting that cabergoline has protective effect through repressing of ERK over-activation.	O1-9-6-2 MPTP誘発パーキンソン病モデルマウスに対するノルアドレナリン作動性・特異的セロトニン作動性抗うつ薬ミルタザピンの治療効果 Therapeutic effect of a noradrenergic and specific serotonergic antidepressant mirtazapine on MPTP-induced mice model for Parkinson's disease ○門口直仁1,2, 岡部真二1, 山村行生1, 深野達也1, 横山宏典1, 笠原二郎1 ○Naoto Kadoguchi1,2, Shinji Okabe1, Yukio Yamamura1, Tatsuya Fukano1, Hironori Yokoyama1, Jiro Kasahara1 徳島大院・薬・神経病態解析1, 高知医療センター・薬剤局2 Dept Neurobiol Therapeu, Grad Sch Pharmaceu Sci, Inst Health Biosci, Univ Tokushima,Tokushima, JAPAN1, Dept Pharm, Kochi Health Sciences Center, Kochi2 Mirtazapine (MTZ), a noradrenergic and specific serotonergic antidepressant (NaSSA), shows multiple pharmacological actions such as inhibiting presynaptic α2 adrenergic receptor and selectively activating 5-hydroxytriptamine (5-HT) 1A receptor. MTZ was also reported to increase dopamine (DA) release in the cortical neurons with these mechanisms, making us expect to expand its application on Parkinson's disease (PD). To examine whether MTZ has a therapeutic potency in PD, we applied this compound on MPTP-treated mice model for PD. Male C57Bl/6 mice were subjected of MPTP treatment to establish PD model. MTZ was administered once in a day after MPTP treatment. MPTP-induced motor dysfunction examined by beam-walk and rota-rod tests was significantly improved by administration of MTZ with 16 mg/kg/day for 3 days. Quantification of DA and its metabolites by high performance liquid chromatography (HPLC) showed increased turnover rate of DA in the striatum by MTZ after MPTP treatment, suggesting MTZ increased DA release. These therapeutic effects of MTZ were cancelled by WAY-100635, an inhibitor for 5HT1A receptor, or by clonidine, a selective agonist for α2 adrenergic receptor, or by prazosin, an inhibitor for α1 adrenergic receptor, respectively, suggesting these receptors were involved in the action of MTZ. On the other hand, MTZ did not recovered MPTP-induced decrease of DA, its metabolites, and protein expression of markers for DA neurons, indicating it did not inhibit the neurodegenerative process of nigro-striatal DA neurons triggered by MPTP. All of these results we found strongly suggest MTZ has a therapeutic potency against PD with increasing DA release in striatum by 5-HT and/or noradrenergic receptor(s)-dependent manner. Since depression is one of a frequently observed psychiatric disturbance in addition to the extrapyramidal syndrome in PD, MTZ is expected to exert dual therapeutic effects both on depression and motor dysfunction for PD patients.
O1-9-6-3 パーキンソン病患者の脳内における酸化DJ-1の生成ーパーキンソン病の早期診断バイオマーカーの可能性について Oxidation of DJ-1 in the brain of Parkinson disease patients-possible biomarker for diagnosis of Parkinson disease at early stage ○斎藤芳郎1, 宮坂知宏2, 浜窪隆雄3, 二木鋭雄4, 井原康夫2, 野口範子1 ○Yoshiro Saito1, Tomohiro Miyasaka2, Takao Hamakubo3, Etsuo Niki4, Yasuo Ihara2, Noriko Noguchi1 同志社大・生命医・システム生命科学1, 同志社大・生命医・神経病理2, 東大・先端研3, 産総研・健康工学4 Sys. Life Sci. Lab., Fac. of Life Med. Sci., Doshisha Univ.1, Neuropath., Fac. of Life Med. Sci., Doshisha Univ.2, RCAST, Univ. of Tokyo3, Health Res. Inst., AIST4 DJ-1, the product of a causative gene of a familial form of Parkinson's disease (PD), has been reported to undergo preferential oxidation of cysteine residue at position 106 (Cys-106) under oxidative stress. Using specific antibodies against Cys-106-oxidized DJ-1, it has been found that the levels of oxidized DJ-1 in erythrocytes of unmedicated PD patients are markedly higher than those in medicated PD patients and healthy subjects. In the present study, we examined oxidized DJ-1 immunoreactivity (oxDJ-1 IR) in brain sections from cases classified with Lewy body (LB) stages, including PD, PD with dementia (PDD), dementia with Lewy body (DLB), and Alzheimer's disease (AD). In neuromelanin-containing neurons of the substantia nigra, oxDJ-1 IR was slightly observed, whereas LBs showed faint oxDJ-1 IR. OxDJ-1 was detected in the reactive astrocytes. It was found that neurons in the inferior olivary nucleus (ION), where LBs were spared, showed prominent oxDJ-1 IR in patients with early LB stage. We observed that oxDJ-1 IR of the ION specifically decreased in PDD patients at LB stage 4 and 5, but not in DLB and AD patients with same LB stage. Our observations suggest that DJ-1 oxidation is biologically significant for neuronal cell survival and the process of neurodegenerative diseases. These results also suggest that the oxidative modification of DJ-1 in the brain and erythrocytes is involved in the pathogenesis of PD. In this presentation, we will discuss the potential application of the oxDJ-1 levels for diagnosis of PD at early-stage.	O1-9-6-4 Metabolic Brain Network Mediating the Placebo Response in Parkinson's Disease ○Ji Hyun Ko1, Chris Chengke Tang1, Andrew Feigin1, Yilong Ma1, Matthew J. During2, Michael G. Kaplitt3, Eidelberg David1 Feinstein Institute for Medical Research1, Ohio State University College of Medicine, Columbus, OH, USA2 Objective: Recently, the general practice of sham surgery as a placebo-control condition for surgical trials has been challenged reasoning unethical for patients' right to receive the best available care and high probability of rejecting efficient treatment due to the potent placebo effects. While consensus alternatives for research strategy have been lacking, we propose a novel approach to use an imaging-based biomarker for placebo effect which expresses distinctive feature from the real treatment effect. Method: We have investigated 23 sham-surgery-treated Parkinson's disease (PD) patients who underwent FDG-PET scans at pre-surgery (baseline) and 6 months after. 16 patients showed clinical improvement measured by UPDRS-III. Among those improved, 8 patients were selected and analyzed with Ordinal Trends/Canonical Variates Analysis, which identified the brain metabolic pattern that is increased 6 months after the surgery compared to the baseline. Then, we prospectively computed this placebo-related pattern (PlcRP) expression in another set of patients who benefited (#1) and not benefited (#2) from sham surgery, patients who benefited from the real gene therapy (#3), and patients who received open-label levodopa (#4). Result: The resulting PlcRP was consisted of increased FDG uptake in the subgenual anterior cingulate cortex, cerebellar vermis and other limbic regions. The pattern expression was significantly different between the improved (#1) and non-improved (#2) patients (p=0.031). In addition, the increase in PlcRP expression was positively correlated with improved clinical output (p &It; 0.001). This was not found in patients who received real treatment (#3 & #4, p>0.05). Conclusion: This result suggests that one can prove that the underlying mechanisms of the real treatment effect is distinct from placebo treatment effect, even if the clinical outcome (e.g., UPDRS motor scores) are only marginally different.

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