Ouary S, Bizat N, Altairac S, Ménétrat H, Mittoux V, Condé F, Hantraye P, Brouillet E
Service Hospitalier Frédéric Joliot, Unité de Recherche Associée 2210, Commissariat à l'Energie Atomique-Centre National de Recherche Scientifique, Département de Recherche Médicale, Direction des Sciences du Vivant, Orsay, France.
Neuroscience. 2000;97(3):521-30. doi: 10.1016/s0306-4522(00)00020-8.
Chronic systemic treatment with 3-nitropropionic acid in rats produces persistent dystonia and bradykinesia, and striatal lesions reminiscent of Huntington's disease. However, the interpretation of results obtained with this model are complicated by a heterogeneous distribution of the response to a given toxic dose of 3-nitropropionic acid: approximately half of the animals develop selective striatal lesions, which in certain cases are associated with extrastriatal lesions, and the other half are apparently spared. Thus, the chronic 3-nitropropionic acid lesion model can be difficult for neuroprotection studies in which a consistent response to neurotoxic treatment is prerequisite. We hypothesized that some of the variability in the model was related to the use of Sprague-Dawley rats, since inter-individual variability in response to various stressful conditions has been described previously in this rat strain. We therefore compared 3-nitropropionic acid toxicity in rat strains known to be highly (Fisher 344) or poorly (Lewis) responsive to stress and compared the distribution of responses to that of Sprague-Dawley rats. In a protocol of intraperitoneal injection, toxicity of 3-nitropropionic acid was highest in Fisher rats, intermediate in Sprague-Dawley rats and lowest in Lewis rats. In addition, survival curves showed a more heterogeneous response to 3-nitropropionic acid toxicity in Sprague-Dawley rats than that observed in Lewis and Fisher rats. These differences between Sprague-Dawley and Lewis rats were confirmed in a protocol of subcutaneous 3-nitropropionic acid intoxication using osmotic minipumps, where doses up to 36-45mg/kg per day for five days were necessary to induce striatal lesions in Lewis rats as compared to 12-14mg/kg per day for five days in Sprague-Dawley rats. The selectivity of the striatum to lesions, and homogeneous progression of symptoms and neurodegeneration, were more consistently observed in Lewis as compared to Sprague-Dawley rats. These results suggest that vulnerability to 3-nitropropionic acid may depend on genetic factors, which could also influence the physiological response to stress. The present findings also establish an improved model of progressive striatal degeneration in the rat adapted for the testing of new neuroprotective strategies.
用3-硝基丙酸对大鼠进行慢性全身治疗会导致持续性肌张力障碍和运动迟缓，并产生类似于亨廷顿病的纹状体病变。然而，该模型所得结果的解读因对给定毒性剂量的3-硝基丙酸的反应分布不均而变得复杂：约一半的动物会出现选择性纹状体病变，某些情况下还伴有纹状体以外的病变，而另一半则明显未受影响。因此，对于神经保护研究而言，慢性3-硝基丙酸损伤模型可能存在困难，因为这类研究需要对神经毒性治疗有一致的反应。我们推测该模型中的一些变异性与使用斯普拉格-道利大鼠有关，因为此前已描述过该大鼠品系对各种应激条件的个体间反应变异性。因此，我们比较了已知对压力高度敏感（费希尔344大鼠）或不敏感（刘易斯大鼠）的大鼠品系中3-硝基丙酸的毒性，并将反应分布与斯普拉格-道利大鼠的进行了比较。在腹腔注射方案中，3-硝基丙酸的毒性在费希尔大鼠中最高，在斯普拉格-道利大鼠中居中，在刘易斯大鼠中最低。此外，生存曲线显示，斯普拉格-道利大鼠对3-硝基丙酸毒性的反应比刘易斯大鼠和费希尔大鼠更具异质性。在使用渗透微型泵进行皮下3-硝基丙酸中毒的方案中，斯普拉格-道利大鼠和刘易斯大鼠之间的这些差异得到了证实，与斯普拉格-道利大鼠连续五天每天12 - 14mg/kg的剂量相比，刘易斯大鼠需要连续五天每天高达36 - 45mg/kg的剂量才能诱导纹状体病变。与斯普拉格-道利大鼠相比，刘易斯大鼠纹状体对病变的选择性以及症状和神经退行性变的均匀进展更为一致。这些结果表明，对3-硝基丙酸的易感性可能取决于遗传因素，这也可能影响对应激的生理反应。目前的研究结果还建立了一种改进的大鼠进行性纹状体变性模型，适用于测试新的神经保护策略。
