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脊髓内凋亡和血管内皮生长因子系统受损与神经鞘磷脂病相关的大鼠后肢轻瘫模型

Hind-limb paraparesis in a rat model for neurolathyrism associated with apoptosis and an impaired vascular endothelial growth factor system in the spinal cord.

机构信息

Research Unit of Molecular Cell Biology, College of Pharmacy, Nihon University, Chiba 274-8555, Japan.

出版信息

J Comp Neurol. 2010 Mar 15;518(6):928-42. doi: 10.1002/cne.22257.

Abstract

Neurolathyrism is a motor neuron disease characterized by lower limb paraparesis. It is associated with ingestion of a plant excitotoxin, beta-N-oxalyl-L-alphabeta-diaminopropionic acid (L-beta-ODAP), an agonist of alpha-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid (AMPA)/kainate-type glutamatergic receptors. Previously, a limited model of neurolathyrism was reported for the rat. To improve upon the model, we stressed rat pups by separation from their mothers, followed by the subcutaneous L-beta-ODAP treatment, resulting in a 4.6-fold higher incidence (14.0-15.6%) of the paraparesis compared with the prior study. The number and size of motor neurons in these rats were decreased only in the lumbar and sacral cord segments, at approximately 13-36 weeks after treatment. Only lumbar and sacral spinal cord tissue revealed pathological insults typical of physical and ischemic spinal cord injury in the surviving motor neurons. In addition, extensive but transient hemorrhage occurred in the ventral spinal cord parenchyma of the rat, and numerous TdT-mediated dUTP-biotin nick end-labeling (TUNEL)-positive cells were also observed. In parallel, vascular endothelial growth factor receptor (VEGFR)-2 (Flk-1) levels were significantly lowered in the lumbosacral spinal cord of the paraparetic rats compared with their controls, suggesting a failure of the VEGF system to protect neurons against L-beta-ODAP toxicity. We propose, based on these data, a novel pathological process of motor neuron death induced by peripheral L-beta-ODAP. For the first time, we present a model of the early molecular events that occur during chemically induced spinal cord injury, which can potentially be applied to other neurodegenerative disorders.

摘要

神经莱尔病是一种以下肢轻瘫为特征的运动神经元疾病。它与植物兴奋性毒素β-N-草酰基-L-α-β-二氨基丙酸(L-β-ODAP)的摄入有关,L-β-ODAP 是α-氨基-3-羟基-5-甲基-4-异恶唑丙酸(AMPA)/海人藻酸型谷氨酸能受体的激动剂。以前,曾报道过一种有限的大鼠神经莱尔病模型。为了改进该模型,我们通过将幼鼠与其母亲分离来对其进行应激处理,然后对其进行皮下 L-β-ODAP 处理,导致轻瘫的发生率(14.0-15.6%)比以前的研究高 4.6 倍。在治疗后大约 13-36 周,这些大鼠的腰椎和骶段脊髓中的运动神经元数量和大小减少。只有腰椎和骶段脊髓组织显示出存活运动神经元中物理和缺血性脊髓损伤的典型病理性损伤。此外,在大鼠的脊髓腹侧实质中还发生了广泛但短暂的出血,并且还观察到了许多 TdT 介导的 dUTP-生物素切口末端标记(TUNEL)阳性细胞。同时,在轻瘫大鼠的腰骶部脊髓中,血管内皮生长因子受体(VEGFR)-2(Flk-1)水平明显降低,这表明 VEGF 系统未能保护神经元免受 L-β-ODAP 毒性的影响。我们根据这些数据提出了一种由周围 L-β-ODAP 诱导的运动神经元死亡的新病理过程。我们首次提出了一种化学诱导性脊髓损伤早期分子事件的模型,该模型可能适用于其他神经退行性疾病。

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