Mechanisms of Cadmium Neurotoxicity
镉神经毒性机制

Abstract 抽象的

Cadmium is a heavy metal that increasingly contaminates food and drink products. Once ingested, cadmium exerts toxic effects that pose a significant threat to human health. The nervous system is particularly vulnerable to prolonged, low-dose cadmium exposure. This review article provides an overview of cadmium’s primary mechanisms of neurotoxicity. Cadmium gains entry into the nervous system via zinc and calcium transporters, altering the homeostasis for these metal ions. Once within the nervous system, cadmium disrupts mitochondrial respiration by decreasing ATP synthesis and increasing the production of reactive oxygen species. Cadmium also impairs normal neurotransmission by increasing neurotransmitter release asynchronicity and disrupting neurotransmitter signaling proteins. Cadmium furthermore impairs the blood–brain barrier and alters the regulation of glycogen metabolism. Together, these mechanisms represent multiple sites of biochemical perturbation that result in cumulative nervous system damage which can increase the risk for neurological and neurodegenerative disorders. Understanding the way by which cadmium exerts its effects is critical for developing effective treatment and prevention strategies against cadmium-induced neurotoxic insult.
镉是一种重金属，对食品和饮料产品的污染日益严重。一旦摄入，镉就会产生毒性作用，对人类健康构成重大威胁。神经系统特别容易受到长期、低剂量镉的影响。这篇综述文章概述了镉的主要神经毒性机制。镉通过锌和钙转运蛋白进入神经系统，改变这些金属离子的稳态。一旦进入神经系统，镉就会通过减少 ATP 合成和增加活性氧的产生来扰乱线粒体呼吸。镉还通过增加神经递质释放的异步性和破坏神经递质信号蛋白来损害正常的神经传递。镉还会损害血脑屏障并改变糖原代谢的调节。总之，这些机制代表了多个位点的生化扰动，导致累积的神经系统损伤，从而增加神经系统和神经退行性疾病的风险。了解镉发挥其作用的方式对于制定针对镉引起的神经毒性损伤的有效治疗和预防策略至关重要。

1. Introduction 一、简介

Cadmium is a highly toxic pollutant that permeates environmental, industrial, and agricultural spaces. The Agency for Toxic Substances and Disease Registry ranked cadmium as the seventh most hazardous substance to human health [1], and the Department of Health and Human Services listed cadmium as a known human carcinogen in 2021 [2]. Recent anthropogenic activities have increased human exposure to cadmium. Most commercial cadmium is a byproduct of zinc ore mining that is used in electroplating, battery production, paint pigments, and plastics [3,4]. These activities introduce cadmium to the agricultural sphere, where plants readily absorb cadmium from contaminated soil and water. Additionally, cadmium contamination of ethanol is common, with variable levels detected in wine, beer, whiskey, gin, and other alcoholic products [5]. As a result, the most common source of exposure for the general population is contaminated food and drink products [3].
镉是一种剧毒污染物，渗透到环境、工业和农业空间中。有毒物质和疾病登记局将镉列为对人类健康第七大危害物质[ 1 ]，美国卫生与公众服务部于2021年将镉列为已知的人类致癌物[ 2 ]。最近的人类活动增加了人类对镉的接触。大多数商业镉是锌矿开采的副产品，用于电镀、电池生产、油漆颜料和塑料 [ 3 , 4 ]。这些活动将镉引入农业领域，植物很容易从受污染的土壤和水中吸收镉。此外，乙醇的镉污染很常见，在葡萄酒、啤酒、威士忌、杜松子酒和其他酒精产品中检测到的镉含量各不相同[ 5 ]。因此，普通人群最常见的接触源是受污染的食品和饮料产品[ 3 ]。

Cadmium enters the human body by various routes. Uptake is facilitated by the ingestion of contaminated food and beverage products, the inhalation of aerosolized cadmium particles in cigarette smoke, and particle accumulation in the olfactory bulb following industrial fume exposure [6,7]. Due to its abiogenic nature, cadmium has no endogenous mechanism of clearance and thus exhibits a low urinary excretion rate. It accumulates in the human body with an estimated half-life of up to 23.5 years [8]. As a result of this accumulation, the estimated mass of cadmium within adults in the U.S. and Europe who have not been occupationally exposed to cadmium is between 9.5 mg and 40 mg [9]. Moreover, blood concentrations of cadmium were found to be ~0.4 µg/L [10] and cerebrospinal fluid (CSF) concentrations of cadmium were found to be 72 ng/L in humans [10,11]. Thus, CSF concentrations of cadmium in humans are only roughly five-fold lower than in blood.
镉通过多种途径进入人体。摄入受污染的食品和饮料、吸入香烟烟雾中的雾化镉颗粒以及接触工业烟雾后嗅球中的颗粒积聚都会促进镉的吸收[ 6 , 7 ]。由于其非生物性质，镉没有内源性清除机制，因此尿排泄率较低。它在人体内蓄积，估计半衰期长达 23.5 年 [ 8 ]。由于这种积累，美国和欧洲未因职业接触镉的成年人体内的镉含量估计在 9.5 毫克至 40 毫克之间[ 9 ]。此外，人类的血液镉浓度约为 0.4 µg/L [ 10 ]，脑脊液 (CSF) 镉浓度为 72 ng/L [ 10 , 11 ]。因此，人体脑脊液中的镉浓度仅比血液中的镉浓度低大约五倍。

Chronic accumulation of cadmium results in multiorgan toxicity, primarily targeting the kidney, skeleton, liver, and nervous system [12], reviewed in [9]. Among these, the nervous system is a particularly vulnerable target for cadmium toxicity. Cadmium can increase risk of peripheral neuropathy, altered equilibrium, and poor performance on visuomotor tasks [13]. Exposure to cadmium is correlated with reduced concentration, poorer cognitive function in older adults, and adverse learning outcomes in children [13,14,15,16]. Cadmium exposure has also been associated with neurodegenerative disease pathologies observed in Alzheimer’s disease (AD), Parkinson’s disease (PD), and amyotrophic lateral sclerosis (ALS) [17,18,19]. Cadmium exerts its neurotoxic outcomes via diverse means [12,20,21] (Figure 1). Here, we review the current knowledge concerning the sites of exogenous cadmium insult that result in nervous system dysfunction.
镉的慢性蓄积会导致多器官毒性，主要针对肾脏、骨骼、肝脏和神经系统[ 12 ]，详见[ 9 ]。其中，神经系统是镉毒性特别脆弱的目标。镉会增加周围神经病变、平衡改变和视觉运动任务表现不佳的风险[ 13 ]。接触镉与老年人注意力下降、认知功能较差以及儿童学习成绩不良相关[ 13,14,15,16 ]。镉暴露还与阿尔茨海默病 (AD)、帕金森病 (PD) 和肌萎缩侧索硬化症( ALS ) 中观察到的神经退行性疾病病理相关[ 17,18,19 ]。镉通过多种方式发挥其神经毒性作用[12,20,21 ] （图1 ） 。在这里，我们回顾了有关导致神经系统功能障碍的外源性镉损伤部位的最新知识。

Figure 1. The diverse major pathways by which cadmium can increase risk for neurodegenerative disease. Cadmium accumulates in the olfactory bulb following inhalation. When either inhaled or ingested, cadmium passes into the bloodstream, which can decrease the integrity of the blood–brain barrier (BBB) via weakening of tight junctions. This allows cadmium to enter into nervous system tissue. Once within the nervous tissue, cadmium can efficiently pass the cellular membrane by co-opting transporters for other divalent cations. The primary mechanisms of neurotoxicity are disruption of glycogen metabolism, changes to neurotransmitter signaling, and mitochondrial disruption leading to oxidative stress. These perturbations together increase the risk for neurodegenerative disease.
图 1.镉增加神经退行性疾病风险的多种主要途径。镉吸入后会积聚在嗅球中。当吸入或摄入时，镉会进入血液，通过削弱紧密连接来降低血脑屏障（BBB）的完整性。这使得镉进入神经系统组织。一旦进入神经组织，镉就可以通过选择其他二价阳离子的转运蛋白来有效地穿过细胞膜。神经毒性的主要机制是糖原代谢的破坏、神经递质信号传导的改变以及导致氧化应激的线粒体破坏。这些干扰共同增加了神经退行性疾病的风险。

2. Cadmium Entry to the Nervous System
2. 镉进入神经系统

Cadmium gains entry to the nervous system primarily by oral ingestion, at which point it is absorbed into the bloodstream and can damage the blood–brain barrier (BBB) to accumulate within nervous system tissue. Cadmium inhalation provides an even more direct route to the nervous system, since the olfactory epithelium lacks protection offered by the BBB and permits cadmium uptake directly into nervous tissue [22]. Cadmium is similar to bioessential metal cations implicated in neuronal transmission, particularly calcium and zinc. Cadmium, calcium, and zinc are primarily divalent cations that possess similar chemical properties and favor the oxidation state of +2. Calcium and cadmium share similar ionic radii (0.97 Å and 0.99 Å, respectively) and charge/radius ratios (Ca²⁺ = 2.02 e/Å, Cd²⁺ = 2.06 e/Å), granting each the ability to exert similarly strong electrostatic forces on biogenic macromolecules (reviewed in [23]). Cadmium and zinc are elements in Group IIB of the periodic table with the same electron configuration, allowing similar chemical behavior within ion-protein interaction. In this way, cadmium can permeate nervous system cells and organelles by taking advantage of endogenous zinc- and calcium-specific transporters.
镉主要通过口服进入神经系统，然后被吸收到血液中，并会损害血脑屏障（BBB）并在神经系统组织内积聚。镉吸入为神经系统提供了更直接的途径，因为嗅觉上皮缺乏血脑屏障提供的保护，允许镉直接吸收到神经组织中[ 22 ]。镉与参与神经元传递的生物必需金属阳离子类似，特别是钙和锌。镉、钙和锌主要是二价阳离子，具有相似的化学性质并有利于+2氧化态。钙和镉具有相似的离子半径（分别为 0.97 Å 和 0.99 Å）和电荷/半径比（Ca ²⁺ = 2.02 e/Å，Cd ²⁺ = 2.06 e/Å），从而赋予各自施加类似强静电的能力对生物大分子的作用力（综述于[ 23 ]）。镉和锌是元素周期表第 IIB 族的元素，具有相同的电子构型，因此在离子-蛋白质相互作用中具有相似的化学行为。通过这种方式，镉可以利用内源性锌和钙特异性转运蛋白渗透神经系统细胞和细胞器。

