Vigh Lóránd, Smith R Glenn, Soós Judit, Engelhardt József I, Appel Stanley H, Siklós László
Institute of Biophysics, Biological Research Center, P.O. Box 521, 6701, Szeged, Hungary.
Acta Neuropathol. 2005 Jun;109(6):567-75. doi: 10.1007/s00401-004-0977-1. Epub 2005 Jun 3.
4-Hydroxynonenal (4-HNE), a major lipid peroxidation product, induces oxidative stress, acts as an autonomous effector of cell death in motor neuron hybrid cell cultures, and is elevated in the cerebrospinal fluid (CSF) of patients with amyotrophic lateral sclerosis (ALS). Elevation of the total intracellular calcium has also been demonstrated in motor axon terminals of ALS patients as well as in spinal motor neurons of animal models of familial and sporadic ALS. Since the association of intracellular calcium and oxidative stress has been suggested in ALS, the in vivo effect of intrathecally administered 4-HNE on the motor neuronal calcium level was examined in the spinal cord of rats. After 12 days of treatment, total intracellular calcium was assayed by electron microscopic histochemistry using the oxalate-pyroantimonate method. Morphology of spinal motor neurons was characterized by light and electron microscopy. In rats, 4-HNE treatment induced a mild impairment of gait, elevation of 4-HNE in the CSF, loss of spinal motor neurons, and reduction of total calcium in the surviving, structurally intact motor neurons. 4-HNE could only cause a lesion if glutathione synthesis was concomitantly inhibited in the animals. The results suggest that upstream components of the oxidative injury in relation to lipid peroxidation are necessary to compromise the glutathione system in ALS, allowing an increase of 4-HNE in the CSF, which further aggravates the primary oxidative lesion. The reduced intracellular calcium in the surviving motor neurons with no morphological features of degeneration may reflect an impaired ionic homeostasis, which may indicate a residual damage of an incomplete degenerative process.
4-羟基壬烯醛（4-HNE）是一种主要的脂质过氧化产物，可诱导氧化应激，在运动神经元杂交细胞培养物中作为细胞死亡的自主效应因子起作用，并且在肌萎缩侧索硬化症（ALS）患者的脑脊液（CSF）中含量升高。在ALS患者的运动轴突终末以及家族性和散发性ALS动物模型的脊髓运动神经元中也已证实细胞内总钙升高。由于在ALS中已提示细胞内钙与氧化应激有关联，因此在大鼠脊髓中研究了鞘内注射4-HNE对运动神经元钙水平的体内影响。治疗12天后，使用草酸-焦锑酸盐法通过电子显微镜组织化学测定细胞内总钙。通过光学显微镜和电子显微镜对脊髓运动神经元的形态进行表征。在大鼠中，4-HNE治疗导致步态轻度受损、CSF中4-HNE升高、脊髓运动神经元丢失以及存活的结构完整的运动神经元中总钙减少。只有在动物体内谷胱甘肽合成同时受到抑制时，4-HNE才会导致损伤。结果表明，与脂质过氧化相关的氧化损伤的上游成分对于损害ALS中的谷胱甘肽系统是必要的，这使得CSF中4-HNE增加，进而加剧原发性氧化损伤。存活的运动神经元中细胞内钙减少且无变性的形态学特征可能反映离子稳态受损，这可能表明不完全变性过程的残余损伤。
