Simultaneous blockade of NMDA receptors and PARP-1 activity synergistically alleviate immunoexcitotoxicity and bioenergetics in 3-nitropropionic acid intoxicated mice: Evidences from memantine and 3-aminobenzamide interventions
Simultaneous blockade of NMDA receptors and PARP-1 activity synergistically alleviate immunoexcitotoxicity and bioenergetics in 3-nitropropionic acid intoxicated mice: Evidences from memantine and 3-aminobenzamide interventions
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DOI：
10.1016/j.ejphar.2017.03.023
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发表时间：
2017-05-15
影响因子：
5
通讯作者：
Ganapathy, Ramakrishnan
中科院分区：
文献类型：
--
作者：
Chidambaram, Saravana Babu;Vijayan, Ranju;Ganapathy, Ramakrishnan
兴奋性毒性和细胞生物能量消耗之间的相互联系被认为是包括亨廷顿病（HD）在内的许多神经退行性疾病的中心恶化途径之一。3-硝基丙酸（3-NP）的长期给药消耗ATP和NAV（+），并增加TNF α、IL-6和谷氨酸含量，导致“免疫兴奋性毒性”。本研究旨在确定美金刚（MN）和3-氨基苯甲酰胺（3-AB），PARP抑制剂，是否可以改善免疫兴奋性毒性和改善生物能量学的方式比单独给药对3-NP中毒小鼠。将动物分为8组（n=20/组），并分配至不同的治疗方案。3-NP（10 mg/kg，i.p.）每隔4天给药一次，持续28天的时间（总剂量：70 mg/kg;分7次给药）。测量纹状体琥珀酸脱氢酶（SDH）、ATP和NAD水平（作为生物能量标记物）;谷氨酸、小胶质细胞标记物（IBA-1）、星形胶质细胞标记物（GFAP）、细胞因子（TNF-α和IL-6）和神经营养因子（BDNF）作为免疫兴奋毒性组分。联合处理（MN +3-AB）可降低3-NP中毒小鼠脑内谷氨酸水平，下调IBA-1，上调GFAP和BDNF表达。此外，组合（COM）治疗恢复ATP/NAD和SDH活性，并且还改善运动性能;并且因此赋予比单独治疗协同的神经保护。总之，同时阻断NMDAr和抑制PARP活性对于改善3-NP诱导的神经退行性变中的免疫兴奋性毒性和改善生物能量学是必要的。MN+3-AB治疗可能是HD症状管理的有效方案，至少部分如此。
Interlink between excitotoxicity and cellular bioenergetics depletion is implicated as one of the central deteriorative pathways in many neurodegenerative diseases including Huntington's disease (HD). Chronic administration of 3-nitropropionic acid (3-NP) depletes ATP and NAV(+;) and increases TNF alpha, IL-6 and glutamate content resulting in "immunoexcitotoxicity". Present study was designed to determine whether the combination of memantine (MN) and 3-aminobenzamide (3-AB), PARP inhibitor, can ameliorate immunoexcitotoxicity and improve bioenergetics in a better manner than individual administration against 3-NP intoxication in mice. Animals were divided into eight groups (n=20/group) and allocated to different treatment protocols. 3-NP (10 mg/kg, i.p.) was administered once in 4 days interval for a period of 28 days (total dose: 70 mg/kg; in seven divided doses). Striatal succinate dehydrogenase (SDH), ATP and NAD levels (as bioenergetic markers); glutamate, microglial marker (IBA-1), astroglial marker (GFAP), cytokines (TNF-alpha and IL-6), and neurotrophin (BDNF) as immunoexcitotoxicity components were measured. Combination treatment (MN +3-AB) decreased brain glutamate, down-regulated IBA-1, up-regulated GFAP and BDNF expressions in 3-NP intoxicated mice. Further, combination (COM) treatment restored ATP/NAD and SDH activity, and also improved motor performance; and thus conferred a synergetic neuroprotection than individual treatments. To conclude, simultaneous blockade of NMDAr and suppression of PARP activity is necessary to ameliorate immunoexcitotoxicity and improve bioenergetics in 3-NP induced neurodegeneration. Treatment with MN+3-AB can be an efficient regimen in the symptomatic management of HD, at least partly.