Several studies have implicated cadmium as a competitive voltage-gated calcium channel (VGCC) inhibitor [24,25,26]. Cadmium enters the rat cerebellar granular neuron primarily through dihydropyridine-sensitive (L-type) VGCCs as it competes with Ca²⁺ for within the channel pore. Exposure to 100 µM cadmium prevented an increase in cytosolic calcium concentration after neuronal depolarization, and cadmium was able to permeate the neuron. The N-type VGCC is also implicated in cadmium-induced blockage of Ca²⁺ current in frog sympathetic neurons [27]. Cadmium completely and rapidly blocked Ca²⁺ current at voltages when Ca²⁺ channels are primarily open (0 to +30 mV), indicating that the N-type VGCC is a route of cadmium entry into sympathetic neurons. Because VGCCs are densely concentrated at the presynaptic site, the presynaptic terminal is a notable location of cadmium uptake in neuronal cells (reviewed in [28]).
多项研究表明镉是一种竞争性电压门控钙通道 (VGCC) 抑制剂 [ 24 , 25 , 26 ]。镉主要通过二氢吡啶敏感（L 型）VGCC 进入大鼠小脑颗粒神经元，因为它与 Ca ²⁺竞争通道孔内的空间。暴露于 100 µM 镉可阻止神经元去极化后胞质钙浓度的增加，并且镉能够渗透神经元。 N 型 VGCC 还与镉诱导的青蛙交感神经元 Ca ²⁺电流阻断有关 [ 27 ]。当Ca ²⁺通道主要打开时（0至+30 mV），镉在电压下完全且快速地阻断Ca ²⁺电流，表明N型VGCC是镉进入交感神经元的途径。由于 VGCC 密集地集中在突触前位点，因此突触前末梢是神经元细胞中镉摄取的一个显着位置（[ 28 ]中有综述）。

Cadmium also enters neuronal cells through zinc transporters, the most significant of which are the ZIP6 and ZnT3 transporters [28,29]. ZIP6, an importer, is localized to the plasma membrane of hippocampal pyramidal neurons while ZnT3 is an exporter plentiful on the presynaptic neuronal membrane that regulates the brain’s vesicular pool [30,31], reviewed in [22]. Mimouna et al. found that early-life cadmium exposure increased cadmium accumulation in the brain, increased ZIP6 gene expression, and decreased ZnT3 expression [29]. The simultaneous upregulation of the ZIP6 importer and downregulation of the ZnT3 exporter may lead to cadmium accumulation in these neurons. In a later study, Mimouna et al. investigated interactions between cadmium and ZnT3 in hippocampal neurons. Treatment of rat hippocampal neurons with cadmium chloride (0, 0.5, 5, 10, 25, or 50 µM) and zinc chloride (0, 10, 30, 50, 70, or 90 µM) for either 24 or 48 h downregulated ZnT3 mRNA expression, an effect attenuated by the application of zinc. Zinc supplementation at 30 µM significantly ameliorated cadmium-induced neurotoxicity in cells treated with 10 and 25 µM cadmium [32]. Presumably, the physicochemical similarities between cadmium and zinc allow cadmium to enter synaptic vesicles through ZnT3 and accumulate, ultimately resulting in cell death and disruption of neuronal plasticity.
镉还通过锌转运蛋白进入神经元细胞，其中最重要的是 ZIP6 和 ZnT3 转运蛋白 [ 28 , 29 ]。 ZIP6 是一种输入蛋白，位于海马锥体神经元的质膜上，而 ZnT3 是一种输出蛋白，大量存在于突触前神经元膜上，调节大脑的囊泡池 [ 30 , 31 ]，详见 [ 22 ]。米穆纳等人。发现生命早期接触镉会增加大脑中镉的积累，增加 ZIP6 基因表达，并降低 ZnT3 表达[ 29 ]。 ZIP6 输入蛋白的同时上调和 ZnT3 输出蛋白的下调可能导致这些神经元中镉的积累。在后来的研究中，Mimouna 等人。研究了海马神经元中镉和 ZnT3 之间的相互作用。用氯化镉（0、0.5、5、10、25 或 50 µM）和氯化锌（0、10、30、50、70 或 90 µM）处理大鼠海马神经元 24 或 48 小时，下调 ZnT3 mRNA表达，锌的应用减弱了这种效应。在用 10 µM 和 25 µM 镉处理的细胞中，补充 30 µM 锌可显着改善镉诱导的神经毒性 [ 32 ]。据推测，镉和锌之间的物理化学相似性使得镉能够通过 ZnT3 进入突触小泡并积累，最终导致细胞死亡和神经元可塑性破坏。

3. Cadmium Effects on Mitochondrial Respiration
3. 镉对线粒体呼吸的影响

Mitochondria in the nervous system perform critical roles not only in energy production [33] but also in neuronal development, function, and survival [34]. Neurons, the functional unit of the nervous system, are particularly high consumers of ATP due to their constant need to maintain the neuronal concentration gradient necessary for action potential propagation, operate the cellular machinery associated with the vesicle cycle, facilitate axonal transport, and provide energy for synaptic plasticity [33,34,35]. Thus, any disruption in mitochondrial function can result in energy deficits, significantly compromising neural activity and health.
神经系统中的线粒体不仅在能量产生中发挥着关键作用[ 33 ]，而且在神经元发育、功能和存活中也发挥着关键作用[ 34 ]。神经元是神经系统的功能单位，是 ATP 的高消耗者，因为它们不断需要维持动作电位传播所需的神经元浓度梯度、操作与囊泡循环相关的细胞机制、促进轴突运输并提供能量突触可塑性[33,34,35 ] 。因此，线粒体功能的任何破坏都可能导致能量不足，从而严重损害神经活动和健康。

Oxidative phosphorylation relies on a strong mitochondrial membrane potential (ΔΨm) in order to produce ATP via ATP synthase [35]. The electron transport chain (ETC), embedded within the inner mitochondrial matrix uses the potential energy from electron-carrying molecules in order to produce a robust ΔΨm. The four protein complexes that comprise the ETC must deftly handle redox molecules in order to appropriately produce a proton gradient, the basis of the ΔΨm. Furthermore, reactive oxygen species (ROS) are produced at low concentrations as a byproduct of the ETC. Low levels of ROS can be mitigated by antioxidant molecules within the mitochondria, such as glutathione. However, if ROS are allowed to proliferate, either via external influence or inappropriate regulation of the ETC, the resultant oxidative stress results in cellular damage.
氧化磷酸化依赖于强大的线粒体膜电位 (ΔΨm)，以便通过 ATP 合酶产生 ATP [ 35 ]。嵌入线粒体内部基质中的电子传递链 (ETC) 利用电子携带分子的势能来产生强大的 ΔΨm。组成 ETC 的四种蛋白质复合物必须巧妙地处理氧化还原分子，以便适当地产生质子梯度，这是 ΔΨm 的基础。此外，作为 ETC 的副产品，会产生低浓度的活性氧 (ROS)。线粒体内的抗氧化剂分子（例如谷胱甘肽）可以缓解低水平的 ROS。然而，如果允许 ROS 增殖，无论是通过外部影响还是 ETC 的不当调节，所产生的氧化应激都会导致细胞损伤。

This ΔΨm gradient can be regulated via mitochondrial uncoupling proteins, which can serve to respond to cellular energetic needs, maintain consistent temperature, or control osmotic swelling. However, various pathological conditions can disrupt ΔΨm, leading to impaired mitochondrial respiration. For instance, mitochondrial permeability transition pore (PTP) opening can be triggered by factors like oxidative stress that can result in ΔΨm depolarization [36]. Such depolarization can inhibit ATP synthesis and compromise overall mitochondrial function.
这种 ΔΨm 梯度可以通过线粒体解偶联蛋白进行调节，线粒体解偶联蛋白可以响应细胞的能量需求、保持一致的温度或控制渗透膨胀。然而，各种病理状况会破坏 ΔΨm，导致线粒体呼吸受损。例如，氧化应激等因素可以触发线粒体通透性转换孔（PTP）开放，从而导致 ΔΨm 去极化[ 36 ]。这种去极化会抑制 ATP 合成并损害线粒体的整体功能。

