Review 审查

Signal transduction associated with lead-induced neurological disorders: A review
与铅诱发的神经系统疾病相关的信号转导：综述

2.1. Calcium dyshomeostasis
2.1.钙稳态失调

Pb exposure can affect learning ability and memory, and damage sensory organs and their innervation (Liu et al., 2012; Galal et al., 2019; Babinsky et al., 2016). Indeed, treatment of rats with Pb during the juvenile growth period has been shown to impair learning and memory as evidenced in the Morris water maze and passive avoidance tests (Cai et al., 2019). Pb's primary effects include increased intracellular free Ca concentrations as well as interferences Ca-dependent CaMKIIα/CREB signaling pathway in Pb-exposed neurons (Zhou et al., 2020; Zhao et al., 2018). Cytosolic-free calcium ion (Ca²⁺), as an intracellular second messenger, is a key signal molecule for a series of neuronal processes, playing a vital role in regulating learning and memory (Beheshti et al., 2018; Park et al., 2020). Cognition and learning reflect a series of changes in the release intensity of neurotransmitters, a calcium-mediated biochemical process (Berridge, 2014). Highly enriched in brain tissue and present throughout the body, calcium/calmodulin-dependent kinase II (CaMKII) is a crucial mediator of learning and memory that is regulated by the Ca²⁺/calmodulin complex (YAMAUCHI, 2005). Several studies have shown that disrupted intracellular Ca²⁺ homeostasis could affect the Ca2+/CaMKII and cyclic adenosine 30,50-monophosphate (cAMP) response element binding protein (CREB), and inhibit neurite outgrowth and synapse formation (Pullara et al., 2017). The phosphorylation of CREB, a transcription factor, is affected by CaMKII, which is regulated by the intracellular Ca²⁺ homeostasis.
铅暴露会影响学习能力和记忆力，损害感觉器官及其神经支配( Liu等，2012 ； Galal等，2019 ； Babinsky等，2016 )。事实上，莫里斯水迷宫和被动回避测试证明，在幼年生长期对大鼠进行铅治疗会损害学习和记忆（ Cai et al., 2019 ）。 Pb 的主要作用包括增加细胞内游离 Ca 浓度以及干扰 Pb 暴露神经元中 Ca 依赖性 CaMKIIα/CREB ​​信号通路（ Zhou et al., 2020 ； Zhao et al., 2018 ）。胞质游离钙离子（Ca ²⁺ ）作为细胞内第二信使，是一系列神经元过程的关键信号分子，在调节学习和记忆中发挥着至关重要的作用( Beheshti et al., 2018 ; Park et al. 2018 ) ，2020 ）。认知和学习反映了神经递质释放强度的一系列变化，这是一种钙介导的生化过程（ Berridge，2014 ）。钙/钙调蛋白依赖性激酶 II (CaMKII) 在脑组织中高度丰富并存在于全身，是学习和记忆的重要介质，受 Ca ²⁺ /钙调蛋白复合物调节 ( YAMAUCHI, 2005 )。 多项研究表明，细胞内 Ca ²⁺稳态被破坏可能会影响 Ca2+/CaMKII 和环腺苷 30,50-单磷酸 (cAMP) 反应元件结合蛋白 (CREB)，并抑制神经突生长和突触形成 ( Pullara et al., 2017) ）。 CREB（一种转录因子）的磷酸化受到 CaMKII 的影响，而 CaMKII 受细胞内 Ca ²⁺稳态调节。

Both Pb and Ca are structurally similar, divalent metals. Moreover, the transport mechanisms for the two metals are analogous (Dudev et al., 2018). Therefore, Pb²⁺ can mimic and simulate Ca²⁺ signaling, disturb Ca²⁺-dependent biological processes, and result in intracellular Ca disorders, thus interfering interfere with normal synaptic signaling events (Neal and Guilarte, 2010). Under normal conditions, the activation of voltage-gated Ca²⁺ channels (VGCCs) promote Ca²⁺ influx in an electrochemical gradient, leading to cytoplasmic Ca²⁺ concentration-dependent enzyme activation and neurotransmitter release (Ureshino et al., 2019). However, Pb²⁺ has been shown to inhibit presynaptic VGCCs may prevent the necessary rise in internal Ca²⁺ required for fast, Ca²⁺-dependent vesicular release, thus interfering with neurotransmission (Neal and Guilarte, 2010). In other words, under pathological conditions, increasing the release of Ca²⁺ from the endoplasmic reticulum (ER) Ca²⁺ pool of neurons, causing intracellular Ca disorders, which, in turn, could affect Ca signaling pathways, leading to neurodegeneration (Ureshino et al., 2019; Yu et al., 2016). CaMKII is activated following Long-Term Potentiation (LTP) synaptic stimulation protocols and undergoes auto-phosphorylation and resultant conversion to a Ca²⁺/CaM-independent (autonomous) activity (Pullara et al., 2017). Indeed, CaMKII-knockout mice have been shown to exhibit memory loss owing to defects in the LTP (Paul et al., 2004). CREB, a downstream transcriptional factor, is phosphorylated and activated by phosphorylated CaMKII, thereby promoting cognition (Kandel, 2012). Pb-induced alterations in intracellular Ca transient and the ensuing increase in Ca²⁺ concentrations decrease the expression of CaMKIIα and CREB phosphorylation and result in impairments in long-term memory and cognitive function (Zhou et al., 2020). Thus, Pb can initiate neuronal dysfunction by regulating the Ca²⁺/CaMKII/CREB mnemonic pathway (Neal and Guilarte, 2010; Chen et al., 2020). In addition, intracellular calcium overload could induce NLRP3 (NOD-like receptor protein 3) inflammasome formation it is well established that CaMKII is involved in this process (Murakami et al., 2012). The main process is as follows: CaMKII is an upstream of c-Jun N-terminal protein kinase 1 (JNK1) (Lim et al., 2020), and the later directly phosphorylates NLRP3, which is essential for inflammasome activation (Shim and Lee, 2018). Furthermore, downstream regulatory element antagonist modulator (DREAM, alternatively known as calsenilin) and possibly other neuronal calcium sensors (NCS) proteins bind to Pb²⁺ with a higher affinity than that for Ca²⁺, and Pb²⁺ interactions with NCS proteins may contribute to neurotoxicity (Azam and Miksovska, 2019). Thus, Pb²⁺ could causes learning and memory impairment by interfering with Ca²⁺ homeostasis.
Pb 和 Ca 都是结构相似的二价金属。此外，两种金属的传输机制是相似的（ Dudev 等人，2018 ）。因此，Pb ²⁺可以模仿和模拟Ca ²⁺信号传导，扰乱Ca ²⁺依赖的生物过程，导致细胞内Ca紊乱，从而干扰正常的突触信号传导事件( Neal and Guilarte, 2010 )。正常情况下，电压门控Ca ²⁺通道（VGCC）的激活会促进电化学梯度中的Ca ²⁺内流，导致细胞质Ca ²⁺浓度依赖性酶激活和神经递质释放（ Ureshino et al., 2019 ）。然而，Pb ²⁺已被证明抑制突触前 VGCC 可能会阻止快速、Ca ²⁺依赖性囊泡释放所需的内部 Ca ²⁺必要的升高，从而干扰神经传递（ Neal 和 Guilarte，2010 ）。换句话说，在病理条件下，增加神经元内质网（ER）Ca ²⁺库释放的 Ca ²⁺ ，引起细胞内 Ca 紊乱，进而影响 Ca 信号通路，导致神经变性（ Ureshino等人，2019 ；余等人，2016 ）。 CaMKII 在长时程增强 (LTP) 突触刺激方案后被激活，并经历自身磷酸化并最终转化为 Ca ²⁺ /CaM 独立（自主）活性（ Pullara 等人，2017 ）。事实上，CaMKII 敲除小鼠已被证明由于 LTP 缺陷而表现出记忆丧失（ Paul 等，2004 ）。 CREB是下游转录因子，被磷酸化的CaMKII磷酸化并激活，从而促进认知（ Kandel，2012 ）。 Pb 诱导的细胞内 Ca 瞬时变化和随之而来的 Ca ²⁺浓度增加会降低 CaMKIIα 和 CREB ​​磷酸化的表达，并导致长期记忆和认知功能受损 ( Zhou et al., 2020 )。因此，Pb可以通过调节Ca ²⁺ /CaMKII/CREB助记通路引发神经元功能障碍( Neal and Guilarte, 2010 ; Chen et al., 2020 )。此外，细胞内钙超载可诱导 NLRP3（NOD 样受体蛋白3）炎症小体形成，CaMKII 参与这一过程已被证实（ Murakami 等，2012 ）。主要过程如下：CaMKII是c-Jun N端蛋白激酶1（JNK1）的上游（ Lim et al.，2020），后者直接磷酸化 NLRP3，这对于炎性体激活至关重要（ Shim 和 Lee，2018 ）。此外，下游调节元件拮抗剂调节剂（DREAM，也称为钙老素）和可能的其他神经元钙传感器（NCS）蛋白以比 Ca ²⁺更高的亲和力与 Pb ²⁺结合，并且 Pb ²⁺与 NCS 蛋白的相互作用可能导致神经毒性（ Azam 和 Miksovska，2019 ）。因此，Pb ²⁺可能通过干扰Ca ²⁺稳态而导致学习和记忆障碍。

