Targeting Sentinel Proteins and Extrasynaptic Glutamate Receptors: a Therapeutic Strategy for Preventing the Effects Elicited by Perinatal Asphyxia?
Targeting Sentinel Proteins and Extrasynaptic Glutamate Receptors: a Therapeutic Strategy for Preventing the Effects Elicited by Perinatal Asphyxia?
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DOI：
10.1007/s12640-017-9795-9
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发表时间：
2018-03
影响因子：
3.7
通讯作者：
Cassels BK
中科院分区：
文献类型：
--
作者：
Herrera-Marschitz M;Perez-Lobos R;Lespay-Rebolledo C;Tapia-Bustos A;Casanova-Ortiz E;Morales P;Valdes JL;Bustamante D;Cassels BK
围产期窒息 (PA) 是临产时和生存稳定时死亡的相关原因，与短期和长期发育障碍相关，需要卫生系统和家庭的过度护理。全球范围内其患病率很高（1 至 10/1000 活产）。目前，除了低温治疗之外，几乎没有什么治疗选择，遗憾的是，如果在损伤后不久应用，只能提供有限的保护。 PA 意味着主要侮辱和次要侮辱。主要损伤与缺氧有关，次要损伤与再氧合、活性氧 (ROS) 和活性氮 (RNS) 物质的形成以及谷氨酸受体过度激活和线粒体缺陷引发的氧化应激有关。 PA 会诱导许多前哨蛋白过度激活，包括缺氧诱导因子 1α (HIF-1α) 和基因组保护聚（ADP-核糖）聚合酶 1 (PARP-1)。激活后，PARP-1 会消耗大量 ATP，而此时这种代谢物稀缺，进而加剧窒息引起的能量危机。能源危机还损害了 ATP 依赖性运输，包括星形胶质细胞对谷氨酸的再摄取。烟酰胺是一种 PARP-1 抑制剂，可防止初级阶段引发的代谢级联反应，避免 NAD+ 耗尽和能量危机。然而，在再氧合后，氧化应激会导致 NF-κB 亚基 p65 的核易位、促炎细胞因子 IL-1β 和 TNF-α 的过度表达以及谷氨酸兴奋性毒性，这是由于神经胶质-谷氨酸转运受损、细胞外谷氨酸溢出和 NMDA 受体（主要是突触外类型）过度激活所致。这会导致钙流入、线粒体损伤和抗氧化酶失活，进一步增加促氧化酶的活性，从而使幸存的新生儿在涉及氧化应激时容易受到反复代谢损伤。在这里，我们讨论的证据表明，(i) 烟酰胺抑制 PARP-1 过度激活和 (ii) 美金刚抑制突触外 NMDA 受体过度激活可以预防 PA 的短期和长期后果。这些假设已在大鼠 PA 临床前模型中进行了评估，旨在确定导致损伤引起的长期后果的代谢级联，并评估出生后对反复氧化损伤的脆弱性。因此，我们提出并讨论了证据，证明 PA 会引起与能量和氧化应激相关的代谢途径的长期变化，从而引发神经元和神经胶质表型细胞的脆弱性。 PA 引起的效应具有区域依赖性，黑质特别容易发生细胞死亡。 PA 的短期和长期后果问题为解决涉及中枢神经系统可塑性的基本问题提供了一个框架，因为围产期侮辱会引发多米诺骨牌般的一系列事件，使发育中的个体容易受到反复出现的不利条件的影响，并由于出生时发生的相关侮辱而减少了他/她的应对能力。
Perinatal asphyxia (PA) is a relevant cause of death at the time of labour, and when survival is stabilised, associated with short- and long-term developmental disabilities, requiring inordinate care by health systems and families. Its prevalence is high (1 to 10/1000 live births) worldwide. At present, there are few therapeutic options, apart from hypothermia, that regrettably provides only limited protection if applied shortly after the insult. PA implies a primary and a secondary insult. The primary insult relates to the lack of oxygen, and the secondary one to the oxidative stress triggered by re-oxygenation, formation of reactive oxygen (ROS) and reactive nitrogen (RNS) species, and overactivation of glutamate receptors and mitochondrial deficiencies. PA induces overactivation of a number of sentinel proteins, including hypoxia-induced factor-1α (HIF-1α) and the genome-protecting poly(ADP-ribose) polymerase-1 (PARP-1). Upon activation, PARP-1 consumes high amounts of ATP at a time when this metabolite is scarce, worsening in turn the energy crisis elicited by asphyxia. The energy crisis also impairs ATP-dependent transport, including glutamate re-uptake by astroglia. Nicotinamide, a PARP-1 inhibitor, protects against the metabolic cascade elicited by the primary stage, avoiding NAD+ exhaustion and the energetic crisis. Upon re-oxygenation, however, oxidative stress leads to nuclear translocation of the NF-κB subunit p65, overexpression of the pro-inflammatory cytokines IL-1β and TNF-α, and glutamate-excitotoxicity, due to impairment of glial-glutamate transport, extracellular glutamate overflow, and overactivation of NMDA receptors, mainly of the extrasynaptic type. This leads to calcium influx, mitochondrial impairment, and inactivation of antioxidant enzymes, increasing further the activity of pro-oxidant enzymes, thereby making the surviving neonate vulnerable to recurrent metabolic insults whenever oxidative stress is involved. Here, we discuss evidence showing that (i) inhibition of PARP-1 overactivation by nicotinamide and (ii) inhibition of extrasynaptic NMDA receptor overactivation by memantine can prevent the short- and long-term consequences of PA. These hypotheses have been evaluated in a rat preclinical model of PA, aiming to identify the metabolic cascades responsible for the long-term consequences induced by the insult, also assessing postnatal vulnerability to recurrent oxidative insults. Thus, we present and discuss evidence demonstrating that PA induces long-term changes in metabolic pathways related to energy and oxidative stress, priming vulnerability of cells with both the neuronal and the glial phenotype. The effects induced by PA are region dependent, the substantia nigra being particularly prone to cell death. The issue of short- and long-term consequences of PA provides a framework for addressing a fundamental issue referred to plasticity of the CNS, since the perinatal insult triggers a domino-like sequence of events making the developing individual vulnerable to recurrent adverse conditions, decreasing his/her coping repertoire because of a relevant insult occurring at birth.
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影响因子：
3.3
作者：
Chen, HSV;Wang, YF;Jensen, FE
通讯作者：
Jensen, FE
影响因子：
3.7
作者：
Aschbacher, Kirstin;O'Donovan, Aoife;Wolkowitz, Owen M.;Dhabhar, Firdaus S.;Su, Yali;Epel, Elissa
通讯作者：
Epel, Elissa
影响因子：
2.5
作者：
Block, F;Schwarz, M
通讯作者：
Schwarz, M
影响因子：
3.4
作者：
BERGER, NA
通讯作者：
BERGER, NA
DOI：
10.1073/pnas.97.16.9082
发表时间：
2000-08-01
影响因子：
11.1
作者：
Bruick, RK
通讯作者：
Bruick, RK