坏死性凋亡参与NMDA诱导大鼠皮层神经元的兴奋性神经毒作用
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摘要
谷氨酸是中枢神经系统重要的兴奋性神经递质,在神经发育、突触传递、突触可塑性、学习、记忆等一系列脑功能活动中发挥重要作用。而过量谷氨酸可引起NMDA受体的过度活化并诱导神经元死亡,该作用被称为兴奋性神经毒(excitotoxicity)。兴奋毒在许多急慢性疾病中发挥重要作用包括神经退行性疾病、不同原因造成的神经损伤包括缺血/再灌的损伤。根据谷氨酸作用的相对强度和持续时间不同,兴奋毒引起的损伤可能存在坏死或凋亡等不同的细胞死亡形式。坏死性凋亡是新近发现的一种细胞死亡方式,由于兼具坏死及凋亡的特征因此得名,包括出现坏死的形态特征及某些凋亡的信号通路同时伴随自噬的活化。Necrostatin-1(Nec-1)是一种特异且有效的抑制坏死性凋亡的小分子物质,可用来鉴定在神经损伤中是否存在坏死性凋亡的途径。迄今为止,坏死性凋亡的机制并不清楚,Nec-1的发现为评价坏死性凋亡的特征及作用提供了唯一的可能。本研究利用Nec-1作为工具药,通过观察Nec-1对NMDA诱导的兴奋毒的抑制作用,从而明确NMDA诱导的兴奋毒中是否存在坏死性凋亡以及钙超载在其中的作用。实验中通过检测细胞活力、LDH释放及Calcein-AM染色观察NMDA的毒性作用及证实Nec-1的抑制作用,通过激光共聚焦检测NMDA引起的胞内Ca~(2+)升高及Nec-1的作用,证实Ca~(2+)超载在坏死性凋亡的作用。
结果显示:1. Nec-1抑制NMDA引起的细胞活力的降低。换句话也就是说Nec-1预处理引起细胞活力的增加,并呈剂量依赖性。Nec-1(30μmol/L)和Nec-1(100μmol/L)分别使其增加12%(p < 0.05)和26%(p < 0.01),但Nec-1(10μmol/L)并不能抑制NMDA引起的细胞活力的降低。
2. Nec-1抑制NMDA引起的活细胞数的减少。Nec-1(30μmol/L)和Nec-1(100μmol/L)分别使活细胞数增加11%(p < 0.05)和23%(p < 0.01)。
3. Nec-1抑制NMDA引起的LDH释放的增加。Nec-1(30μmol/L)和Nec-1(100μmol/L)分别使LDH释放减少14%(p < 0.05)和28%(p < 0.01)。
4. Nec-1抑制NMDA引起的胞内Ca~(2+)的升高。Nec-1(100μmol/L)使NMDA诱导的胞内Ca~(2+)的升高降低36%(p < 0.05)。
上述结果表明,除坏死和凋亡外,坏死性凋亡也参与兴奋性神经毒的病理过程。由于NMDA引起兴奋毒在多种损伤中发挥重要作用,因此预防和治疗兴奋毒对预防和治疗神经损伤有至关重要的意义。由于坏死性凋亡具有可调控的特征,因此提供了一个更有意义的预防治疗兴奋性神经毒的靶点。结论:1.坏死性凋亡参与NMDA诱导的兴奋毒;2.胞内Ca~(2+)升高可能是坏死性凋亡发生的机制之一;3.尽管坏死性凋亡在NMDA诱导的兴奋毒中起作用,但其作用可能仅占其中一小部分。
Glutamate is the primary excitatory amino acid neurotransmitter in the central nervous system. Excess of glutamate can cause excessive activation of N-methyl-D-aspartate (NMDA) receptors and induce neuronal death described as excitotoxicity. Excitotoxicity is involved in a wide range of acute and chronic diseases with both necrosis and apoptosis, depending on the relative intense and time course. Necroptosis is a newly discovered type of cell death characterized with the combined biochemical and ultrastructural features of necrosis and apoptosis. Nec-1 has been reported to exhibit the selective inhibition for necroptosis, which has now been used as an operational definition of necroptosis. The purpose of this study was to evaluate whether necroptosis is involved in the NMDA-induced excitotoxicity and furthermore whether the elevation of intracellular Ca~(2+) is involved in the NMDA-induced necroptosis. Our findings showed that Nec-1 (100μmol/L) inhibited NMDA-induced decrease of cell viability by 26% (p < 0.01), suppressed NMDA-induced decrease of living cells by 23% (p < 0.01) and attenuated NMDA-induced leakage of LDH by 28% (p < 0.01). In addition, Nec-1 also suppressed NMDA-induced the elevation of intracellular Ca~(2+) by 36% (p < 0.05). These findings indicated for the first time that necroptosis contributes to the NMDA-induced excitotoxicity, and the elevation of intracellular Ca~(2+) may be one of potential mechanisms underlying NMDA-induced necroptosis. Although necroptosis involved in the NMDA-induced excitotoxicity, it may just constitute a small contribution.