The significance of mitochondria becomes most apparent in the context of neurodegenerative diseases, including AD, PD, and ALS. These conditions are characterized by mitochondrial dysfunction [35]. Abnormalities encompass impaired energy production, heightened ROS production, and compromised calcium handling, collectively contributing to neuronal degeneration and the clinical manifestations of these diseases [36].
线粒体的重要性在神经退行性疾病（包括 AD、PD 和 ALS）的背景下变得最为明显。这些病症的特点是线粒体功能障碍[ 35 ]。异常包括能量产生受损、ROS 产生增加和钙处理受损，共同导致神经元变性和这些疾病的临床表现[ 36 ]。

3.1. Cadmium Interference with the Electron Transport Chain
3.1.镉对电子传输链的干扰

The mitochondria have emerged as primary targets in cadmium toxicity (for an excellent review focusing exclusively on this topic, see [37]). This is supported by experimental evidence in a rodent model, where cadmium exposure on isolated mitochondria from mouse livers led to extensive organelle damage [38]. One mechanism by which cadmium disrupts mitochondrial function is by interfering with specific protein complexes within the ETC such that ΔΨm is reduced and the proton-motive force that drives ATP synthesis is subsequently weakened. Cadmium interacts with Complex I of the ETC at both the Q-binding site and the NADH-binding site, decreasing the ability of Complex I to shuttle electrons and transport protons to create and maintain ΔΨm. Cadmium’s interaction with the Q_o site of Complex III redirects ROS production toward the intermembrane space, effectively bypassing the matrix antioxidant defenses [39,40]. By disrupting the normal function in Complexes I and III, the resultant decrease in ΔΨm ultimately leads to a decreased ability to efficiently synthesize ATP and increase in damaging cytosolic ROS.
线粒体已成为镉毒性的主要目标（有关专门关注该主题的优秀评论，请参阅[ 37 ]）。啮齿动物模型中的实验证据支持了这一点，其中小鼠肝脏分离线粒体的镉暴露导致广泛的细胞器损伤[ 38 ]。镉破坏线粒体功能的一种机制是干扰 ETC 内的特定蛋白质复合物，从而减少 ΔΨm，从而削弱驱动 ATP 合成的质子动力。镉与 ETC 复合物 I 在 Q 结合位点和 NADH 结合位点相互作用，降低复合物 I 穿梭电子和传输质子以产生和维持 ΔΨm 的能力。镉与复合物 III 的 Q _o位点的相互作用将 ROS 的产生重定向到膜间空间，有效地绕过基质抗氧化防御 [ 39 , 40 ]。通过破坏复合物 I 和 III 的正常功能，由此产生的 ΔΨm 减少最终导致有效合成 ATP 的能力下降，并增加破坏性胞质 ROS。

3.2. Cadmium Opens the Permeability Transition Pore
3.2.镉打开渗透性转变孔

Furthermore, cadmium induces the opening of the permeability transition pore (PTP), a dynamic protein complex residing at the interface between the inner and outer mitochondrial compartments [41]. The PTP allows for the diffusion of small molecules through the inner mitochondrial membrane, dissipating the ΔΨm and thereby halting ATP synthesis. Opening of the PTP also acts as a signal for apoptosis via release of stores of cytochrome C. The weakening of the inner mitochondrial gradient itself can trigger opening of the PTP in a feedforward mechanism that results in eventual cell death. It is not clear to what extent cadmium opens the PTP via weakening of the ΔΨm in mechanisms described above, or whether cadmium directly interacts with the PTP itself to increase the likelihood of opening, or both.
此外，镉会诱导渗透性过渡孔（PTP）的打开，这是一种位于线粒体内外隔室之间界面的动态蛋白质复合物[ 41 ]。 PTP 允许小分子通过线粒体内膜扩散，消散 ΔΨm，从而停止 ATP 合成。 PTP 的打开还通过释放细胞色素 C 储备来充当细胞凋亡的信号。线粒体内部梯度本身的减弱可以在前馈机制中触发 PTP 的打开，从而导致最终的细胞死亡。目前尚不清楚镉在上述机制中通过削弱 ΔΨm 在多大程度上打开 PTP，或者镉是否直接与 PTP 本身相互作用以增加打开的可能性，或两者兼而有之。

There is some evidence to suggest that cadmium directly interacts with the PTP to increase opening, independent of cadmium’s effects on ΔΨm. Cadmium interacts with a constituent of the PTP complex, the adenine nucleotide translocator (ANT), at the thiol groups present on the cysteine residues, potentially leading to modifications of ANT function [39]. ANT exchanges cytosolic ADP and matrix ATP, enabling cytosolic ATP export out of the mitochondria while delivering ADP to the mitochondria [39,40]. Structural studies have shown that ADP/ATP exchange of ANT proteins occurs via an “induced transition fit” model. This process begins with ADP binding at the “c-state”, where the protein is exclusively open to the intermembrane space. This binding triggers a conformational shift to “m-state”, where the protein becomes exclusively open to the mitochondrial matrix, facilitating the exchange of ADP for ATP [42]. Inhibiting ANT blocks this cadmium-induced PTP opening [43]. This cadmium-induced PTP opening can also be blocked via addition of an inhibitor of the mitochondrial calcium importer, indicating that cadmium is gaining access to the inner mitochondria via this transporter [39].
有一些证据表明镉直接与 PTP 相互作用以增加开口，与镉对 ΔΨm 的影响无关。镉与 PTP 复合物的成分、腺嘌呤核苷酸易位子 (ANT) 在半胱氨酸残基上的硫醇基团处相互作用，可能导致 ANT 功能的改变 [ 39 ]。 ANT 交换胞质 ADP 和基质 ATP，使胞质 ATP 从线粒体输出，同时将 ADP 输送到线粒体 [ 39 , 40 ]。结构研究表明，ANT 蛋白的 ADP/ATP 交换是通过“诱导过渡拟合”模型发生的。该过程始于 ADP 在“c 状态”的结合，此时蛋白质完全向膜间空间开放。这种结合触发构象转变为“m 状态”，此时蛋白质完全向线粒体基质开放，促进 ADP 与 ATP 的交换 [ 42 ]。抑制 ANT 可阻断镉诱导的 PTP 开放 [ 43 ]。这种镉诱导的 PTP 打开也可以通过添加线粒体钙输入抑制剂来阻断，这表明镉正在通过这种转运蛋白进入线粒体内部 [ 39 ]。

Furthermore, while calcium can induce PTP opening via a cyclosporin A (CsA)-dependent mechanism [43], cadmium opens the PTP independent from this calcium-CsA pathway. Because increased calcium is a potent intracellular signal within neurons for apoptosis, cadmium’s ability to bypass calcium-induced mechanisms of apoptosis represent an alternative pathway for unregulated neuronal death. The regulatory mechanisms of this CsA-independent apoptotic pathway are as yet unclear.
此外，钙可以通过环孢素 A (CsA) 依赖性机制诱导 PTP 打开 [ 43 ]，而镉则独立于钙-CsA 途径打开 PTP。由于钙的增加是神经元内细胞凋亡的有效细胞内信号，因此镉绕过钙诱导的细胞凋亡机制的能力代表了不受调节的神经元死亡的另一种途径。这种不依赖于 CsA 的凋亡途径的调节机制尚不清楚。

3.3. Recent Focuses of Mitochondrial Apoptosis/Dysfunction: ER Stress and SIRT1
3.3.线粒体凋亡/功能障碍的最新焦点：ER 应激和 SIRT1

It is increasingly clear that the relationship between mitochondrial stress and endoplasmic reticulum (ER) stress both contribute to cadmium’s toxic effects. According to multiple studies, cadmium exposure may induce crosstalk between the stress responses of the ER and mitochondria, which culminates in cell apoptosis [44,45]. One important aspect of this crosstalk is the involvement of proapoptotic proteins Bim and Bax, which are upregulated following acute cadmium exposure. Bax, in particular, translocates from the cytosol to the mitochondria causing the apoptosis of the mitochondria. Furthermore, cadmium exposure leads to the release of cytochrome c from the mitochondria to the cytoplasm. This release triggers apoptotic signaling and activates caspases, leading to cell apoptosis [44,46,47].
越来越清楚的是，线粒体应激和内质网（ER）应激之间的关系都会导致镉的毒性作用。根据多项研究，镉暴露可能会引起内质网和线粒体应激反应之间的串扰，最终导致细胞凋亡 [ 44 , 45 ]。这种串扰的一个重要方面是促凋亡蛋白 Bim 和 Bax 的参与，它们在急性镉暴露后表达上调。特别是 Bax 从细胞质转移到线粒体，导致线粒体凋亡。此外，镉暴露会导致细胞色素c从线粒体释放到细胞质。这种释放触发细胞凋亡信号并激活半胱天冬酶，导致细胞凋亡[ 44,46,47 ]。

Furthermore, exposure of cadmium to human cell lines led to an increase of intracellular ROS levels in a dose dependent manner. This generation of ROS occurred in a feed-forward fashion that ultimately induces GADD153, a marker that initiates cell death [45]. A protective measure against this process is the antioxidant resveratrol, which inhibits ER stress and GADD153 and activates sirtuin1 (SIRT1) [48].
此外，人类细胞系暴露于镉会导致细胞内ROS水平以剂量依赖性方式增加。这一代 ROS 以前馈方式发生，最终诱导 GADD153，这是一种启动细胞死亡的标记物 [ 45 ]。针对这一过程的保护措施是抗氧化剂白藜芦醇，它抑制 ER 应激和 GADD153 并激活 Sirtuin1 (SIRT1) [ 48 ]。