2.2. Apoptosis 2.2.细胞凋亡

Previous studies have shown that Pb induces neuronal apoptosis in the developing mouse brain (Dribben et al., 2011). In addition, it has been that low micro-molar doses of Pb²⁺ promote apoptosis (Sharifi et al., 2010; Metryka et al., 2020a). Notably, at doses well within the blood Pb range, which has been shown to impair CNS function in children and to alter synaptogenesis in the neonatal rat brain (Skerfving et al., 2015; Chen et al., 2019; Zhou et al., 2018). Pb effect's include programmed cell death (apoptosis), which is a gene-regulated phenomenon (Hatok and Racay, 2016). Protein of the B-cell lymphoma 2 (Bcl-2) constitutes one of the most biologically relevant classes of apoptosis regulatory gene products acting at the effect stage of apoptosis (Hatok and Racay, 2016; Chen et al., 2012). Bax and Bcl-2 are the major proteins acting as apoptotic inducer and an inhibitor, respectively (Yin et al., 2020). The ratio of inducer to inhibitor determines whether or not a cell will respond to an apoptotic signal (Zhang et al., 2019). P53 is a tumor suppressor gene, which blocks the cell cycle, and induces cell differentiation and apoptosis (Yao et al., 2017). P53 modulates apoptosis mainly by altering the balance of the Bax/Bcl-2 ratio, with ensuing mitochondrial dysfunction (Sharifi et al., 2010; Chen et al., 2012). Pb exposure has been shown to increase p53 and Bax expressions, altering the Bax/Bcl-2 ratio, and promoting Pb-induced neurotoxicity (Baranowska-Bosiacka et al., 2013; Hosseini et al., 2015; Xu et al., 2008). In corroboration, Yang et al. (2019) have demonstrated that Bcl-2 expression was attenuated and the expression of Bax and cleaved casapase-3 (an effector caspase, identified as a key mediator of apoptosis of mammalian cells) were enhanced in brains of Pb-exposed mice, consistent with apoptotic changes (Yang et al., 2019; Kiran Kumar et al., 2009). It is known that IP3 receptors (IP3Rs) and ryanodine receptors (RyRs, the largest known Ca-regulating channel) play critical roles in Ca²⁺-mediated apoptosis (Bahar et al., 2016). The IP3R in the ER membrane, promotes Ca²⁺ release from the ER to cytosol (Ureshino et al., 2019), IP3R-1 was shown to act as a caspase-3 substrate (Julien and Wells, 2017); the RyR mediates the efflux of Ca from the ER, meanwhile it could be regulated by the intracellular free Ca²⁺ levels (Zhou et al., 2020). Furthermore, studies have reported that Pb²⁺ induces ER calcium release through the IP3R and RyR in hippocampal neurons (Ureshino et al., 2019; Fan et al., 2013).
先前的研究表明，Pb 会诱导发育中的小鼠大脑中的神经元凋亡（ Dribben 等人，2011 ）。此外，低微摩尔剂量的Pb ²⁺会促进细胞凋亡（ Sharifi et al., 2010 ； Metryka et al., 2020a ）。值得注意的是，在血液 Pb 范围内的剂量下，已被证明会损害儿童的 CNS 功能并改变新生大鼠大脑中的突触发生（ Skerfving 等人，2015 年； Chen 等人，2019 年； Zhou 等人， 2018 ）。 Pb 效应包括程序性细胞死亡（细胞凋亡），这是一种基因调节现象（ Hatok 和 Racay，2016 ）。 B 细胞淋巴瘤蛋白 2 (Bcl-2) 构成了在细胞凋亡效应阶段发挥作用的最具生物学相关性的细胞凋亡调节基因产物类别之一（ Hatok 和 Racay，2016 ； Chen 等，2012 ）。 Bax 和 Bcl-2 是分别充当细胞凋亡诱导剂和抑制剂的主要蛋白质 ( Yin et al., 2020 )。诱导剂与抑制剂的比例决定细胞是否会对凋亡信号做出反应（ Zhang et al., 2019 ）。 P53是一种抑癌基因，可阻断细胞周期，诱导细胞分化和凋亡( Yao et al., 2017 )。 P53主要通过改变Bax/Bcl-2比例的平衡来调节细胞凋亡，从而导致线粒体功能障碍( Sharifi等，2010 ； Chen等，2012 )。铅暴露已被证明会增加 p53 和 Bax 的表达，改变 Bax/Bcl-2 比率，并促进铅诱导的神经毒性（ Baranowska-Bosiacka 等，2013 ； Hosseini 等，2015 ； Xu 等，2008） ）。杨等人证实了这一点。 (2019)证明，在铅暴露小鼠的大脑中，Bcl-2 表达减弱，而 Bax 和 cleaved casapase-3（一种效应 caspase ，被确定为哺乳动物细胞凋亡的关键介质）的表达增强，这与细胞凋亡变化（ Yang et al., 2019 ； Kiran Kumar et al., 2009 ）。已知IP3受体(IP3Rs)和兰尼碱受体(RyRs，已知最大的Ca调节通道)在Ca ²⁺介导的细胞凋亡中发挥关键作用( Bahar et al., 2016 )。 ER 膜中的 IP3R 促进 Ca ²⁺从 ER 释放到细胞质中（ Ureshino 等人，2015）。，2019），IP3R-1 被证明可以作为 caspase-3 底物（ Julien 和 Wells，2017 ）； RyR介导Ca从内质网流出，同时可以通过细胞内游离Ca ²⁺水平进行调节( Zhou et al., 2020 )。此外，研究报道Pb ²⁺通过海马神经元中的IP3R和RyR诱导ER钙释放（ Ureshino等，2019 ； Fan等，2013 ）。

