Department of Environmental and Public Health Sciences, College of Medicine, University of Cincinnati, 160 Panzeca Way, Cincinnati, Ohio 45267-0056, United States.
Department of Neurology and Rehabilitation Medicine, College of Medicine, University of Cincinnati, Cincinnati, Ohio 45267-0536, United States.
ACS Chem Neurosci. 2021 Jul 7;12(13):2347-2359. doi: 10.1021/acschemneuro.1c00096. Epub 2021 Jun 17.
Parkinson's disease (PD) is a debilitating neurodegenerative disorder. Early symptoms include motor dysfunction and impaired olfaction. Toxic aggregation of α-synuclein (aSyn) in the olfactory bulb (OB) and substantia nigra pars compacta (SNpc) is a hallmark of PD neuropathology. Intranasal (IN) carnosine (2 mg/d for 8 weeks) was previously demonstrated to improve motor behavior and mitochondrial function in Thy1-aSyn mice, a model of PD. The present studies evaluated the efficacy of IN carnosine at a higher dose in slowing progression of motor deficits and aSyn accumulation in Thy1-aSyn mice. After baseline neurobehavioral assessments, IN carnosine was administered (0.0, 2.0, or 4.0 mg/day) to wild-type and Thy1-aSyn mice for 8 weeks. Olfactory and motor behavioral measurements were repeated prior to end point tissue collection. Brain sections were immunostained for aSyn and tyrosine hydroxylase (TH). Immunopositive cells were counted using design-based stereology in the SNpc and OB mitral cell layer (MCL). Behavioral assessments revealed a dose-dependent improvement in motor function with increasing carnosine dose. Thy1-aSyn mice treated with 2.0 or 4.0 mg/d IN carnosine exhibited fewer aSyn-positive (aSyn(+)) cell bodies in the SNpc compared to vehicle-treated mice. Moreover, the number of aSyn(+) cell bodies in carnosine-treated Thy1-aSyn mice was reduced to vehicle-treated wild-type levels in the SNpc. Carnosine treatment did not affect the number of aSyn(+) cell bodies in the OB-MCL or the number of TH(+) cells in the SNpc. In summary, intranasal carnosine treatment decreased aSyn accumulation in the SNpc, which may underlie its mitigation of motor deficits in the Thy1-aSyn mice.
帕金森病（PD）是一种使人虚弱的神经退行性疾病。早期症状包括运动功能障碍和嗅觉受损。α-突触核蛋白（aSyn）在嗅球（OB）和黑质致密部（SNpc）中的毒性聚集是 PD 神经病理学的标志。先前已经证明，鼻内（IN）肌肽（2 mg/d，持续 8 周）可改善 Thy1-aSyn 小鼠（PD 模型）的运动行为和线粒体功能。本研究评估了 IN 肌肽在更高剂量下减缓运动缺陷进展和 Thy1-aSyn 小鼠中 aSyn 积累的疗效。在基线神经行为评估后，向野生型和 Thy1-aSyn 小鼠施用 IN 肌肽（0.0、2.0 或 4.0 mg/天）8 周。在终点组织采集之前重复嗅觉和运动行为测量。用免疫组织化学法对 aSyn 和酪氨酸羟化酶（TH）进行免疫染色。使用基于设计的立体学在 SNpc 和 OB 僧帽细胞层（MCL）中对免疫阳性细胞进行计数。行为评估显示，随着肌肽剂量的增加，运动功能呈剂量依赖性改善。与 vehicle 处理的小鼠相比，用 2.0 或 4.0 mg/d IN 肌肽处理的 Thy1-aSyn 小鼠的 SNpc 中 aSyn 阳性（aSyn(+))细胞体数量减少。此外，肌肽处理的 Thy1-aSyn 小鼠的 SNpc 中 aSyn(+))细胞体数量减少到 vehicle 处理的野生型水平。肌肽处理不会影响 OB-MCL 中的 aSyn(+))细胞体数量或 SNpc 中的 TH(+)细胞数量。总之，鼻内肌肽治疗可减少 SNpc 中 aSyn 的积累，这可能是其减轻 Thy1-aSyn 小鼠运动缺陷的基础。