More recent research has also pointed towards SIRT1 as a critical regulator of the biochemical response to oxidative stress [45]. SIRT1 is a nicotinamide dinucleotide (NAD⁺)-dependent deacylases known for its ability to regulate cellular processes such as DNA repair, inflammation, fatty acid oxidation, fat differentiation, and more [48]. This suppression of SIRT1 by cadmium leads to a marked increase in oxidative stress within neuronal cells. The ensuing oxidative stress disrupts mitochondrial function, which, in turn, culminates in the death of neural cells. This phenomenon has been observed in both PC12 cells, a neuron-like cell line, and primary rat cerebral cortical neurons [45]. Activating SIRT1 prevented the buildup of ROS and cellular loss and expounds on a potential mechanism by which SIRT activators affect SIRT1 activity, particularly by deacetylating PGC-1a. This deacetylation is believed to contribute to the enhancement of oxidative metabolism, playing a crucial role in the cellular response to oxidative stress [49]. SIRT1 is structurally important for the nervous system as it promotes axonal elongation, neurite outgrowth, and dendritic branching. Furthermore, it has been found to be crucial for memory formation and its protective measures against neurodegenerative diseases such as Alzheimer’s, Parkinson’s, and motor neuron diseases [50,51,52,53].
最近的研究还指出 SIRT1 是氧化应激生化反应的关键调节因子 [ 45 ]。 SIRT1 是一种烟酰胺二核苷酸 (NAD ⁺ ) 依赖性脱酰酶，以其调节 DNA 修复、炎症、脂肪酸氧化、脂肪分化等细胞过程的能力而闻名 [ 48 ]。镉对 SIRT1 的抑制导致神经元细胞内氧化应激显着增加。随之而来的氧化应激会破坏线粒体功能，最终导致神经细胞死亡。这种现象已在 PC12 细胞（一种神经元样细胞系）和原代大鼠大脑皮层神经元中观察到[ 45 ]。激活 SIRT1 可以防止 ROS 的积累和细胞损失，并阐述了 SIRT 激活剂影响 SIRT1 活性的潜在机制，特别是通过去乙酰化 PGC-1a。这种脱乙酰化被认为有助于增强氧化代谢，在细胞对氧化应激的反应中发挥着至关重要的作用[ 49 ]。 SIRT1 在结构上对神经系统很重要，因为它促进轴突伸长、神经突生长和树突分支。此外，它被发现对于记忆形成及其针对阿尔茨海默氏症、帕金森氏症和运动神经元疾病等神经退行性疾病的保护措施至关重要[ 50,51,52,53 ]。

The precise molecular mechanism underlying cadmium-induced neurotoxicity in the context of mitochondria-associated ER membranes (MAMs) remains unclear. MAMs consist of a diverse array of proteins, including mitofusin 2 (Mfn2), voltage-dependent anion channel (VDAC), and glucose-regulated protein 75 (Grp75). These proteins facilitate the transport of calcium ions from the ER to the mitochondria through the inositol 1,4,5-triphosphate receptors (IP3R) on the ER and the voltage-dependent anion-selective channel protein (VDAC) on the mitochondria [49]. Exposure to cadmium increased expression of Mfn2, Grp75, and VDAC1 [52]. Additionally, both PC12 cells and primary neurons exhibited a significant reduction in mitochondrial calcium uptake when Mfn2 was knocked out in response to cadmium treatment. Notably, this unveiled that the principal driver of cadmium-induced autophagy in neuronal cells may be the uptake of mitochondrial calcium facilitated by MAMs, specifically that the IP3R-Grp75-VDAC1 complex is regulated by Mfn2. The interplay between Mfn2 and the operation of the IP3R-Grp75-VDAC1 complex represents a breakthrough in the understanding of mitochondrial dysfunction following cadmium exposure [50].
线粒体相关内质网膜 (MAM) 中镉诱导的神经毒性的确切分子机制仍不清楚。 MAM 由多种蛋白质组成，包括线粒体融合蛋白 2 (Mfn2)、电压依赖性阴离子通道 (VDAC) 和葡萄糖调节蛋白 75 (Grp75)。这些蛋白质通过 ER 上的肌醇 1,4,5-三磷酸受体 (IP3R) 和线粒体上的电压依赖性阴离子选择性通道蛋白 (VDAC) 促进钙离子从 ER 转运至线粒体 [ 49 ] 。暴露于镉会增加 Mfn2、Grp75 和 VDAC1 的表达[ 52 ]。此外，当镉处理导致 Mfn2 被敲除时，PC12 细胞和原代神经元的线粒体钙吸收均显着减少。值得注意的是，这揭示了镉诱导神经元细胞自噬的主要驱动因素可能是 MAM 促进的线粒体钙的摄取，特别是 IP3R-Grp75-VDAC1 复合物受 Mfn2 调节。 Mfn2 与 IP3R-Grp75-VDAC1 复合物的运作之间的相互作用代表了对镉暴露后线粒体功能障碍的理解的突破 [ 50 ]。

3.4. Cadmium-Induced Autophagy
3.4.镉诱导的自噬

Autophagy, a regulated form of cell death, involves a series of steps directing targeted materials to the lysosome for recycling (for an extensive review focusing on autophagy in neurodegenerative diseases, see [51]). Cadmium-induced autophagy is associated with neurodegenerative disease, though the nature of the relationship remains somewhat controversial [52,53,54]. Hence, this section focuses on recently published papers on the topic of cadmium-induced autophagy.
自噬是一种受调节的细胞死亡形式，涉及一系列将目标材料引导至溶酶体进行回收的步骤（有关神经退行性疾病中自噬的广泛综述，请参阅[ 51 ]）。镉诱导的自噬与神经退行性疾病有关，尽管这种关系的性质仍然存在一些争议[ 52,53,54 ]。因此，本节重点介绍最近发表的有关镉诱导自噬主题的论文。

Since autophagy is a key process for eliminating excess protein, it is thought that disruption in autophagy process via cadmium can result in excess misfolded protein leading to neurodegenerative disease [12]. Cadmium triggers neuronal apoptosis through an increase in autophagosome formation, marked by elevated LC3-II and p62 in neuronal cells, resulting in neuronal apoptosis [55]. The drug rapamycin prevents cadmium-induced increase in LC3-II and p62. Cadmium-induced apoptosis is dependent on the overproduction of autophagosomes by preventing autophagosome–lysosome fusion [55,56,57]. However, other recent studies have shown that cadmium inhibits autophagy through calcium-dependent activation of the JNK signaling pathway in a cell culture model [58].
由于自噬是消除过量蛋白质的关键过程，因此人们认为，通过镉破坏自噬过程可能会导致过量的错误折叠蛋白质，从而导致神经退行性疾病[ 12 ]。镉通过增加自噬体形成来触发神经元凋亡，其标志是神经元细胞中 LC3-II 和 p62 升高，从而导致神经元凋亡 [ 55 ]。药物雷帕霉素可防止镉诱导的 LC3-II 和 p62 增加。镉诱导的细胞凋亡依赖于自噬体的过量产生，通过阻止自噬体-溶酶体融合[ 55,56,57 ]。然而，最近的其他研究表明，镉在细胞培养模型中通过钙依赖性激活 JNK 信号通路来抑制自噬 [ 58 ]。

Recent research has advanced the study of ameliorative strategies for preventing cadmium-induced changes to autophagic flux. Potentilla anserine, an herb native to the Qinghai–Tibet Plateau of China, is renowned for its nutrient richness and application in Chinese medicine. Emerging research highlights Potentilla anserine polysaccharide (PAP), a major bioactive component of this herb, as a candidate to prevent oxidative stress, mitochondrial cell death, and apoptosis [59,60,61,62]. PAP potentially mitigates cadmium-induced neuronal death via autophagy by suppressing the PI3K class III/Beclin-1 signaling pathway [63]. Interestingly, drugs that increase autophagy also seem to have some promise in preventing cadmium-induced neurotoxic damage. Linagliptin, an FDA-approved antidiabetic drug used to treat type 2 diabetes, also shows neuroprotective effects against cognitive decline [64,65]. Studies of linagliptin’s neuroprotective effects against cadmium exposure in rats have shown that linagliptin prevented the cognitive deficit induced by cadmium. However, linagliptin stimulated the hippocampal AMPK/mTOR pathway, which positively impacts autophagy progression. It is thought that this increase in autophagy stimulated clearance of neuronal misfolded proteins, resulting in improvement in cognitive impairment in this context [66]. Together, these results point toward the need for the further exploration of cadmium’s role in autophagic processes.
最近的研究推进了预防镉诱导的自噬通量变化的改善策略的研究。鹅委陵菜是一种原产于中国青藏高原的草本植物，以其营养丰富和在中药中的应用而闻名。新兴研究强调委陵菜多糖（PAP）是这种草药的主要生物活性成分，可作为预防氧化应激、线粒体细胞死亡和细胞凋亡的候选药物[59,60,61,62 ] 。 PAP 通过抑制 PI3K III 类/Beclin-1 信号通路，可能通过自噬减轻镉诱导的神经元死亡 [ 63 ]。有趣的是，增加自噬的药物似乎也有望预防镉引起的神经毒性损伤。利格列汀是 FDA 批准的用于治疗 2 型糖尿病的抗糖尿病药物，也显示出针对认知能力下降的神经保护作用 [ 64 , 65 ]。利格列汀对大鼠镉暴露的神经保护作用的研究表明，利格列汀可以预防镉引起的认知缺陷。然而，利格列汀刺激海马 AMPK/mTOR 通路，从而对自噬进展产生积极影响。据认为，自噬的增加刺激了神经元错误折叠蛋白的清除，从而改善了这种情况下的认知障碍[ 66 ]。总之，这些结果表明需要进一步探索镉在自噬过程中的作用。

