Institute of Medical Sciences, University of Aberdeen, Aberdeen, UK.
Department of Neuroscience, University of Cagliari, Cagliari, Italy.
J Neurochem. 2023 Jan;164(2):121-142. doi: 10.1111/jnc.15699. Epub 2022 Nov 9.
Parkinson's disease (PD) is a heterogeneous multi-systemic disorder unique to humans characterized by motor and non-motor symptoms. Preclinical experimental models of PD present limitations and inconsistent neurochemical, histological, and behavioral readouts. The 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) mouse model of PD is the most common in vivo screening platform for novel drug therapies; nonetheless, behavioral endpoints yielded amongst laboratories are often discordant and inconclusive. In this study, we characterized neurochemically, histologically, and behaviorally three different MPTP mouse models of PD to identify translational traits reminiscent of PD symptomatology. MPTP was intraperitoneally (i.p.) administered in three different regimens: (i) acute-four injections of 20 mg/kg of MPTP every 2 h; (ii) sub-acute-one daily injection of 30 mg/kg of MPTP for 5 consecutive days; and (iii) chronic-one daily injection of 4 mg/kg of MPTP for 28 consecutive days. A series of behavioral tests were conducted to assess motor and non-motor behavioral changes including anxiety, endurance, gait, motor deficits, cognitive impairment, circadian rhythm and food consumption. Impairments in balance and gait were confirmed in the chronic and acute models, respectively, with the latter showing significant correlation with lesion size. The sub-acute model, by contrast, presented with generalized hyperactivity. Both, motor and non-motor changes were identified in the acute and sub-acute regime where habituation to a novel environment was significantly reduced. Moreover, we report increased water and food intake across all three models. Overall, the acute model displayed the most severe lesion size, while across the three models striatal dopamine content (DA) did not correlate with the behavioral performance. The present study demonstrates that detection of behavioral changes following MPTP exposure is challenging and does not correlate with the dopaminergic lesion extent.
帕金森病（PD）是一种独特的人类多系统异质性疾病，其特征为运动和非运动症状。PD 的临床前实验模型存在局限性，并且神经化学、组织学和行为学检测结果不一致。1-甲基-4-苯基-1,2,3,6-四氢吡啶（MPTP）PD 小鼠模型是新型药物治疗的最常用体内筛选平台；然而，实验室之间的行为终点往往不一致且没有定论。在这项研究中，我们从神经化学、组织学和行为学方面对三种不同的 MPTP PD 小鼠模型进行了表征，以确定具有 PD 症状特征的转化特征。MPTP 通过腹腔内（i.p.）给药，采用三种不同方案：（i）急性-每 2 小时给予 4 次 20mg/kg 的 MPTP；（ii）亚急性-连续 5 天每天给予 30mg/kg 的 MPTP；（iii）慢性-连续 28 天每天给予 4mg/kg 的 MPTP。进行了一系列行为测试，以评估运动和非运动行为变化，包括焦虑、耐力、步态、运动缺陷、认知障碍、昼夜节律和食物消耗。慢性和急性模型分别确认了平衡和步态受损，后者与病变大小呈显著相关性。相比之下，亚急性模型表现出广泛的过度活跃。急性和亚急性方案均发现了运动和非运动变化，对新环境的习惯显著减少。此外，我们报告了所有三种模型的水和食物摄入量增加。总体而言，急性模型显示出最严重的病变大小，而三种模型的纹状体多巴胺含量（DA）与行为表现没有相关性。本研究表明，MPTP 暴露后行为变化的检测具有挑战性，并且与多巴胺能病变程度无关。