Pb has been reported to trigger neurodegeneration by increasing the level of free calcium and activation of the calcium-dependent ERK/Bcl2 apoptotic signaling pathway (Zhou et al., 2020). As mentioned earlier, Pb²⁺ can substitute for Ca²⁺ in numerous cellular processes and to interfere with reactions that require Ca²⁺. Notably, the ER is the largest cellular organelle and is responsible for a variety of functions, and intracellular Ca²⁺ is mainly stored in its lumen, to ensure proper protein-folding (Ureshino et al., 2019). In turn, ER Ca²⁺ imbalance can greatly impact the folding capacity and induce ER stress (Bahar et al., 2016; Min et al., 2017). ER stress is a major trigger for the initiation of apoptosis (Walter and Ron, 2011). In addition, Mitochondria are known to modulate and synchronize Ca²⁺ signaling. Massive accumulation of Ca²⁺ in the mitochondria leads to apoptosis (Jeong and Seol, 2008). Pb exposure-induced Ca overload has been shown to cause not only depression in Ca-dependent memory-related signaling pathways (Dudev et al., 2018), but also in the activation of the Ca-dependent, apoptosis-related signaling pathway (Min et al., 2017). The extracellular signal–regulated extracellular signal–regulated kinase 1 and 2 (ERK1/2) regulate several important signaling functions (Johnson and Lapadat, 2002; Li et al., 2016). Pb stimulate an increase in Ca transient followed by ER and mitochondrial Ca uptake, and activation of ERK1/2 and decreased the expression of anti-apoptotic protein Bcl2, causing cytotoxicity and cellular apoptosis (Zhou et al., 2020; Zieg et al., 2008). In addition, because mitochondria are at the core of cellular energy metabolism, the large accumulation of Ca²⁺in these organelles may also lead to energy metabolism disorders (Nicholls, 2008). Therefore, Pb has been shown to upregulate the levels of IP3R and RyRs, leading to Ca²⁺overload, followed by activation of the ERK/Bcl2 apoptotic pathway and energy metabolism disorders, and subsequent initiation of neurodegeneration.
据报道，Pb 通过增加游离钙水平和激活钙依赖性 ERK/Bcl2 凋亡信号通路来触发神经退行性变（ Zhou et al., 2020 ）。如前所述，Pb ²⁺可以在许多细胞过程中替代Ca ²⁺并干扰需要Ca ²⁺的反应。值得注意的是，内质网是最大的细胞器，负责多种功能，细胞内Ca ²⁺主要储存在其内腔中，以确保正确的蛋白质折叠( Ureshino et al., 2019 )。反过来，内质网Ca ²⁺不平衡会极大地影响折叠能力并诱发内质网应激( Bahar et al., 2016 ; Min et al., 2017 )。 ER 应激是细胞凋亡启动的主要触发因素（ Walter 和 Ron，2011 ）。此外，已知线粒体可以调节和同步Ca ²⁺信号传导。 Ca ²⁺在线粒体中的大量积累导致细胞凋亡（ Jeong 和 Seol，2008 ）。铅暴露引起的 Ca 超载已被证明不仅会导致 Ca 依赖性记忆相关信号通路的抑制 ( Dudev et al., 2018 )，还会导致 Ca 依赖性、凋亡相关信号通路的激活 ( Min等人，2017 ）。 细胞外信号调节激酶 1 和 2 (ERK1/2) 调节多种重要的信号传导功能（ Johnson 和 Lapadat，2002 ； Li 等，2016 ）。 Pb 刺激 Ca 瞬时增加，随后导致 ER 和线粒体 Ca 摄取，激活 ERK1/2，并降低抗凋亡蛋白 Bcl2的表达，导致细胞毒性和细胞凋亡（ Zhou et al., 2020 ； Zieg et al., 2008 ）。此外，由于线粒体是细胞能量代谢的核心，Ca ²⁺在这些细胞器中的大量积累也可能导致能量代谢紊乱( Nicholls，2008 )。因此，Pb已被证明可以上调IP3R和RyRs的水平，导致Ca ²⁺超载，随后激活ERK/Bcl2凋亡途径和能量代谢紊乱，并随后引发神经变性。