4. The Role of Cadmium in Synaptic Transmission
4. 镉在突触传递中的作用

The synapse itself is a vulnerable target for cadmium toxicity. For the efficient transmission of a neuronal signal, biological metal cations must act in conjunction with a series of voltage-gated and ligand-gated channels. Cadmium’s physicochemical similarities to these ions, particularly calcium and zinc, permit its neurotoxicity at the synaptic level as cadmium permeates the presynaptic neuron, induces oxidative stress, and ultimately aggravates neuronal degeneration.
突触本身是镉毒性的脆弱目标。为了有效传输神经元信号，生物金属阳离子必须与一系列电压门控和配体门控通道协同作用。镉与这些离子（特别是钙和锌）的物理化学相似性，使其在突触水平具有神经毒性，因为镉渗透到突触前神经元，诱导氧化应激，并最终加剧神经元变性。

4.1. Cadmium-Induced Asynchronous Neurotransmitter Release
4.1.镉诱导的异步神经递质释放

Synchrony of neurotransmitter release is a marker of efficacious neural communication. The release of a neurotransmitter occurs within hundreds of milliseconds following the action potential to ensure precise communication between neurons [28]. Indeed, several studies have linked asynchronous release to neurodegenerative disease pathologies in AD, spinal muscular atrophy (SMA), and ALS [67,68,69,70]. Cadmium may augment asynchronous neurotransmitter release, further aggravating these neurodegenerative disease pathologies.
神经递质释放的同步是有效神经通讯的标志。神经递质的释放发生在动作电位后数百毫秒内，以确保神经元之间的精确通信[ 28 ]。事实上，一些研究已将异步释放与 AD、脊髓性肌萎缩症 (SMA) 和 ALS 中的神经退行性疾病病理联系起来 [67,68,69,70 ] 。镉可能会增加异步神经递质释放，进一步加剧这些神经退行性疾病的病理。

Cadmium application of 0.1 µM desynchronized neurotransmitter release in the distal compartment of the frog nerve terminal. This asynchrony was accompanied by a sharp increase in mitochondrial ROS production and lipid peroxidation, suggesting that cadmium-induced oxidative stress co-occurs with this desynchronization. Desynchronization was completely blocked by the administration of antioxidants and NADPH-oxidase inhibitors [55]. One possible mechanism of this asynchrony relies on cadmium’s action as a VGCC antagonist in addition to its role as initiator of oxidative stress. Extracellular cadmium likely replaced native calcium as the metal ion flowing through L-type VGCCs. This decrease of calcium inward current in the presence of cadmium leads to a blunted presynaptic spike of cytosolic calcium, which is integral for the coordination of vesicular machinery. Therefore, in the presence of cadmium, VGCCs must remain open for a longer period of time to allow sufficient calcium influx for the initiation of calcium-dependent presynaptic processes. The prolonged period in which VGCCs are open may lengthen the delay observed between the arrival of the depolarizing action potential and neurotransmitter release, accounting for the observed asynchrony.
在青蛙神经末梢的远端室中应用 0.1 µM 去同步神经递质释放的镉。这种异步性伴随着线粒体活性氧产生和脂质过氧化的急剧增加，表明镉诱导的氧化应激与这种去同步性同时发生。给予抗氧化剂和 NADPH 氧化酶抑制剂可以完全阻断去同步化[ 55 ]。这种异步性的一种可能机制依赖于镉除了作为氧化应激引发剂的作用之外还作为 VGCC 拮抗剂的作用。细胞外镉可能取代天然钙作为流经 L 型 VGCC 的金属离子。镉存在下钙内向电流的减少导致胞质钙的突触前尖峰减弱，这对于囊泡机械的协调是不可或缺的。因此，在存在镉的情况下，VGCC 必须保持较长时间的开放状态，以允许足够的钙流入，从而启动钙依赖性突触前过程。 VGCC 长时间开放可能会延长去极化动作电位到达和神经递质释放之间观察到的延迟，从而解释了观察到的异步性。

4.2. Cadmium Disruption of Neurotransmission
4.2.镉对神经传递的干扰

In addition to delaying neurotransmitter release, cadmium disrupts neurotransmitter packaging within synaptic vesicles, decreasing the amount of neurotransmitter available for each release event. There is particular evidence for this in glutamatergic neurons. Vesicular transporters rely on the proton electrochemical gradient generated by V-ATPase to package neurotransmitters into vesicles [71,72]. A volume of 50 µM of cadmium in isolated Wistar rat synaptosomes caused the dissipation of the proton gradient necessary to package glutamate into its synaptic vesicles, resulting in decreased depolarization-evoked exocytosis of glutamate and reduced extracellular glutamate concentration [73]. Although the mechanism by which the V-ATPase is disrupted was not directly observed, interaction with the thiol groups in the cysteine residues of the V-ATPase is a likely culprit.
除了延迟神经递质释放外，镉还会破坏突触小泡内的神经递质包装，减少每次释放事件可用的神经递质数量。在谷氨酸能神经元中有特别的证据表明这一点。囊泡转运蛋白依靠 V-ATP 酶产生的质子电化学梯度将神经递质包装到囊泡中 [ 71 , 72 ]。分离的 Wistar 大鼠突触体中 50 µM 的镉会导致将谷氨酸包装到突触囊泡中所需的质子梯度消散，导致去极化引起的谷氨酸胞吐作用减少，并降低细胞外谷氨酸浓度 [ 73 ]。尽管没有直接观察到 V-ATP 酶被破坏的机制，但与 V-ATP 酶半胱氨酸残基中的硫醇基团的相互作用可能是罪魁祸首。

Additionally, cadmium exposure has been observed to induce changes in cholinergic muscarinic receptors and acetylcholinesterase (AChE) variants [74]. Specifically, Cd²⁺ exposure documented an elevation of the gene expression of AChE-S (the synaptic variant) while reducing the gene expression of AChE-R (the readthrough variant). This modification in AChE variants has been linked to cell death in these neurons. Moreover, cadmium treatment disrupts muscarinic receptors, particularly the M1 and M3 receptors, which play crucial roles in the regulation of memory and learning processes. This interference with the receptors may contribute to the cognitive impairments observed following exposure to cadmium. Although the precise mechanisms by which cadmium alters muscarinic receptors and AChE variants remain incompletely elucidated, oxidative stress has been posited as a potential intermediary factor in this process.
此外，已观察到镉暴露会引起胆碱能毒蕈碱受体和乙酰胆碱酯酶（AChE）变体的变化[ 74 ]。具体而言，Cd ²⁺暴露记录了 AChE-S（突触变体）的基因表达升高，同时降低了 AChE-R（通读变体）的基因表达。 AChE 变体的这种修饰与这些神经元的细胞死亡有关。此外，镉治疗会破坏毒蕈碱受体，特别是 M1 和 M3 受体，它们在调节记忆和学习过程中发挥着至关重要的作用。这种对受体的干扰可能会导致接触镉后观察到的认知障碍。尽管镉改变毒蕈碱受体和乙酰胆碱酯酶变体的精确机制尚未完全阐明，但氧化应激已被认为是这一过程中的潜在中间因素。

5. Cadmium and Other Metals
5. 镉和其他金属

5.1. Cadmium Disruption of Zinc Signaling and Homeostasis
5.1.镉破坏锌信号传导和体内平衡

Zinc, which itself can protect against cadmium-induced hippocampal neurotoxicity [25], decreased quantal release and markedly desynchronized neurotransmitter release at a concentration of 25 µM. Zinc can function as either a prooxidant or antioxidant in cellular systems, with both excesses and deficiencies resulting in oxidative stress (reviewed in [75]). Zinc-induced oxidative stress has been connected to neurodegeneration and cell death in cultured cortical neurons [44,47] and AD [45]. The influx of cadmium through zinc transporters may disrupt this zinc allostasis, resulting in exacerbated oxidative stress. Therefore, zinc and cadmium may act synergistically to induce oxidative stress in presynaptic terminals, ultimately resulting in decreased quantal release and asynchrony that advance neurodegeneration.
锌本身可以防止镉引起的海马神经毒性[ 25 ]，在浓度为 25 µM 时，会减少量子释放并显着使神经递质释放不同步。锌可以在细胞系统中充当促氧化剂或抗氧化剂，过量和缺乏都会导致氧化应激（[ 75 ]中综述）。锌诱导的氧化应激与培养的皮质神经元 [ 44 , 47 ] 和 AD [ 45 ] 中的神经变性和细胞死亡有关。镉通过锌转运蛋白的流入可能会破坏这种锌的动态平衡，导致氧化应激加剧。因此，锌和镉可能协同作用，诱导突触前末梢氧化应激，最终导致量子释放减少和异步，从而促进神经退行性变。

