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Differential mechanisms of tolerance induced by NMDA and 3,5-dihydroxyphenylglycine (DHPG) preconditioning.
Journal of Neurochemistry ( IF 4.2 ) Pub Date : 2020-04-28 , DOI: 10.1111/jnc.15033
Elisabetta Gerace 1, 2 , Elisa Zianni 3 , Elisa Landucci 2 , Tania Scartabelli 2 , Rolando Berlinguer Palmini 1 , Daniela Iezzi 1 , Flavio Moroni 1 , Monica Di Luca 3 , Guido Mannaioni 1 , Fabrizio Gardoni 3 , Domenico E Pellegrini-Giampietro 2
Affiliation  

We investigated the molecular events triggered by NMDA and 3,5‐dihydroxyphenylglycine (DHPG) preconditioning, that lead to neuroprotection against excitotoxic insults (AMPA or oxygen and glucose deprivation) in rat organotypic hippocampal slices, with particular attention on glutamate receptors and on cannabinoid system. We firstly evaluated the protein expression of NMDA and AMPA receptor subunits after preconditioning using western blot analysis performed in post‐synaptic densities. We observed that following NMDA, but not DHPG preconditioning, the expression of GluA1 was significantly reduced and this reduction appeared to be associated with the internalization of AMPA receptors. Whole‐cell voltage clamp recordings on CA1 pyramidal neurons of organotypic slices show that 24 hr after exposure to NMDA and DHPG preconditioning, AMPA‐induced currents were significantly reduced. To clarify the mechanisms induced by DHPG preconditioning, we then investigated the involvement of the endocannabinoid system. Exposure of slices to the CB1 antagonist AM251 prevented the development of tolerance to AMPA toxicity induced by DHPG but not NMDA. Accordingly, the MAG‐lipase inhibitor URB602, that increases arachidonoylglycerol (2‐AG) content, but not the FAAH inhibitor URB597, that limits the degradation of anandamide, was also able to induce tolerance versus AMPA and OGD toxicity, suggesting that 2‐AG is responsible for the DHPG‐induced tolerance. In conclusion, preconditioning with NMDA or DHPG promotes differential neuroprotective mechanisms: NMDA by internalization of GluA1‐AMPA receptors, DHPG by producing the endocannabinoid 2‐AG.

中文翻译:

NMDA和3,5-二羟基苯基甘氨酸(DHPG)预处理诱导的耐受性差异机制。

我们调查了由NMDA和3,5-二羟基苯基甘氨酸(DHPG)预处理触发的分子事件,这些事件导致对大鼠器官型海马切片中的兴奋性中毒损伤(AMPA或氧气和葡萄糖剥夺)的神经保护,特别注意谷氨酸受体和大麻素系统。我们首先使用突触后密度进行的蛋白质印迹分析,对预处理后的NMDA和AMPA受体亚基的蛋白质表达进行了评估。我们观察到,NMDA而非DHPG预处理后,GluA1的表达显着降低,并且这种降低似乎与AMPA受体的内在化有关。在器官型切片的CA1锥体神经元上的全细胞电压钳记录显示,暴露于NMDA和DHPG预处理后24小时,AMPA感应的电流显着降低。为了阐明DHPG预处理诱导的机制,我们然后研究了内源性大麻素系统的参与。将切片暴露于CB1拮抗剂AM251可以防止由DHPG诱导的对AMPA毒性的耐受性,但不能阻止NMDA。因此,增加花生四烯酸甘油酯(2-AG)含量的MAG-脂肪酶抑制剂URB602,但限制了Anandamide降解的FAAH抑制剂URB597,却不能诱导对AMPA和OGD毒性的耐受性,表明2-AG负责DHPG诱导的耐受性。总之,用NMDA或DHPG进行预处理可促进不同的神经保护机制:通过内在化GluA1-AMPA受体来实现NMDA,通过产生内源性大麻素2-AG来促进DHPG。为了阐明DHPG预处理诱导的机制,我们然后研究了内源性大麻素系统的参与。将切片暴露于CB1拮抗剂AM251可以防止由DHPG诱导的对AMPA毒性的耐受性,但不能阻止NMDA。因此,增加花生四烯酸甘油酯(2-AG)含量的MAG-脂肪酶抑制剂URB602,但限制了Anandamide降解的FAAH抑制剂URB597,却不能诱导对AMPA和OGD毒性的耐受性,表明2-AG负责DHPG诱导的耐受性。总之,用NMDA或DHPG进行预处理可促进不同的神经保护机制:通过内在化GluA1-AMPA受体来实现NMDA,通过产生内源性大麻素2-AG来促进DHPG。为了阐明DHPG预处理诱导的机制,我们然后研究了内源性大麻素系统的参与。将切片暴露于CB1拮抗剂AM251可以防止由DHPG诱导的对AMPA毒性的耐受性,但不能阻止NMDA。因此,增加花生四烯酸甘油酯(2-AG)含量的MAG-脂肪酶抑制剂URB602,但限制了Anandamide降解的FAAH抑制剂URB597,却不能诱导对AMPA和OGD毒性的耐受性,表明2-AG负责DHPG诱导的耐受性。总之,用NMDA或DHPG进行预处理可促进不同的神经保护机制:通过内在化GluA1-AMPA受体来实现NMDA,通过产生内源性大麻素2-AG来促进DHPG。然后,我们调查了内源性大麻素系统的参与。将切片暴露于CB1拮抗剂AM251可以防止由DHPG诱导的对AMPA毒性的耐受性,但不能阻止NMDA。因此,增加花生四烯酸甘油酯(2-AG)含量的MAG-脂肪酶抑制剂URB602,但限制了Anandamide降解的FAAH抑制剂URB597,却不能诱导对AMPA和OGD毒性的耐受性,表明2-AG负责DHPG诱导的耐受性。总之,用NMDA或DHPG进行预处理可促进不同的神经保护机制:通过内在化GluA1-AMPA受体来实现NMDA,通过产生内源性大麻素2-AG来促进DHPG。然后,我们调查了内源性大麻素系统的参与。将切片暴露于CB1拮抗剂AM251可以防止由DHPG诱导的对AMPA毒性的耐受性,但不能阻止NMDA。因此,增加花生四烯酸甘油酯(2-AG)含量的MAG-脂肪酶抑制剂URB602,但限制了Anandamide降解的FAAH抑制剂URB597,却不能诱导对AMPA和OGD毒性的耐受性,表明2-AG负责DHPG诱导的耐受性。总之,用NMDA或DHPG进行预处理可促进不同的神经保护机制:通过内在化GluA1-AMPA受体来实现NMDA,通过产生内源性大麻素2-AG来促进DHPG。MAG-脂肪酶抑制剂URB602可增加花生四烯酸甘油酯(2-AG)的含量,但FAAH抑制剂URB597不能抑制花生四烯酸的降解,它也能够诱导对AMPA和OGD毒性的耐受性,表明2-AG是造成这种情况的原因DHPG诱导的耐受性。总之,用NMDA或DHPG进行预处理可促进不同的神经保护机制:通过内在化GluA1-AMPA受体来实现NMDA,通过产生内源性大麻素2-AG来促进DHPG。MAG-脂肪酶抑制剂URB602可增加花生四烯酸甘油酯(2-AG)的含量,但FAAH抑制剂URB597不能抑制花生四烯酸的降解,它也能够诱导对AMPA和OGD毒性的耐受性,表明2-AG是造成这种情况的原因DHPG诱导的耐受性。总之,用NMDA或DHPG进行预处理可促进不同的神经保护机制:通过内在化GluA1-AMPA受体来实现NMDA,通过产生内源性大麻素2-AG来促进DHPG。
更新日期:2020-04-28
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