Intravitreal MPTP drives retinal ganglion cell loss with oral nicotinamide treatment providing robust neuroprotection.

IF 6.2 2区 医学 Q1 NEUROSCIENCES Acta Neuropathologica Communications Pub Date : 2024-05-21 DOI:10.1186/s40478-024-01782-3
Anne Rombaut, Danica Jovancevic, Raymond Ching-Bong Wong, Alan Nicol, Rune Brautaset, David I Finkelstein, Christine T O Nguyen, James R Tribble, Pete A Williams
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Abstract

Neurodegenerative diseases have common underlying pathological mechanisms including progressive neuronal dysfunction, axonal and dendritic retraction, and mitochondrial dysfunction resulting in neuronal death. The retina is often affected in common neurodegenerative diseases such as Parkinson's and Alzheimer's disease. Studies have demonstrated that the retina in patients with Parkinson's disease undergoes changes that parallel the dysfunction in the brain. These changes classically include decreased levels of dopamine, accumulation of alpha-synuclein in the brain and retina, and death of dopaminergic nigral neurons and retinal amacrine cells leading to gross neuronal loss. Exploring this disease's retinal phenotype and vision-related symptoms is an important window for elucidating its pathophysiology and progression, and identifying novel ways to diagnose and treat Parkinson's disease. 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) is commonly used to model Parkinson's disease in animal models. MPTP is a neurotoxin converted to its toxic form by astrocytes, transported to neurons through the dopamine transporter, where it causes mitochondrial Complex I inhibition and neuron degeneration. Systemic administration of MPTP induces retinal changes in different animal models. In this study, we assessed the effects of MPTP on the retina directly via intravitreal injection in mice (5 mg/mL and 50 mg/mL to 7, 14 and 21 days post-injection). MPTP treatment induced the reduction of retinal ganglion cells-a sensitive neuron in the retina-at all time points investigated. This occurred without a concomitant loss of dopaminergic amacrine cells or neuroinflammation at any of the time points or concentrations tested. The observed neurodegeneration which initially affected retinal ganglion cells indicated that this method of MPTP administration could yield a fast and straightforward model of retinal ganglion cell neurodegeneration. To assess whether this model could be amenable to neuroprotection, mice were treated orally with nicotinamide (a nicotinamide adenine dinucleotide precursor) which has been demonstrated to be neuroprotective in several retinal ganglion cell injury models. Nicotinamide was strongly protective following intravitreal MPTP administration, further supporting intravitreal MPTP use as a model of retinal ganglion cell injury. As such, this model could be utilized for testing neuroprotective treatments in the context of Parkinson's disease and retinal ganglion cell injury.

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视网膜内 MPTP 会导致视网膜神经节细胞缺失,而口服烟酰胺可提供强有力的神经保护。
神经退行性疾病具有共同的潜在病理机制,包括进行性神经元功能障碍、轴突和树突回缩,以及导致神经元死亡的线粒体功能障碍。帕金森病和阿尔茨海默病等常见的神经退行性疾病通常会影响视网膜。研究表明,帕金森病患者的视网膜会发生与大脑功能障碍相似的变化。这些变化通常包括多巴胺水平下降、α-突触核蛋白在大脑和视网膜中积聚、多巴胺能黑质神经元和视网膜杏仁核细胞死亡,从而导致神经元的严重缺失。探索这种疾病的视网膜表型和视力相关症状是阐明其病理生理学和进展的一个重要窗口,也是确定诊断和治疗帕金森病的新方法的一个重要窗口。1-甲基-4-苯基-1,2,3,6-四氢吡啶(MPTP)通常用于在动物模型中模拟帕金森病。MPTP 是一种神经毒素,由星形胶质细胞转化为毒性形式,通过多巴胺转运体转运到神经元,导致线粒体复合体 I 受抑制和神经元变性。在不同的动物模型中,MPTP 的全身给药会诱发视网膜变化。在本研究中,我们直接通过静脉注射(5 毫克/毫升和 50 毫克/毫升,注射后 7 天、14 天和 21 天)评估了 MPTP 对小鼠视网膜的影响。在所有调查时间点上,MPTP 处理都会导致视网膜神经节细胞(视网膜中的一种敏感神经元)减少。在测试的任何时间点或浓度下,都不会同时出现多巴胺能羊膜细胞的丢失或神经炎症。观察到的神经变性最初影响视网膜神经节细胞,这表明这种 MPTP 给药方法可以快速、直接地建立视网膜神经节细胞神经变性模型。为了评估这种模型是否可以用于神经保护,小鼠口服了烟酰胺(一种烟酰胺腺嘌呤二核苷酸前体)。尼古丁酰胺在玻璃体内注射 MPTP 后具有很强的保护作用,进一步支持将玻璃体内注射 MPTP 用作视网膜神经节细胞损伤模型。因此,该模型可用于测试帕金森病和视网膜神经节细胞损伤的神经保护疗法。
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来源期刊
Acta Neuropathologica Communications
Acta Neuropathologica Communications Medicine-Pathology and Forensic Medicine
CiteScore
11.20
自引率
2.80%
发文量
162
审稿时长
8 weeks
期刊介绍: "Acta Neuropathologica Communications (ANC)" is a peer-reviewed journal that specializes in the rapid publication of research articles focused on the mechanisms underlying neurological diseases. The journal emphasizes the use of molecular, cellular, and morphological techniques applied to experimental or human tissues to investigate the pathogenesis of neurological disorders. ANC is committed to a fast-track publication process, aiming to publish accepted manuscripts within two months of submission. This expedited timeline is designed to ensure that the latest findings in neuroscience and pathology are disseminated quickly to the scientific community, fostering rapid advancements in the field of neurology and neuroscience. The journal's focus on cutting-edge research and its swift publication schedule make it a valuable resource for researchers, clinicians, and other professionals interested in the study and treatment of neurological conditions.
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