The downregulation of the zinc transporter ZnT3 resulting from cadmium exposure results in downstream effects that affect critical signaling pathways in the brain. This downregulation initiates a cascade that decreases hippocampal brain-derived neurotrophic factor-tropomyosin receptor kinase B (BDNF-TrkB) and Erk1/2 signaling, intracellular messengers that play integral roles in neuronal plasticity and growth [50]. The TrkB neurotrophin receptor and subsequent BDNF activation are essential for advancing neuronal plasticity, and antidepressant binding to neurotrophin receptors, particularly TrkB, has been previously evidenced to facilitate BDNF activation and initiate neuronal plasticity [51]. While antidepressants bound to the TrkB neurotrophin receptor aid neuronal plasticity via BDNF activation, other xenobiotics like cadmium may inhibit it via indirect mechanisms such as ZnT3 downregulation. Further research is necessary to elucidate the mechanisms by which cadmium impedes neuronal plasticity.
镉暴露导致锌转运蛋白 ZnT3 下调，导致下游效应，影响大脑中的关键信号通路。这种下调会引发级联反应，减少海马脑源性神经营养因子原肌球蛋白受体激酶 B (BDNF-TrkB) 和 Erk1/2 信号传导，这些细胞内信使在神经元可塑性和生长中发挥着不可或缺的作用 [ 50 ]。 TrkB 神经营养蛋白受体和随后的 BDNF 激活对于促进神经元可塑性至关重要，抗抑郁药与神经营养蛋白受体（特别是 TrkB）的结合先前已被证明可促进 BDNF 激活并启动神经元可塑性 [ 51 ]。虽然与 TrkB 神经营养蛋白受体结合的抗抑郁药通过激活 BDNF 来帮助神经元可塑性，但镉等其他外源物质可能通过 ZnT3 下调等间接机制来抑制它。需要进一步的研究来阐明镉阻碍神经元可塑性的机制。

Neuronal senescence is a hallmark of cumulative cellular damage. However, the mechanisms of neuronal senescence are varied and complex. Oxidative stress and neuronal senescence have been closely linked in several studies [48,58,59]. The presence of excess ROS results in proteolysis that impacts cell function and manifests as aging. Garfinkel introduced the “zinc hypothesis of aging” [76]. According to this hypothesis, dietary zinc deficiency results in less zinc availability for its metalloenzymes, leading to metalloenzyme dysregulation. This dysregulation, which varies by cell type, precipitates protein malformation and accumulation, which ultimately manifests as aging. He later predicted that zinc deficiency was secondary to cadmium toxicity [77]. According to this hypothesis, cadmium may drive zinc dysfunction and ultimately catalyze neuronal senescence in both control and neurodegenerative models.
神经元衰老是累积细胞损伤的标志。然而，神经元衰老的机制多种多样且复杂。多项研究表明氧化应激和神经元衰老密切相关[ 48,58,59 ]。过量活性氧的存在会导致蛋白水解，从而影响细胞功能并表现为衰老。加芬克尔提出了“衰老的锌假说”[ 76 ]。根据这一假设，饮食中缺锌会导致其金属酶的锌利用率减少，从而导致金属酶失调。这种失调因细胞类型而异，会导致蛋白质畸形和积累，最终表现为衰老。他后来预测锌缺乏是继发于镉毒性的[ 77 ]。根据这一假设，在对照模型和神经退行性模型中，镉可能会导致锌功能障碍并最终催化神经元衰老。

In 2020, Xie et al. reviewed zinc’s role in the development of Alzheimer’s, explaining that the disruption of zinc homeostasis may have implications for AD. In the CNS, ZnT3 packages zinc into presynaptic vesicles of zincergic neurons concentrated in the hippocampus, amygdala, and cerebral cortex. Presynaptic release of zinc from zincergic neurons has been postulated to modulate neuronal plasticity and learning and memory [78]. However, post-mortem brain tissue analysis of AD patients revealed decreases in the mRNA and protein levels of ZnT3 [79,80]. ZnT3 downregulation prevents packaging of zinc into vesicles, resulting in an excess of intracellular zinc within the neuron that readily binds to amyloid-beta (Aβ) oligomers associated with AD pathogenesis. The binding of zinc to Aβ alters the secondary structure of Aβ such that it promotes the formation of neurotoxic spherical species [60] while also limiting the bioavailability of zinc for its role as plasticity modulator. AD patients exhibit zinc deficiency in serum, which may be explained by this continual interaction between zinc and Aβ that promotes neurotoxic oligomer and fibril formation, effectively sequestering zinc from fulfilling its natural biological roles.
2020 年，谢等人。回顾了锌在阿尔茨海默病发展中的作用，解释说锌稳态的破坏可能对阿尔茨海默病有影响。在中枢神经系统中，ZnT3 将锌包装到集中在海马体、杏仁核和大脑皮层的锌能神经元的突触前囊泡中。锌能神经元突触前释放锌被认为可以调节神经元可塑性以及学习和记忆[ 78 ]。然而，AD 患者死后脑组织分析显示 ZnT3 的 mRNA 和蛋白质水平降低 [ 79 , 80 ]。 ZnT3 下调会阻止锌包装到囊泡中，导致神经元内细胞内锌过量，很容易与与 AD 发病机制相关的淀粉样蛋白-β (Aβ) 寡聚物结合。锌与 Aβ 的结合改变了 Aβ 的二级结构，从而促进神经毒性球形物质的形成 [ 60 ]，同时也限制了锌作为可塑性调节剂的生物利用度。 AD 患者血清中表现出锌缺乏，这可能是由于锌和 Aβ 之间的持续相互作用促进了神经毒性低聚物和原纤维的形成，从而有效地阻碍了锌发挥其天然生物学作用。

5.2. Cadmium Contributions to Metal Imbalance in Alzheimer’s Disease
5.2.镉导致阿尔茨海默病金属失衡

Several trace metals have been implicated in AD pathogenesis and progression in addition to cadmium (reviewed in [81]). Zinc dysregulation induced by cadmium may be a risk factor for aggravating and advancing Alzheimer’s disease. Although research exists to probe the link between zinc and Alzheimer’s [82,83,84], little is known about the relationship between cadmium, zinc, and neuronal senescence. The imbalance of bioessential metal ions, particularly zinc, copper, and iron, has been observed in AD patients [85]. In a 2023 meta-analysis of 73 studies measuring levels of trace elements in AD patients, Li et al. reported alterations in the levels of copper in serum, iron in plasma, and zinc in hair [86]. Although Li et al. did not address cadmium levels, a 2017 meta-analysis of toxic metals in the circulation of AD patients reported increased cadmium levels as compared to controls [87]. Each aforementioned metal ion imbalance has consequences for neurodegeneration, and their complex, unique interplay may manifest as AD pathology.
除镉外，还有几种痕量金属与 AD 发病机制和进展有关（[ 81 ] 中综述）。镉引起的锌失调可能是加重和进展阿尔茨海默病的危险因素。尽管已有研究探讨锌与阿尔茨海默病之间的联系[82,83,84 ] ，但人们对镉、锌与神经元衰老之间的关系知之甚少。在AD患者中观察到生物必需金属离子，特别是锌、铜和铁的不平衡[ 85 ]。在 2023 年对 73 项测量 AD 患者微量元素水平的研究进行的荟萃分析中，Li 等人。报道了血清中铜、血浆中铁和头发中锌水平的变化[ 86 ]。尽管李等人。没有解决镉含量问题，2017 年对 AD 患者循环中有毒金属的荟萃分析报告称，与对照组相比，镉含量有所增加 [ 87 ]。上述每种金属离子失衡都会对神经变性产生影响，它们复杂、独特的相互作用可能表现为 AD 病理。

Imbalances of copper, iron, and zinc coupled with exogenous cadmium exposure appear to induce a cycle of exacerbated oxidative stress and promote toxic Aβ formation. As previously discussed, cadmium influx through zinc transports disrupts zinc homeostasis, intensifies oxidative stress, and downregulates the ZnT3 transporter [88]. A downregulation in ZnT3 is also observed in AD patients, indicating that zinc imbalance is closely linked to exogenous cadmium exposure [64,65]. Excess intracellular zinc not sequestered into vesicles by ZnT3 may then readily bind to Aβ monomers, promoting the production of toxic oligomers [60]. Recent research exploring the relationship between copper levels and AD has yielded mixed results. Some analyses report increases in copper levels of AD patients as compared to controls while other studies report no significant alterations in copper levels [86]. However, copper, specifically Cu(II), has been observed to bind to Aβ and contribute to plaques in the brain, which ultimately advances oxidative stress and neuroinflammation just as exogenous cadmium and zinc imbalances contribute to oxidative stress [89]. Iron also binds to Aβ monomers, establishing a structural change in these monomers that promotes toxic Aβ oligomer formation. Iron binds to Aβ via three histidine residues and one tyrosine residue in the N-terminal region of the Aβ monomer, which reduces the helical structure of Aβ and increases beta sheet content [90]. This structural alteration encourages the formation of toxic Aβ oligomers and aggravates neuroinflammation, which may then exacerbate iron imbalance and oxidative stress just as observed with respect to cadmium, zinc, and copper [91]. Cadmium, zinc, copper, and iron are all implicated in the progression of AD. The imbalance of each contributes to a perpetual cycle of oxidative stress and neuroinflammation that remains to be further researched and ultimately contributes to the production of toxic Aβ oligomers, a hallmark of AD pathology.
铜、铁和锌的失衡加上外源性镉暴露似乎会诱发氧化应激加剧的循环，并促进有毒 Aβ 的形成。如前所述，镉通过锌转运流入会破坏锌稳态，加剧氧化应激，并下调 ZnT3 转运蛋白 [ 88 ]。在 AD 患者中也观察到 ZnT3 的下调，表明锌失衡与外源性镉暴露密切相关 [ 64 , 65 ]。未被 ZnT3 隔离到囊泡中的过量细胞内锌可能很容易与 Aβ 单体结合，促进有毒低聚物的产生 [ 60 ]。最近探索铜水平与 AD 之间关系的研究得出了不同的结果。一些分析报告称，与对照组相比，AD 患者的铜水平有所增加，而其他研究报告称，铜水平没有显着变化 [ 86 ]。然而，铜，特别是 Cu(II)，已被观察到与 Aβ 结合并导致大脑中的斑块，最终加剧氧化应激和神经炎症，就像外源性镉和锌失衡会导致氧化应激一样[ 89 ]。铁还与 Aβ 单体结合，使这些单体发生结构变化，从而促进有毒 Aβ 寡聚物的形成。铁通过 Aβ 单体 N 端区域的 3 个组氨酸残基和 1 个酪氨酸残基与 Aβ 结合，从而减少 Aβ 的螺旋结构并增加 β 片层含量 [ 90 ]。 这种结构改变会促进有毒 Aβ 寡聚体的形成，并加剧神经炎症，从而可能加剧铁失衡和氧化应激，正如在镉、锌和铜中观察到的那样 [ 91 ]。镉、锌、铜和铁都与 AD 的进展有关。每种物质的不平衡都会导致氧化应激和神经炎症的永久循环，这有待进一步研究，并最终导致有毒 Aβ 寡聚物的产生，这是 AD 病理学的一个标志。

