Studies on mechanism of neuronal death induced by an amyotrophic lateral sclerosis

S-烯丙基-L-半胱氨酸（SAC）是老化大蒜提取物中的一种有机硫化合物，具有多种生物学效应，包括神经营养活性。我们研究了淀粉样β蛋白（Aβ）、4-羟基壬烯醛（HNE）、衣霉素（Tm）和营养因子剥夺诱导的神经元死亡，并研究了SAC是否以及如何预防培养的大鼠海马神经元的这些神经元死亡。用SAC处理可防止A-和衣霉素诱导的神经元死亡，这已被证明主要通过以浓度依赖性方式下调内质网（ER）应激（ER）反应来介导。与此相反，它没有提供对HNE和营养因子剥夺诱导的细胞死亡的保护，其中caspase-3在这些神经元死亡中发挥了关键作用。这些结果表明，SAC可以保护海马中由ER功能障碍触发的神经元细胞死亡，并且它对依赖于caspase-3介导的通路的神经元死亡没有影响。我们还研究了HNE诱导的神经毒性的情况下，和存在的L-谷氨酸（Glu）在器官型海马和脊髓切片培养制备6或7日龄大鼠。在切片培养物中，仅用HNE（25-100 μM）或Aβ（25和50 mM）处理时观察到很少的神经毒性。尽管单独的Glu（2.5和5.0 mM）在培养的脊髓中表现出轻微的神经元死亡，但在存在HNE（50 μM）的情况下，这种神经元死亡显著增加。泛半胱天冬酶抑制剂z-VAD-favorite可部分保护神经元免受Glu与HNE联合诱导的神经元死亡。这些结果表明，半胱天冬酶介导的途径是，至少部分，负责这种神经元死亡。

S-allyl-L-cysteine (SAC), one of the organosulfur compounds in aged garlic extract, has been shown to possess various biological effects including neurotrophic activity. We characterized neuronal death induced by amyloid beta-protein (Aβ), 4-hydroxynonenal (HNE), Tunicamycin (Tm) and trophic factor deprivation, and investigated whether and how SAC could prevent these neuronal deaths in cultured hippocampal neurons in rats. Treatment with SAC protected against A- and tunicamycin-induced neuronal death which has been shown to be mediated predominantly through the down regulation of endoplasmic reticurum (ER) stress (ER) response in a concentration-dependent manner. In contrast, it afforded no protection against HNE- and trophic factor deprivation-induced cell death, in which caspase-3 played a pivotal role in these neuronal deaths. These results suggest that SAC could protect against neuronal cell death which is triggered by ER dysfunction in the hippocampus, and that it has no effect on neuronal death which is dependent on caspase-3 mediated pathway. We also examined HNE-induced neurotoxicity in the absence and presence of L-glutamic acid (Glu) in organotypic hippocampal and spinal cord slice coltures prepared from 6- or 7-day-old rats. In slice cultures, little neurotoxicity was observed by the treatment with HNE (25-100 μM) or Aβ (25 and 50 mM) alone. Although Glu (2.5 and 5.0 mM) alone exhibited slight neuronal death in cultured spinal cord, this neuronal death was dramatically increased in the presence of HNE (50 μM). A pan-caspase inhibitor, z-VAD-fmk, partially protected neurons from neuronal death induced by Glu in combination with HNE. These results suggest that caspases-mediated pathway is, at lease in part, responsible for this neuronal death.