2.3. SIRT1/CREB/BDNF

It has been posited that the SIRT1/CREB/BDNF pathway might be associated with Pb-induced cognitive deficits. Silent mating type information regulation 2 homolog 1 (SIRT1), a member of the sirtuin family of proteins, is a histone deacetylase (Huang et al., 2017; Tang, 2016). Brain-derived neurotrophic factor (BDNF) is a member of the neuro-trophin family, and is involved in several functions, such as neuronal growth, survival, synaptic plasticity and memorization (Chen et al., 2017). Recent studies have linked SIRT1 and CREB to synaptic plasticity, memory formation, neurogenesis, and neuroprotection (Dribben et al., 2011; Pardo et al., 2017). Feng et al. have found that the expression of SIRT1 was significantly decreased, accompanied by decreased expressions of CREB phosphorylation and the downstream protein of BDNF, in the hippocampus of Pb-treated developing rats (Feng et al., 2016). Similarly, Gąssowska et al. found that lower levels of BDNF were observed in the brains of Pb-treated animals compared with control (Gassowska et al., 2016a). The suppression of SIRT1 can inhibit CREB activity by upregulating miR-134 (negatively regulates dendritic spine development), thus decreasing the binding of CREB to BDNF promoters, which induces a reduction of BDNF at both mRNA and protein levels (Shen et al., 2018). Interestingly, it has been demonstrated that monosialoganglioside exerts a protective effect on Pb-induced impairment of learning and memory via antioxidant and anti-apoptotic activities, as well as by activating the SIRT1/CREB/BDNF pathway in developing hippocampus (Chen et al., 2019). Thus, lead may cause learning and memory disorders by inhibiting the SIRT1/CREB/BDNF signaling pathway, and this process may involve oxidative stress and apoptosis.
据推测，SIRT1/CREB/BDNF 通路可能与 Pb 诱导的认知缺陷有关。沉默交配型信息调节 2 同源物 1 (SIRT1) 是沉默调节蛋白家族的成员，是一种组蛋白脱乙酰酶( Huang et al., 2017 ; Tang, 2016 )。脑源性神经营养因子（BDNF）是神经营养蛋白家族的一员，参与神经元生长、存活、突触可塑性和记忆等多种功能（ Chen et al., 2017 ）。最近的研究将 SIRT1 和 CREB ​​与突触可塑性、记忆形成、神经发生和神经保护联系起来（ Dribben 等，2011 ； Pardo 等，2017 ）。冯等人。等人发现，在Pb处理的发育中的大鼠海马中，SIRT1的表达显着降低，同时伴随着CREB磷酸化和BDNF下游蛋白表达的降低( Feng et al., 2016 )。同样，Gąssowska 等人。发现与对照组相比，经铅处理的动物大脑中 BDNF 的水平较低（ Gassowska 等人，2016a ）。 SIRT1的抑制可以通过上调miR-134（负向调节树突棘发育）来抑制CREB活性，从而减少CREB与BDNF启动子的结合，从而诱导BDNF在mRNA和蛋白质水平上的减少（ Shen et al., 2018） ）。有趣的是，已经证明单唾液酸神经节苷脂通过抗氧化和抗细胞凋亡活性以及通过激活发育中的海马体中的 SIRT1/CREB/BDNF 通路对 Pb 诱导的学习和记忆障碍发挥保护作用（ Chen 等人， 2019 ）。由此可见，铅可能通过抑制SIRT1/CREB/BDNF信号通路而导致学习记忆障碍，该过程可能涉及氧化应激和细胞凋亡。

2.4. SIRT1/AMPK

Previous studies have demonstrated that Pb may cause inflammation, apoptosis and autophagy by suppressing the SIRT1/AMPK signaling pathways in brains (Feng et al., 2016; Zhang et al., 2017). Mitogen-activated protein kinases (MAPKs) represent a family of protein kinases (Velagapudi et al., 2017), in turn phosphorylating specific serine and threonine on target protein substrates to regulate cellular activities ranging from gene expression, mitosis, movement, metabolism, and programmed death (Salminen et al., 2016). SIRT1 known as a crucial regulator of AMPK activation in mitochondrial function (Zhang et al., 2017). Therefore, SIRT1and AMPK are considered as pivotal regulators, and their dysfunction is noted in several diseases with inherent oxidative stress, inflammation, apoptosis, and altered autophagy (Maiese, 2017; Giovannini and Bianchi, 2017; Liu et al., 2018). Activated SIRT1 may enhance autophagy and inhibit apoptosis (Kwon et al., 2018; Ginsberg et al., 2015). SIRT1/AMPK pathway is closely correlated with Aβ accumulation, neuro-inflammation and neurodegeneration (Liu et al., 2018; Elbaz et al., 2018). A recent study has demonstrated fisetin, a dietary antioxidant, can decrease Pb-induced synaptic dysfunction, neuro-inflammation and neurodegeneration in brains by regulating the same signal pathway (Yang et al., 2019). Therefore, lead induces inflammation, apoptosis, and autophagy through inhibition of the SIRT1/AMPK signaling pathway.
以往的研究表明，Pb可能通过抑制大脑中的SIRT1/AMPK信号通路而引起炎症、细胞凋亡和自噬( Feng等，2016 ； Zhang等，2017 )。丝裂原激活蛋白激酶 (MAPK) 代表蛋白激酶家族 ( Velagapudi et al., 2017 )，反过来磷酸化靶蛋白底物上的特定丝氨酸和苏氨酸，以调节细胞活动，包括基因表达、有丝分裂、运动、代谢和程序性死亡（ Salminen 等，2016 ）。 SIRT1 被认为是线粒体功能中 AMPK 激活的关键调节因子 ( Zhang et al., 2017 )。因此，SIRT1 和 AMPK 被认为是关键调节因子，在多种具有固有氧化应激、炎症、细胞凋亡和自噬改变的疾病中注意到它们的功能障碍（ Maese，2017 ； Giovannini 和 Bianchi，2017 ； Liu 等，2018 ）。激活的 SIRT1 可能增强自噬并抑制细胞凋亡 ( Kwon et al., 2018 ; Ginsberg et al., 2015 )。 SIRT1/AMPK 通路与 Aβ 积累、神经炎症和神经退行性疾病密切相关（ Liu 等，2015）。, 2018;艾尔巴兹等人，2018 ）。最近的一项研究表明，非瑟酮（一种膳食抗氧化剂）可以通过调节相同的信号通路来减少铅诱导的大脑突触功能障碍、神经炎症和神经变性（ Yang et al., 2019 ）。因此，铅通过抑制 SIRT1/AMPK 信号通路诱导炎症、细胞凋亡和自噬。

