Hypertension Unit, Chaim Sheba Medical Center, Tel-HaShomer, Ramat Gan 5265601, Israel.
Faculty of Medicine, Tel Aviv University, Tel Aviv 6997801, Israel.
Int J Mol Sci. 2023 Aug 7;24(15):12522. doi: 10.3390/ijms241512522.
The catecholaldehyde hypothesis for the pathogenesis of Parkinson's disease centers on accumulation of 3,4-dihydroxyphenylacetaldehyde (DOPAL) in dopaminergic neurons. To test the hypothesis, it is necessary to reduce DOPAL and assess if this improves locomotor abnormalities. Systemic administration of rotenone to rats reproduces the motor and central neurochemical abnormalities characterizing Parkinson's disease. In this study, we used the monoamine oxidase inhibitor (MAOI) deprenyl to decrease DOPAL production, with or without the antioxidant N-acetylcysteine (NAC). Adult rats received subcutaneous vehicle, rotenone (2 mg/kg/day via a minipump), or rotenone with deprenyl (5 mg/kg/day i.p.) with or without oral NAC (1 mg/kg/day) for 28 days. Motor function tests included measures of open field activity and rearing. Striatal tissue was assayed for contents of dopamine, DOPAL, and other catechols. Compared to vehicle, rotenone reduced locomotor activity (distance, velocity and rearing); increased tissue DOPAL; and decreased dopamine concentrations and inhibited vesicular sequestration of cytoplasmic dopamine and enzymatic breakdown of cytoplasmic DOPAL by aldehyde dehydrogenase (ALDH), as indicated by DA/DOPAL and DOPAC/DOPAL ratios. The addition of deprenyl to rotenone improved all the locomotor indices, increased dopamine and decreased DOPAL contents, and corrected the rotenone-induced vesicular uptake and ALDH abnormalities. The beneficial effects were augmented when NAC was added to deprenyl. Rotenone evokes locomotor and striatal neurochemical abnormalities found in Parkinson's disease, including DOPAL buildup. Administration of an MAOI attenuates these abnormalities, and NAC augments the beneficial effects. The results indicate a pathogenic role of DOPAL in the rotenone model and suggest that treatment with MAOI+NAC might be beneficial for Parkinson's disease treatment.
儿茶酚醛假说认为帕金森病的发病机制与多巴胺能神经元中 3,4-二羟苯乙醛（DOPAL）的积累有关。为了验证这一假说，有必要减少 DOPAL 的含量，并评估这是否能改善运动异常。向大鼠系统给予鱼藤酮可复制出帕金森病的运动和中枢神经化学异常。在这项研究中，我们使用单胺氧化酶抑制剂（MAOI）deprenyl 来减少 DOPAL 的产生，同时使用或不使用抗氧化剂 N-乙酰半胱氨酸（NAC）。成年大鼠接受皮下载体、鱼藤酮（每天通过微型泵 2mg/kg）或鱼藤酮与 deprenyl（每天腹腔内 5mg/kg），同时或不给予口服 NAC（每天 1mg/kg），共 28 天。运动功能测试包括开放场活动和站立测试。纹状体组织中多巴胺、DOPAL 和其他儿茶酚的含量进行了检测。与载体相比，鱼藤酮降低了运动活性（距离、速度和站立）；增加了组织中的 DOPAL；降低了多巴胺浓度，并抑制了囊泡摄取细胞质多巴胺和细胞质 DOPAL 的酶促分解，如 DA/DOPAL 和 DOPAC/DOPAL 比值所示。将 deprenyl 加入到鱼藤酮中可以改善所有的运动指标，增加多巴胺并减少 DOPAL 的含量，并纠正了鱼藤酮诱导的囊泡摄取和 ALDH 异常。当将 NAC 添加到 deprenyl 中时，有益效果会增强。鱼藤酮引发了帕金森病中发现的运动和纹状体神经化学异常，包括 DOPAL 的积累。给予 MAOI 可减轻这些异常，而 NAC 则增强了有益效果。结果表明 DOPAL 在鱼藤酮模型中具有致病性作用，并提示 MAOI+NAC 治疗可能对帕金森病的治疗有益。
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