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首页> 外文期刊>The European Journal of Neuroscience >NMDA antagonists exacerbate neuronal death caused by proteasome inhibition in cultured cortical and striatal neurons.
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NMDA antagonists exacerbate neuronal death caused by proteasome inhibition in cultured cortical and striatal neurons.

机译：NMDA拮抗剂加剧了在培养的皮层和纹状体神经元中蛋白酶体抑制引起的神经元死亡。

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摘要

The proteasome is involved in multiple cellular processes including control of the cell cycle, apoptosis and intracellular signalling; loss of proteasome function has been postulated to participate in the pathogenesis of triplet repeat diseases. We examined the vulnerability of central neurons to proteasome inhibition and tested the ability of anti-excitotoxic and anti-apoptotic treatments to attenuate proteasome inhibition-induced neuronal death. Exposure of murine neocortical cultures to proteasome inhibitors (0.1-10 microm clasto-lactacystin beta-lactone or MG-132) for 48 h resulted in widespread neuronal death associated with a reduction in intracellular free calcium; higher inhibitor concentrations killed astrocytes. Cultured striatal neurons were more vulnerable than cortical neurons. Within each population, the NADPH diaphorase-positive neuronal subpopulation was more vulnerable than the general neuronal population. Enhancing calcium entry with S(-)BayK8644 or kainate, or blocking apoptosis with cycloheximide, actinomycin D or Z-VAD.FMK attenuated neuronal death, whereas, reducing calcium entry with NMDA antagonists or R(+)BayK8644 potentiated neuronal death. These findings suggest that proteasome inhibition can induce selective neuronal apoptosis associated with intracellular calcium starvation, and point to manipulation of intracellular calcium as a specific therapeutic strategy. In particular, concern is raised that glutamate receptor antagonists might exacerbate, rather than attenuate, proteasome inhibition-induced neuronal death.
机译：蛋白酶体参与多个细胞过程，包括控制细胞周期，细胞凋亡和细胞内信号传导。推测蛋白酶体功能的丧失参与三联体重复疾病的发病机理。我们检查了中枢神经元对蛋白酶体抑制作用的脆弱性，并测试了抗兴奋性和抗凋亡疗法减轻蛋白酶体抑制作用诱导的神经元死亡的能力。将鼠新皮层培养物暴露于蛋白酶体抑制剂（0.1-10微米的clasto-lactacystinβ-内酯或MG-132）中48小时会导致广泛的神经元死亡，并伴有细胞内游离钙的减少。较高的抑制剂浓度会杀死星形胶质细胞。培养的纹状体神经元比皮质神经元更脆弱。在每个人群中，NADPH心肌黄递酶阳性的神经元亚群比普通神经元人群更脆弱。用S（-）BayK8644或海藻酸盐增强钙的进入，或用环己酰亚胺，放线菌素D或Z-VAD阻断细胞凋亡。FMK减轻神经元的死亡，而通过NMDA拮抗剂或R（+）BayK8644增强的钙的进入可增强神经元的死亡。这些发现表明蛋白酶体的抑制可以诱导与细胞内钙饥饿相关的选择性神经元凋亡，并指出操纵细胞内钙作为一种特定的治疗策略。特别地，引起关注的是谷氨酸受体拮抗剂可能加剧而不是减弱蛋白酶体抑制引起的神经元死亡。

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