2.5. Inflammation 2.5.炎

Numerous studies have shown the propensity of Pb to affect the developing brain (Baranowska-Bosiacka et al., 2017; Lee et al., 2019). In the brain, exposure to Pb may cause microgliosis and astrogliosis by modulating the TLR4/MyD88/NF-kappa β (NF-κβ) signaling cascade, resulting in the production of pro-inflammatory cytokines (Fitzgerald et al., 2003). Indeed, Pb has been shown to activate the TLR4/MyD88 pathway by regulating the NF-κβ signaling pathway (Fitzgerald et al., 2003; Liu et al., 2015). Hence, the noted increase in CNS inflammatory cytokines might be derived from Pb-induced activation of microglial cells (Khan et al., 2011; von Bernhardi et al., 2016). Microglial cells and astrocytes are known to be susceptible to Pb, and release of tumor necrosis factor-alpha (TNF-α), interleukin-6 (IL-6) and IL-1β, and cyclooxygenase 2 (COX-2) pro-inflammatory enzyme from these cells has been shown in response to Pb treatment (Jane et al., 2011; Liu et al., 2012; Kumawat et al., 2014). It is well known that toll-like receptors (TLRs) recognize specific ligands to initiate the inflammatory process (Labzin et al., 2018), activating signaling molecules to promote microglial phagocytosis and cytokine release (Hanke and Kielian, 2011; Su et al., 2016). This effect is also known to take place upon activation by lipopolysaccharide (LPS), a component of Gram-negative bacteria which induce pro-inflammatory mediators (Płóciennikowska et al., 2014). Furthermore, the adapter protein of most TLRs, myeloid differentiation primary response gene 88 (MyD88) mediates signaling from the innate immune receptors TLRs and interleukin-1 receptor (IL-1R), in turn, increasing the expression of pro-inflammatory mediators (Yang et al., 2019), along with migration of microglia and macrophages to injury sites (Garces et al., 2020; Peng et al., 2015). This, in turn, results in the phosphorylation and degradation of IκB in the proteasome, and thereby the release of NF-κB, increasing the release of inflammatory factors (Yang et al., 2019). Conversely, administration of MyD88 inhibitory peptide attenuates hippocampal microglia activation as well as neuronal injury (Liu et al., 2012; Garces et al., 2020). It is well established that MyD88-dependent and -independent pathways for NF-κβ activation exist. Wang et al. have demonstrated that the MyD88-dependent activation of NF-κβ can be suppressed through ubiquitination of MyD88 increases (Peng et al., 2015). In addition, the authors have indicated that administration of MyD88 inhibitory peptide could partially, but significantly relive the aforementioned Pb-induced effects (Liu et al., 2015). This speculation was supported in a MyD88 knock-out study (O'Halloran et al., 2014). In summary, Pb exposure might induce a robust glial response, TLR4/MyD88/NF-κβ signaling activation, inflammatory cytokine generation, leading to abnormality in hippocampal neurogenesis (Liu et al., 2015).
大量研究表明铅会影响大脑的发育（ Baranowska-Bosiacka 等人，2017 年； Lee 等人，2019 年）。在大脑中，接触 Pb 可能会通过调节 TLR4/MyD88/NF-κβ (NF-κβ) 信号级联引起小胶质细胞增生和星形胶质细胞增生，从而导致促炎细胞因子的产生 ( Fitzgerald et al., 2003 )。事实上，Pb 已被证明可以通过调节 NF-κβ 信号通路来激活 TLR4/MyD88 通路（ Fitzgerald 等，2003 ； Liu 等，2015 ）。因此，中枢神经系统炎症细胞因子的显着增加可能源自铅诱导的小胶质细胞激活（ Khan et al., 2011 ； von Bernhardi et al., 2016 ）。已知小胶质细胞和星形胶质细胞对 Pb 敏感，并释放肿瘤坏死因子 α (TNF-α)、白细胞介素 6 (IL-6) 和 IL-1β，以及促炎性环氧合酶 2 (COX-2)这些细胞中的酶已被证明对铅处理有反应（ Jane 等人，2011 ； Liu 等人，2012 ； Kumawat 等人，2014 ）。 众所周知，Toll样受体（TLR）识别特定配体来启动炎症过程（ Labzin等，2018 ），激活信号分子以促进小胶质细胞吞噬作用和细胞因子释放（ Hanke和Kielian，2011 ； Su等，2011）。 ，2016 ）。已知这种效应也会在脂多糖(LPS) 激活后发生，脂多糖是革兰氏阴性菌的一种成分，可诱导促炎介质（ Płóciennikowska 等人，2014 ）。此外，大多数 TLR 的衔接蛋白，骨髓分化初级反应基因 88 (MyD88) 介导先天免疫受体 TLR 和白细胞介素 1 受体 (IL-1R) 的信号传导，进而增加促炎介质的表达。 et al., 2019 ），同时小胶质细胞和巨噬细胞迁移至损伤部位（ Garces et al., 2020 ； Peng et al., 2015 ）。这反过来又导致蛋白酶体中IκB的磷酸化和降解，从而释放NF-κB，增加炎症因子的释放( Yang et al., 2019 )。相反， MyD88抑制肽的施用会减弱海马小胶质细胞的激活以及神经元损伤（ Liu 等，2017）。, 2012 ; Garces 等人，2020 ）。众所周知，NF-κβ 激活存在依赖于 MyD88 和不依赖于 MyD88 的途径。王等人。已经证明，MyD88 依赖性的 NF-κβ 激活可以通过 MyD88 泛素化的增加来抑制 ( Peng et al., 2015 )。此外，作者指出，施用 MyD88 抑制肽可以部分但显着地缓解上述 Pb 诱导的效应（ Liu et al., 2015 ）。这一推测得到了 MyD88 敲除研究的支持（ O'Halloran 等人，2014 ）。总之，Pb暴露可能诱导强烈的神经胶质反应、TLR4/MyD88/NF-κβ信号激活、炎症细胞因子的产生，导致海马神经发生异常( Liu et al., 2015 )。

Necrosis is associated with an inflammatory reaction. It has long been thought that necrosis is seen as an unregulated accidental cell death (ACD) process. However, there is increasing evidence that a death form called necroptosis is similar to apoptosis in the body and is mediated by cellular processes (Weinlich et al., 2016). What they have in common is that they are both regulated by a single signaling system that uses Ca²⁺ as a universal messenger (A V, 2007). Despite these similarities, there are the following differences between apoptosis and necrosis. Apoptosis is described to be nonimmunogenic, because it does not elicit inflammation (Fink and Cookson, 2005). But necroptosis directly triggers inflammation by a massive release of damage-associated molecular patterns (DAMPs) from the disintegrating cell (Pasparakis and Vandenabeele, 2015). This death mode is mainly driven by the activation of TNF-α involving receptor-interacting serine-threonine kinase 1 (RIP1), RIP3, and mixed lineage kinase domain-like (MLKL) (He et al., 2016). Necroptosis, mediated by receptor interacting protein kinase-3 (RIPK3) and its substrate MLKL, is the best-characterized form of regulated necrosis (Pasparakis and Vandenabeele, 2015). Increasing evidence suggests the pivotal role of necroptosis in inflammation. Sobin et al. found that early chronic exposure to Pb disrupted microglia via damage to, loss of, or lack of proliferation of microglia in the developing brains of Pb-exposed animals, rather than a model of increased neuroinflammation (Huang et al., 2018). In conclusion, necrosis is also involved in the lead induced neuroinflammatory response.
坏死与炎症反应有关。长期以来，人们一直认为坏死是一种不受控制的意外细胞死亡（ACD）过程。然而，越来越多的证据表明，一种称为坏死性凋亡的死亡形式类似于体内的细胞凋亡，并且是由细胞过程介导的（ Weinlich et al., 2016 ）。它们的共同点是它们都受到使用 Ca ²⁺作为通用信使的单一信号系统的调节（ AV，2007 ）。尽管有这些相似之处，细胞凋亡和坏死之间仍存在以下差异。细胞凋亡被描述为非免疫原性，因为它不会引起炎症（ Fink 和 Cookson，2005 ）。但坏死性凋亡通过崩解细胞大量释放损伤相关分子模式（DAMP）直接引发炎症（ Pasparakis 和 Vandenabeele，2015 ）。这种死亡模式主要是由 TNF-α 的激活驱动的，涉及受体相互作用的丝氨酸苏氨酸激酶 1 (RIP1)、RIP3 和混合谱系激酶结构域 (MLK​​L) ( He et al., 2016 )。由受体相互作用蛋白激酶 3 (RIPK3) 及其底物 MLKL 介导的坏死性凋亡是调节性坏死的最佳表征形式 ( Pasparakis 和 Vandenabeele, 2015 )。越来越多的证据表明坏死性凋亡在炎症中发挥着关键作用。索宾等人。 发现早期慢性接触铅会通过铅暴露动物发育中大脑中小胶质细胞的损伤、丧失或缺乏增殖来破坏小胶质细胞，而不是神经炎症增加的模型（ Huang et al., 2018 ）。总之，坏死也参与铅诱导的神经炎症反应。