6. Cadmium and the Blood–Brain Barrier
6. 镉与血脑屏障

The BBB possesses a highly specific, tightly regulated architecture of polar epithelial cells that primarily rely on tight junction (TJ) formation for permeability control between cerebral vasculature and extracellular fluid of the nervous system. A collection of transmembrane and membrane-associated cytoplasmic proteins comprise TJs and act to control passive diffusion, restricting the entry of polar solutes into the CNS and anatomically separating CNS tissues from the bloodstream [20,92,93]. TJs are also regulated by pericytes, perivascular microglial cells, astrocytes, and neurons. The collective structural and modulatory elements of the BBB are known as the “neurovascular unit” (NVU), a term introduced in 2001 [94]. However, studies have reported that cadmium has caused disruptive alterations to the BBB that may underlie pathophysiologies in neurodegenerative disorders like AD, PD, and chronic traumatic encephalopathy, though the precise molecular mechanisms are not well understood [20,95].
BBB 拥有高度特异性、严格调节的极性上皮细胞结构，主要依靠紧密连接 (TJ) 的形成来控制脑血管系统和神经系统细胞外液之间的通透性。跨膜和膜相关细胞质蛋白的集合包含 TJ ，并起到控制被动扩散的作用，限制极性溶质进入 CNS 并在解剖学上将 CNS 组织与血流分离[ 20,92,93 ]。 TJ 还受到周细胞、血管周围小胶质细胞、星形胶质细胞和神经元的调节。 BBB 的集体结构和调节元件被称为“神经血管单元”(NVU)，该术语于 2001 年引入[ 94 ]。然而，研究报告称，镉对血脑屏障造成了破坏性改变，这可能是 AD、PD 和慢性创伤性脑病等神经退行性疾病的病理生理学基础，尽管确切的分子机制尚不清楚 [ 20 , 95 ]。

Although cadmium easily crosses the immature BBB of young animals, it is typically restricted from crossing the adult BBB by strict TJ regulation [96]. However, accumulation in the adult brain does occur, particularly when cadmium is coupled with a vehicle that allows passage across the BBB such as ethanol [97,98], which commonly contains trace amounts of cadmium as an adulterant [5]. Interestingly, ethanol initiates a biochemical cascade to alter the permeability of the BBB in a similar fashion as cadmium, both beginning with an indirect upregulation of ROS that leads to a cellular stress response and culminates in a decrease of NVU protein expression [97,99,100].
尽管镉很容易穿过幼年动物的未成熟血脑屏障，但它通常会受到严格的 TJ 调节而无法穿过成年动物的血脑屏障 [ 96 ]。然而，成人大脑中确实会发生积累，特别是当镉与允许穿过血脑屏障的载体（例如乙醇）结合时[ 97 , 98 ]，乙醇通常含有痕量的镉作为掺杂物[ 5 ]。有趣的是，乙醇启动生化级联反应，以与镉类似的方式改变 BBB 的渗透性，两者都是从间接上调 ROS 开始，导致细胞应激反应，最终导致 NVU 蛋白表达减少 [ 97 , 99 , 100 ]。

Branca et al. reported that induction of oxidative stress occurred rapidly after treatment of a rat brain endothelial cell line (RBE4) with 10 µM cadmium chloride (CdCl₂), with ROS production mediating an endoplasmic reticulum (ER) signaling pathway ultimately responsible for structural breakdown of tight junction and cytoskeletal BBB proteins [100]. Following exposure, ROS overproduction peaked at 5 min before returning to normal levels at 10 min and increasing again after two hours, indicating there may be dual short- and long-term oxidative stress responses following acute cadmium administration. Oxidative stress also activated an ER stress response, as evidenced by the authors’ investigation of GRP78, a well-studied chaperone protein indicative of ER stress, and found that CdCl₂ exposure increased GRP78 expression three-fold as compared to controls. The stress response was followed by a significant upregulation of the apoptotic protein caspase-3 measured at 8 h post-exposure and abnormal immunocytochemical staining for three proteins that constitute tight junction and cytoskeletal architecture of the BBB: the zonula occludens-1 (ZO-1) protein, filamentous actin microfilament (F-actin), and vimentin. ZO-1 exhibited a loss of immunocytochemical staining, and stress fiber formation was visible for F-actin. Rupture and stretching of vimentin proteins were also observed. Disruption of these proteins via an oxidative stress-dependent ER stress response characterizes TJ disruption that ultimately results in secondary injury to the CNS similar to those observed in neurodegenerative diseases.
布兰卡等人。报道称，用 10 µM 氯化镉 (CdCl ₂ ) 处理大鼠脑内皮细胞系 (RBE4) 后，氧化应激的诱导迅速发生，ROS 的产生介导内质网 (ER) 信号通路，最终导致紧密连接的结构破坏和细胞骨架 BBB 蛋白 [ 100 ]。暴露后，ROS 过量产生在 5 分钟时达到峰值，然后在 10 分钟时恢复到正常水平，并在两小时后再次增加，表明急性镉施用后可能存在双重短期和长期氧化应激反应。氧化应激也会激活内质网应激反应，作者对 GRP78（一种经过充分研究的表明内质网应激的分子伴侣蛋白）的研究证明了这一点，并发现与对照组相比，CdCl ₂暴露使 GRP78 表达增加了三倍。应激反应后，暴露后 8 小时测量到的凋亡蛋白 caspase-3 显着上调，并且构成 BBB 紧密连接和细胞骨架结构的三种蛋白的免疫细胞化学染色异常：闭锁小带-1 (ZO-1) ) 蛋白质、丝状肌动蛋白微丝 (F-肌动蛋白) 和波形蛋白。 ZO-1 表现出免疫细胞化学染色缺失，并且 F-肌动蛋白可见应力纤维形成。还观察到波形蛋白的破裂和拉伸。通过氧化应激依赖性内质网应激反应破坏这些蛋白质的特征是 TJ 破坏，最终导致中枢神经系统继发性损伤，类似于神经退行性疾病中观察到的情况。

In 2021, Zhang et al. postulated an expanded mechanism by which cadmium disrupts BBB architecture [99]. Exposure of transgenic zebrafish embryos to CdCl₂ (0, 10, 50, 100, or 500 µM) altered BBB morphology by disrupting endothelial cell–cell adhesion and inducing cerebral hemorrhage in a dose-dependent manner. Altered localization and function of BBB proteins ZO-1, vascular endothelial cadherin (VE-cadherin), and F-actin were due to a cadmium-induced oxidative stress cascade. However, this oxidative stress mediated the inhibition of protein tyrosine phosphatase (PTPase), an enzyme which regulates BBB integrity [101]. Oxidative stress has been observed to mediate tight junction damage caused by excessive protein tyrosine phosphorylation due to PTPase inhibition in human nasal epithelial cells [102]. In the zebrafish model, inhibition of PTPase also generated a rapid increase in the phosphorylation of VE-cadherin and ZO-1, initiating their displacement from typical BBB architecture. Inhibition of PTPase results in severe disruption of the BBB and proteolysis of occludin, explaining the increased BBB permeability exhibited by the embryos for 48 h post treatment and subsequent cerebral hemorrhage. Cadmium-induced destruction of the BBB architecture is a result of oxidant-induced cascades, and multiple downstream molecular mechanisms have been implicated in TJ and cytoskeletal disruption. Further research is needed to elucidate possible interactions between these mechanisms that contribute to the comprehensive BBB destruction observed after exogenous cadmium exposure.
2021 年，Zhang 等人。假设镉破坏 BBB 结构的扩展机制 [ 99 ]。将转基因斑马鱼胚胎暴露于 CdCl ₂ （0、10、50、100 或 500 µM）中，通过破坏内皮细胞-细胞粘附并以剂量依赖性方式诱导脑出血，改变了 BBB 形态。 BBB 蛋白 ZO-1、血管内皮钙粘蛋白 (VE-cadherin) 和 F-肌动蛋白的定位和功能改变是由于镉诱导的氧化应激级联反应所致。然而，这种氧化应激介导了蛋白酪氨酸磷酸酶 (PTPase) 的抑制，PTPase 是一种调节 BBB 完整性的酶 [ 101 ]。据观察，氧化应激可介导人鼻上皮细胞中 PTPase 抑制导致蛋白质酪氨酸过度磷酸化引起的紧密连接损伤[ 102 ]。在斑马鱼模型中，PTPase 的抑制还导致 VE-钙粘蛋白和 ZO-1 的磷酸化迅速增加，从而开始将它们从典型的 BBB 结构中取代。 PTPase 的抑制导致 BBB 严重破坏和 occludin 蛋白水解，解释了治疗后 48 小时胚胎表现出的 BBB 通透性增加以及随后的脑出血。镉诱导的 BBB 结构破坏是氧化剂诱导级联反应的结果，多种下游分子机制与 TJ 和细胞骨架破坏有关。需要进一步的研究来阐明这些机制之间可能的相互作用，这些机制有助于在外源性镉暴露后观察到的全面 BBB 破坏。