结果显示:1. Nec-1抑制NMDA引起的细胞活力的降低。换句话也就是说Nec-1预处理引起细胞活力的增加,并呈剂量依赖性。Nec-1(30μmol/L)和Nec-1(100μmol/L)分别使其增加12%(p < 0.05)和26%(p < 0.01),但Nec-1(10μmol/L)并不能抑制NMDA引起的细胞活力的降低。
2. Nec-1抑制NMDA引起的活细胞数的减少。Nec-1(30μmol/L)和Nec-1(100μmol/L)分别使活细胞数增加11%(p < 0.05)和23%(p < 0.01)。
3. Nec-1抑制NMDA引起的LDH释放的增加。Nec-1(30μmol/L)和Nec-1(100μmol/L)分别使LDH释放减少14%(p < 0.05)和28%(p < 0.01)。
4. Nec-1抑制NMDA引起的胞内Ca~(2+)的升高。Nec-1(100μmol/L)使NMDA诱导的胞内Ca~(2+)的升高降低36%(p < 0.05)。
上述结果表明,除坏死和凋亡外,坏死性凋亡也参与兴奋性神经毒的病理过程。由于NMDA引起兴奋毒在多种损伤中发挥重要作用,因此预防和治疗兴奋毒对预防和治疗神经损伤有至关重要的意义。由于坏死性凋亡具有可调控的特征,因此提供了一个更有意义的预防治疗兴奋性神经毒的靶点。结论:1.坏死性凋亡参与NMDA诱导的兴奋毒;2.胞内Ca~(2+)升高可能是坏死性凋亡发生的机制之一;3.尽管坏死性凋亡在NMDA诱导的兴奋毒中起作用,但其作用可能仅占其中一小部分。
Glutamate is the primary excitatory amino acid neurotransmitter in the central nervous system. Excess of glutamate can cause excessive activation of N-methyl-D-aspartate (NMDA) receptors and induce neuronal death described as excitotoxicity. Excitotoxicity is involved in a wide range of acute and chronic diseases with both necrosis and apoptosis, depending on the relative intense and time course. Necroptosis is a newly discovered type of cell death characterized with the combined biochemical and ultrastructural features of necrosis and apoptosis. Nec-1 has been reported to exhibit the selective inhibition for necroptosis, which has now been used as an operational definition of necroptosis. The purpose of this study was to evaluate whether necroptosis is involved in the NMDA-induced excitotoxicity and furthermore whether the elevation of intracellular Ca~(2+) is involved in the NMDA-induced necroptosis. Our findings showed that Nec-1 (100μmol/L) inhibited NMDA-induced decrease of cell viability by 26% (p < 0.01), suppressed NMDA-induced decrease of living cells by 23% (p < 0.01) and attenuated NMDA-induced leakage of LDH by 28% (p < 0.01). In addition, Nec-1 also suppressed NMDA-induced the elevation of intracellular Ca~(2+) by 36% (p < 0.05). These findings indicated for the first time that necroptosis contributes to the NMDA-induced excitotoxicity, and the elevation of intracellular Ca~(2+) may be one of potential mechanisms underlying NMDA-induced necroptosis. Although necroptosis involved in the NMDA-induced excitotoxicity, it may just constitute a small contribution.
引文
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