2.6. Oxidative stress 2.6。氧化应激

Several studies have identified oxidative stress as the primary contributory agent in the pathogenesis of Pb exposure (Feng et al., 2019; Ye et al., 2015a; Shraideh et al., 2018). Oxidative stress has been implicated to affect brain function in response to Pb (Lee et al., 2019). As a defensive response to counteract Pb-induced oxidative stress and toxicity, Nuclear factor E2-related factor 2 (Nrf2) is activated, thereby inducing a rapid increase in Nrf2 nuclear accumulation, as well as Nrf2-ARE binding activities in a reactive oxygen species (ROS)-dependent manner (Ye et al., 2015b). In addition, ROS triggers the activation of the antioxidant system, including heme oxygenase-1 (HO-1), r-GCS, and GSH-Px (Cao et al., 2020). The oxidative damage induced may following Pb intoxication via the Nrf2/HO-1 pathway (Baty et al., 2020). Nrf2 is an intracellular transcription factor that regulates the expression of a number of genes to encode anti-oxidative enzymes, detoxifying factors and anti-apoptotic proteins (Sajadimajd and Khazaei, 2018). HO-1, a stress-inducible protein, and its expression is regarded as an adaptive cellular response to inflammation and oxidative injury (Yoo et al., 2019). Induced by lead, Nrf2 translocates into the nucleus to bind with antioxidant response element; activating several cytoprotective genes including HO-1 (Sandberg et al., 2014). In contrast, Baty et al. (2020) reported that Luteolin is able to stimulate the Nrf2/HO-1 signaling pathway, attenuating neuronal damage induced by Pb by inhibiting oxidative damage, neuro-inflammation, and the cortical cell death. In addition, Prasanthi et al. (2009) showed that the toxic effects of Pb in developing mouse brain can be attributed to Pb-induced oxidative stress, and this burden can be greatly reduced when supplemented with Ca²⁺. This could be due to the Pb-induced Ca²⁺ deficiency as Pb competes and replaces Ca²⁺ in their binding sites (RPJDevi et al., 2009). Moreover, Li et al. (2014) has been proven that lead acetate-induced oxidative stress via PI3K/Akt/GSK-3β in PC12 cells (Li et al., 2014). Therefore, lead could cause neuronal dysfunction through oxidative stress induced by the Nrf2/HO-1 and PI3K/Akt/GSK-3β pathway.
多项研究已确定氧化应激是铅暴露发病机制的主要促成因素（ Feng et al., 2019 ； Ye et al., 2015a ； Shraideh et al., 2018 ）。氧化应激可能会影响大脑对铅的反应功能（ Lee et al., 2019 ）。作为对抗 Pb 诱导的氧化应激和毒性的防御反应，核因子 E2 相关因子 2 (Nrf2) 被激活，从而诱导 Nrf2 核积累快速增加，以及活性氧中 Nrf2-ARE 结合活性（ROS）依赖方式（ Ye et al., 2015b ）。此外，ROS还会触发抗氧化系统的激活，包括血红素加氧酶-1（HO-1）、r-GCS和GSH-Px（ Cao et al., 2020 ）。铅中毒后可能通过 Nrf2/HO-1 途径诱导氧化损伤（ Baty et al., 2020 ）。 Nrf2 是一种细胞内转录因子，可调节许多编码抗氧化酶、解毒因子和抗凋亡蛋白的基因的表达（ Sajadimajd 和 Khazaei，2018 ）。 HO-1是一种应激诱导蛋白，其表达被认为是细胞对炎症和氧化损伤的适应性反应( Yoo et al., 2019 )。 在铅的诱导下，Nrf2易位到细胞核内与抗氧化反应元件结合；激活包括 HO-1 在内的多种细胞保护基因（ Sandberg et al., 2014 ）。相比之下，巴蒂等人。 (2020)报道，木犀草素能够刺激 Nrf2/HO-1 信号通路，通过抑制氧化损伤、神经炎症和皮质细胞死亡来减轻 Pb 引起的神经元损伤。此外，Prasanthi 等人。 (2009) 表明Pb 对发育中的小鼠大脑的毒性作用可归因于Pb 诱导的氧化应激，而补充Ca ²⁺可以大大减轻这种负担。这可能是由于 Pb 诱导的 Ca ²⁺缺乏，因为 Pb在其结合位点竞争并取代了 Ca ²⁺ ( RPJDevi 等人，2009 )。此外，李等人。 (2014)已证明乙酸铅通过PC12细胞中的PI3K/Akt/GSK-3β诱导氧化应激( Li et al., 2014 )。因此，铅可能通过Nrf2/HO-1和PI3K/Akt/GSK-3β通路诱导的氧化应激导致神经元功能障碍。

2.7. Autophagy 2.7.自噬

Autophagy is widespread in eukaryotic cells and is a programmed intracellular degradation process (Zou et al., 2020), in which the misfolded protein, damaged organelles and invading microorganisms are delivered to lysosomes for degradation (Gomes et al., 2017; Mizushima et al., 2008). Recently, much attention has been paid to the role of autophagy in CNS health and disease (Li et al., 2019; Marsh and Dragich, 2019). Autophagy related proteins (ATGs) mediate auto-phagosomes (APs) formation (Heras-Sandoval et al., 2014). LC3, Beclin1 and Atg5 are ATGs required for macro-autophagy and its related process (Zhang et al., 2012). In the process of mature of APs, LC3-I is phosphorylated to LC3-II and the expression of Beclin1 and Atg5 are enhanced (Jiang et al., 2017). Thus, the proportion of LC3-I/LC3-II, and the expression of Beclin1 and Atg5 are commonly used to assess cellular levels of autophagy. Several studies have shown that Pb up-regulated the expression of Atg5, Beclin-1 and enhanced LC3-I to LC3-II conversion (Yang et al., 2019; Kim et al., 2016).
自噬广泛存在于真核细胞中，是一种程序性的细胞内降解过程( Zou et al., 2020 )，其中错误折叠的蛋白质、受损的细胞器和入侵的微生物被传递至溶酶体进行降解( Gomes et al., 2017 ； Mizushima et al. , 2017 ) ., 2008 )。近年来，自噬在中枢神经系统健康和疾病中的作用受到广泛关注（ Li et al., 2019 ； Marsh and Dragich, 2019 ）。自噬相关蛋白(ATG) 介导自噬体 (AP) 的形成 ( Heras-Sandoval et al., 2014 )。 LC3、 Beclin1和Atg5是宏自噬及其相关过程所需的ATG( Zhang et al., 2012 )。 AP成熟过程中，LC3-I被磷酸化为LC3-II，Beclin1和Atg5的表达增强( Jiang et al., 2017 )。因此，LC3-I/LC3-II的比例以及Beclin1和Atg5的表达通常用于评估细胞自噬水平。多项研究表明，Pb 上调 Atg5、Beclin-1 的表达，并增强 LC3-I 到 LC3-II 的转化（ Yang et al., 2019 ； Kim et al., 2016 ）。

