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

s -烯丙基- l-半胱氨酸（SAC）是陈化大蒜提取物中的有机硫化合物之一，具有多种生物效应，包括神经营养活性。我们描述了淀粉样β蛋白（Aβ）、4-羟基壬烯醛（HNE）、Tunicamycin （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治疗可以防止A-和tunicamycin诱导的神经元死亡，这主要是通过内质网（ER）应激（ER）反应的下调以浓度依赖的方式介导的。相反，它对HNE和营养因子剥夺诱导的细胞死亡没有保护作用，其中caspase-3在这些神经元死亡中起关键作用。这些结果表明，SAC对海马内质网功能障碍引发的神经元细胞死亡具有保护作用，而对依赖于caspase-3介导通路的神经元死亡无影响。我们还研究了6日龄或7日龄大鼠制备的器官型海马和脊髓切片结肠在缺乏和存在l -谷氨酸（Glu）的情况下，hne诱导的神经毒性。在切片培养中，HNE （25-100 μM）或Aβ（25和50 mM）单独处理的神经毒性很小。虽然Glu （2.5 mM和5.0 mM）单独在培养脊髓中表现出轻微的神经元死亡，但HNE （50 μM）的存在显著增加了神经元死亡。一种泛caspase抑制剂z-VAD-fmk可以部分保护Glu联合HNE诱导的神经元死亡。这些结果表明，caspase介导的途径至少在一定程度上导致了这种神经元的死亡。

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.