Recent studies have demonstrated that Pb can up-regulate the expression of Atg5, Beclin-1 and enhance LC3-I to LC3-II turnover (Yang et al., 2019; Gu et al., 2019). The kinase mammalian target of rapamycin (mTOR) is the most prominent regulator of autophagy, and it is regulated by various signaling molecules (Zhuo et al., 2020), especially those that sense cellular energetic state to trigger or halt the synthesis of proteins (Qi et al., 2020). As such, suppression of mTOR activity promotes autophagy (Liu et al., 2019). And over inhibition, it may compromise survival by sustained autophagy (Heras-Sandoval et al., 2014). The kinase mTOR itself is regulated upstream by phosphatidylinositol 3 kinase (PI3K) and protein kinase B (AKT) (Xue et al., 2017), and it regulates its downstream target 70-kDa ribosomal protein S6 kinase (p70s6k) (Meng et al., 2016). Notably, Akt is the major downstream target of PI3K (Acebes and Morales, 2012) and its’ phosphorylation has been associated with mTOR (Dibble and Cantley, 2015; Zoncu et al., 2011). Several studies have shown that the PI3K/AKT signaling pathways is activated upon Pb treatment (Li et al., 2016), and Pb also activates AKT directly (Gassowska et al., 2016b). Furthermore, Pb²⁺ has been shown to effectively inhibit the phosphorylation of mTOR and p70s6k (Meng et al., 2016). Hence, Pb might induce autophagy in order to protect neural cells from cellular toxicities, secondary to the activation of PI3K/AKT/mTOR/p70s6k signaling (Li et al., 2016; Meng et al., 2016). More specifically, activation of the PI3K/AKT/mTOR/p70s6k pathway would promote, in principle, survival, neuronal protection, and inhibition of autophagy by mTOR activation (Heras-Sandoval et al., 2014). Research content has given an indication of the fact that glycogen synthase kinase 3 (GSK3) is also connected to PI3K/Akt/mTOR signaling cascades (Mueed et al., 2018). GSK3 is an important upstream signal that activates mTOR (Kitagishi et al., 2012) and Tau-kinases (Gassowska et al., 2016b), also is a key downstream target of the PI3K/Akt pathway (Li et al., 2014). Furthermore, Pb causes hyperphosphorylation of tau, suppressing mTOR signal pathway (Zhang et al., 2012). Gąssowska et al. have proven that activated GSK-3β is involved in Pb-evoked neurotoxic effects (Gassowska et al., 2016a, 2016b). In conclusion, lead can regulate autophagy through the PI3K/AKT/GSK-3β/mTOR/p70s6k pathway and affect neuronal activity. Recent studies indicate that intracellular Ca²⁺ signaling is also involved in autophagy (Ureshino et al., 2014). Both mitochondria and the ER play a critical role in Ca²⁺ homeostasis and regulation of autophagy (Gomez-Suaga et al., 2017). As previously mentioned, Pb can damage mitochondria and cause ER stress, which may disrupt Ca²⁺ homeostasis. These stress conditions can promote Ca²⁺ release and thus increase intracellular Ca²⁺, thereby promoting autophagy (Hu et al., 2019). Therefore, autophagy may be protective at a certain level of lead exposure, but autophagy induced by current exposure above a certain level can cause neurological diseases.
最近的研究表明，Pb可以上调Atg5、Beclin-1的表达并增强LC3-I到LC3-II的转换( Yang等，2019 ； Gu等，2019 )。雷帕霉素哺乳动物靶标激酶(mTOR) 是自噬最重要的调节因子，它受到各种信号分子的调节 ( Zhuo et al., 2020 )，特别是那些感知细胞能量状态以触发或停止蛋白质合成的信号分子 (齐等人，2020 ）。因此，抑制 mTOR 活性会促进自噬 ( Liu et al., 2019 )。过度抑制可能会因持续自噬而损害生存（ Heras-Sandoval et al., 2014 ）。激酶 mTOR 本身受磷脂酰肌醇 3 激酶 (PI3K) 和蛋白激酶 B (AKT) 的上游调节 ( Xue et al., 2017 )，并且调节其下游靶标 70-kDa 核糖体蛋白 S6 激酶 (p70s6k) ( Meng et al. , 2017) .，2016 ）。值得注意的是，Akt 是PI3K的主要下游靶标（ Acebes 和 Morales，2012 ），其磷酸化与 mTOR 相关（ Dibble 和 Cantley，2015 ； Zoncu 等，2011 ）。 多项研究表明，Pb 处理后 PI3K/AKT 信号通路被激活（ Li et al., 2016 ），并且 Pb 还直接激活 AKT（ Gassowska et al., 2016b ）。此外，Pb ²⁺已被证明可以有效抑制 mTOR 和 p70s6k 的磷酸化（ Meng et al., 2016 ）。因此，Pb 可能会诱导自噬，以保护神经细胞免受细胞毒性的影响，继发于 PI3K/AKT/mTOR/p70s6k 信号传导的激活（ Li 等，2016 ； Meng 等，2016 ）。更具体地说，原则上，PI3K/AKT/mTOR/p70s6k 通路的激活将促进存活、神经元保护以及 mTOR 激活对自噬的抑制（ Heras-Sandoval 等，2014 ）。研究内容表明糖原合成酶激酶 3 (GSK3) 也与 PI3K/Akt/mTOR 信号级联有关 ( Mueed et al., 2018 )。 GSK3是激活mTOR（ Kitagishi et al., 2012 ）和Tau激酶（ Gassowska et al., 2016b ）的重要上游信号，也是PI3K/Akt通路的关键下游靶标（ Li et al., 2014 ） 。此外，Pb 会导致 tau 过度磷酸化，抑制 mTOR 信号通路（ Zhang 等，2015）。，2012）。加索斯卡等人。已证明激活的 GSK-3β 参与 Pb 诱发的神经毒性作用（ Gassowska 等人，2016a ， 2016b ）。总之，铅可以通过PI3K/AKT/GSK-3β/mTOR/p70s6k通路调节自噬并影响神经元活动。最近的研究表明细胞内Ca ²⁺信号传导也参与自噬( Ureshino et al., 2014 )。线粒体和内质网在 Ca ²⁺稳态和自噬调节中发挥着关键作用 ( Gomez-Suaga et al., 2017 )。如前所述，Pb 会损害线粒体并引起 ER 应激，从而可能破坏 Ca ²⁺稳态。这些应激条件可以促进Ca ²⁺释放，从而增加细胞内Ca ²⁺ ，从而促进自噬( Hu et al., 2019 )。因此，自噬在一定水平的铅暴露下可能具有保护作用，但超过一定水平的电流暴露诱导的自噬可能会导致神经系统疾病。

2.8. Glial stress 2.8.神经胶质应激

Early life Pb exposure results in permanent cognitive and behavioral changes (Sanders et al., 2009; Li et al., 2015). Many brain regions are influenced by Pb exposure, in particular, the hippocampus is a key target of Pb's effects (Sanders et al., 2009). And hippocampus is a highly heterogeneous structure, containing many cell types, including neurons and glial cells. The effects of lead on neurons have been described previously. The effects of lead on glial cells such as astrocytes, oligodendrocytes and microglial cells are discussed here.
生命早期的铅暴露会导致永久性的认知和行为变化（ Sanders 等，2009 ； Li 等，2015 ）。许多大脑区域都受到铅暴露的影响，特别是海马体是铅影响的关键目标（ Sanders et al., 2009 ）。海马体是一个高度异质的结构，包含多种细胞类型，包括神经元和神经胶质细胞。铅对神经元的影响之前已经描述过。本文讨论铅对星形胶质细胞、少突胶质细胞和小胶质细胞等神经胶质细胞的影响。

Glial cells have important roles in the survival of neurons. The astrocytes are the most abundant cells in the brain, which play a role in dynamic signaling and provide critical support to neurons (Dallérac and Rouach, 2016), but they are also known to accumulate Pb and responsible for its sequestration (Tiffany-Castiglion and Qian, 2001). Furthermore, Rahman et al. have found that astrocytes are more sensitive to Pb toxicity than neurons (Rahman et al., 2019). And, it has been reported that astrocyte apoptosis may contribute to the pathogenesis of neurodegenerative disorders. Moreover, Pb in the pre- and neonatal periods may lead to the impairment of brain energy metabolism and the metabolic cooperation between neurons and astrocytes (Baranowska-Bosiacka et al., 2017). Oligodendrocytes wrap axons in myelin, the latter playing an important role in the maintenance and survival of axons and neurons (Philips and Rothstein, 2017). A key feature of oligodendrocyte lineage cells is the important role for calcium in regulating myelination by influx through ion channels or by activation of receptors (Verkhratsky, 2006; Butt et al., 2019). However, prolonged Pb exposure is known to cause hypo- and demyelination (Wu and Tiffany-Castiglioni, 1987). Chronic Pb exposure may impact brain development, in part, by impairing the timely developmental commitment of oligodendrocyte progenitors, thereby affecting optimal neuron survival, axon growth, and synapse formation (Deng et al., 2001). Microglia act as the first and main form of active immune defense in the brain and spinal cord. Recently, Bakulski et al. showed that glial cell populations, particularly cellular proportions of oligodendrocytes and gene expression in microglia, appear to be the most susceptible to the effects of Pb, and that these effects persist into adulthood (Bakulski et al., 2020). Similarly, early lead exposure may increase sensitivity to neurodegeneration in later life due to reduced microglial activation (vonderEmbse et al., 2017). Interestingly, primary microglia have been found to be more sensitive to lead exposure than astrocytes due to due to oxidative stress response and upregulation of Nrf2 (Peng et al., 2019). As described earlier, glial activation plays a potentially detrimental role upon Pb exposure, leading to the synthesis and release of pro-inflammatory cytokines, such as IL-1β, IL-18 (Struzynska et al., 2007), IL-6, TNF-α (Voet et al., 2019), COX-1 and COX-2 (Metryka et al., 2020b; Chibowska et al., 2020). Indeed, in the hippocampus of mice exposed to Pb, up-regulation of IL-1β, and TNF-α level, has been shown to trigger an inflammatory response (Fakhoury, 2018; Pomilio et al., 2016). In addition, there are indications that glial cells such as astrocytes, oligodendrocytes and microglia trigger pathological manifestations when calcium homeostasis is disturbed by external stress (Wang et al., 2015; Maiuolo et al., 2019; Kettenmann et al., 2011). Taken together, the effect of Pb-induced glial stress may play an important role in the learning and memory deficits pathological processes, and is accompanied by inflammatory events (Baty et al., 2020; Chibowska et al., 2016).
神经胶质细胞在神经元的存活中发挥重要作用。星形胶质细胞是大脑中最丰富的细胞，在动态信号传导中发挥作用，并为神经元提供关键支持（ Dallérac 和 Rouach，2016 ），但它们也能积累铅并负责铅的隔离（ Tiffany-Castiglion 和钱，2001 ）。此外，拉赫曼等人。发现星形胶质细胞比神经元对铅毒性更敏感（ Rahman et al., 2019 ）。并且，据报道，星形胶质细胞凋亡可能有助于神经退行性疾病的发病机制。此外，孕前期和新生儿期的Pb可能会导致脑能量代谢以及神经元和星形胶质细胞之间的代谢合作受损( Baranowska-Bosiacka et al., 2017 )。少突胶质细胞将轴突包裹在髓磷脂中，后者在轴突和神经元的维持和存活中发挥着重要作用（ Philips 和 Rothstein，2017 ）。少突胶质细胞系细胞的一个关键特征是钙通过离子通道流入或通过受体激活来调节髓鞘形成的重要作用（ Verkhratsky，2006 ； Butt等，2019 ）。然而，已知长期接触铅会导致髓鞘减少和脱髓鞘（ Wu 和 Tiffany-Castiglioni，1987 ）。 慢性铅暴露可能会影响大脑发育，部分原因是损害少突胶质细胞祖细胞的及时发育承诺，从而影响最佳神经元存活、轴突生长和突触形成（ Deng et al., 2001 ）。小胶质细胞是大脑和脊髓主动免疫防御的第一个也是主要形式。最近，巴库斯基等人。研究表明，神经胶质细胞群，特别是少突胶质细胞的细胞比例和小胶质细胞中的基因表达，似乎最容易受到铅的影响，并且这些影响持续到成年期（ Bakulski et al., 2020 ）。同样，由于小胶质细胞激活减少，早期铅暴露可能会增加晚年神经退行性变的敏感性（ vonderEmbse 等，2017 ）。有趣的是，由于氧化应激反应和 Nrf2 的上调，原代小胶质细胞被发现比星形胶质细胞对铅暴露更敏感（ Peng et al., 2019 ）。如前所述，神经胶质细胞活化在铅暴露后发挥潜在的有害作用，导致促炎细胞因子的合成和释放，例如 IL-1β、IL-18 ( Struzynska et al., 2007 )、IL-6、TNF -α（ Voet 等人，2019 ）、COX-1 和 COX-2（ Metryka 等人，2020b ； Chibowska 等人，2020 ）。 事实上，在暴露于 Pb 的小鼠海马体中，IL-1β 和 TNF-α 水平的上调已被证明会引发炎症反应（ Fakhoury，2018 ； Pomilio 等，2016 ）。此外，有迹象表明，当钙稳态受到外部应激干扰时，星形胶质细胞、少突胶质细胞和小胶质细胞等胶质细胞会引发病理表现( Wang等，2015 ； Maiuolo等，2019 ； Kettenmann等，2011 )。综上所述，Pb诱导的神经胶质应激可能在学习记忆缺陷病理过程中发挥重要作用，并伴有炎症事件( Baty et al., 2020 ; Chibowska et al., 2016 )。