We would be remiss not to acknowledge that both BBB perturbations and oxidative stress itself can exacerbate neuroinflammation, which is increasingly seen as a causal factor in myriad nervous system disorders, particularly as it relates to neurodegeneration. Though space prevents a full discussion of neuroinflammation and its deleterious effects across the lifespan, this topic has been excellently reviewed elsewhere [103,104,105,106,107]. However, one critical aspect of cadmium-associated neuroinflammation that warrants discussion is the activation of microglia by cadmium. Microglia exhibit macrophage-like functions in the brain, which include antigen presentation to T cells, general immune surveillance, and the secretion of pro-inflammatory cytokines such as TNF-α, IFN-γ, and IL-6 [108]. Cadmium can activate the excessively-damaging, pro-inflammatory functions of microglia by generating ROS and increasing the expression of NF-κB (a transcription factor involved in inflammatory responses) and upregulating caspase-3 (a protein involved in neuronal cell apoptosis) [109,110,111].
如果我们不承认血脑屏障扰动和氧化应激本身都会加剧神经炎症，那就太失职了，神经炎症越来越被视为多种神经系统疾病的致病因素，特别是与神经退行性疾病有关。尽管篇幅限制了对神经炎症及其在整个生命周期中的有害影响的充分讨论，但该主题已在其他地方得到了很好的评论[ 103、104、105、106、107 ]。然而，镉相关神经炎症值得讨论的一个关键方面是镉对小胶质细胞的激活。小胶质细胞在大脑中表现出类似巨噬细胞的功能，包括向 T 细胞呈递抗原、一般免疫监视以及促炎细胞因子（如 TNF-α、IFN-γ 和 IL-6）的分泌[ 108 ]。镉可以通过产生 ROS 和增加 NF-κB（一种参与炎症反应的转录因子）的表达以及上调 caspase-3（一种参与神经元细胞凋亡的蛋白质）来激活小胶质细胞过度损伤的促炎症功能 [ 109 、 110 、 111 ]。

7. Cadmium’s Effects on Glycogen Metabolism
7. 镉对糖原代谢的影响

Glycogen metabolism in the brain is essential for significant central nervous system functions. Energy consumption in the brain is very high, with one study claiming that it accounts for 20–25% of the total body’s resting glucose consumption in adults. Developing brains likely requires an even greater percentage of this energy [112]. While glycogen is necessary as a source of readily available glucose to meet a neuron’s high energy demands, an overabundance of glycogen can lead to neurodegeneration, most commonly observed in glycogen storage diseases [113,114,115]. Thus, impairment of glycogen metabolism and storage is particularly harmful to the neurological function of an organism. Due to cadmium’s interference with cellular glycogen pathways, glycogen dysregulation represents a major avenue of its neurotoxicity.
大脑中的糖原代谢对于重要的中枢神经系统功能至关重要。大脑的能量消耗非常高，一项研究声称它占成人全身静息葡萄糖消耗的 20-25%。大脑的发育可能需要更大比例的这种能量[ 112 ]。虽然糖原是满足神经元高能量需求的容易获得的葡萄糖来源所必需的，但糖原过多会导致神经变性，最常见于糖原贮积病[ 113,114,115 ]。因此，糖原代谢和储存的损害对生物体的神经功能特别有害。由于镉干扰细胞糖原途径，糖原失调是其神经毒性的一个主要途径。

Historically, hypotheses of cadmium’s neurotoxicity in regard to glycogen were based upon cadmium functionally impairing the glycogen phosphorylase (GP) enzyme, which catalyzes the first step of glycogen’s breakdown by facilitating the cleavage of glucose-1-phosphate (G1P) monosaccharides from the glycogen polysaccharide in glycogenolysis [116] (Figure 2). Glycogen phosphorylase exists as three isozymes in humans, of which brain glycogen phosphorylase (bGP) is the main glycogenolysis-facilitating GP isozyme of the central nervous system. Neurons express this bGP enzyme, and astrocytes express both bGP and the muscle GP isozyme [117]. Neurons contain measurable amounts of glycogen, but neighboring glial astrocytes are the primary glycogen-containing cells of the central nervous system [115]. Glycogen accumulation in neurons may actually be a marker of neurodegeneration [118]. Early research has suggested that cadmium’s neurotoxicity arose from inappropriately high accumulation of glycogen. While there is some merit and evidence supporting this original hypothesis, this idea may be inaccurate or present only a piece of the complete picture regarding cadmium’s glycogen-associated neurotoxicity. Recent evidence suggests that the depletion of glycogen reserves, not glycogen accumulation, is the main mechanism of cadmium’s glycogen-associated neurotoxicity.
从历史上看，镉对糖原具有神经毒性的假设是基于镉对糖原磷酸化酶（GP）的功能性损害，该酶通过促进糖原多糖中葡萄糖-1-磷酸（G1P）单糖的裂解来催化糖原分解的第一步糖原分解作用[ 116 ]（图2 ）。糖原磷酸化酶在人体中以三种同工酶的形式存在，其中脑糖原磷酸化酶（bGP）是中枢神经系统主要的促进糖原分解的GP同工酶。神经元表达这种 bGP 酶，星形胶质细胞表达 bGP 和肌肉 GP 同工酶 [ 117 ]。神经元含有可测量量的糖原，但邻近的神经胶质星形胶质细胞是中枢神经系统的主要含糖原细胞[ 115 ]。神经元中的糖原积累实际上可能是神经退行性变的标志[ 118 ]。早期研究表明，镉的神经毒性是由于糖原过度积累所致。虽然有一些优点和证据支持这一最初的假设，但这一想法可能不准确，或者仅代表了镉糖原相关神经毒性的一部分。最近的证据表明，镉糖原相关神经毒性的主要机制是糖原储备的消耗，而不是糖原的积累。

Figure 2. Glycogenolysis is the metabolic process by which cellular stores of glycogen are broken down into glucose. Glycogenesis is the opposite process, by which glucose is polymerized into glycogen. Both glycogenolysis and glycogenesis are mediated by critical enzymes, as shown.
图 2.糖原分解是细胞储存的糖原分解为葡萄糖的代谢过程。糖生成是相反的过程，葡萄糖聚合成糖原。如图所示，糖原分解和糖原生成都是由关键酶介导的。

7.1. Cadmium and Glycogen Phosphorylase Impairment: The Original Hypothesis
7.1.镉和糖原磷酸化酶损伤：最初的假设

Cadmium has been hypothesized to impair the functionality of bGP, leading to the accumulation of glycogen in nervous system cells [116]. The basis for this hypothesis is derived from research demonstrating that thiol groups of cysteine residues in bGP are sensitive to metal ions such as cadmium [116,119]. As a result of glycogenolysis inhibition, an accumulation of glycogen in astrocytes may be a significant mechanism of neurological symptoms resulting from cadmium exposure.
据推测，镉会损害 bGP 的功能，导致神经系统细胞中糖原的积累 [ 116 ]。这一假设的基础源自研究表明 bGP 中半胱氨酸残基的硫醇基团对镉等金属离子敏感 [ 116 , 119 ]。由于糖原分解抑制，星形胶质细胞中糖原的积累可能是镉暴露引起神经系统症状的重要机制。

Other inhibitors of glycogen phosphorylase such as CP-91149, CP-320626, and flavopiridol have been studied in the context of killing cancerous cells [120]. As a result of this enzymatic impairment, glycogenolysis was expectedly blocked, meaning that cells were unable to recycle glucose into the pentose phosphate pathways and were ultimately eliminated by apoptosis. Thus, the original hypothesis of cadmium-induced glycogen-mediated neurotoxicity is that cadmium interferes with the bGP structure at cysteine residues, decreasing enzymatic function, and blocking glycogenolysis, leading to inappropriately high glycogen storage, and eventually leading to neural cell death.
其他糖原磷酸化酶抑制剂（例如 CP-91149、CP-320626 和黄吡醇）已在杀死癌细胞的背景下进行了研究[ 120 ]。由于这种酶促损伤，糖原分解预计会被阻断，这意味着细胞无法将葡萄糖循环到磷酸戊糖途径中，并最终被细胞凋亡消除。因此，镉诱导的糖原介导的神经毒性的最初假设是，镉干扰半胱氨酸残基上的bGP结构，降低酶功能，并阻断糖原分解，导致糖原储存不当，最终导致神经细胞死亡。

This hypothesis is supported by some experimental evidence. For example, in rats, cadmium acetate (CdAc₂) intoxication at a concentration of 0.3 mg/kg of body weight has been found to disrupt the function of glycolytic enzymes, resulting in a 20% increase in glycogen accumulation when CdAc₂ was subcutaneously injected twice weekly for three months [121]. Strikingly, the concentration of 0.3 mg/kg used in this study is well within the estimated range of the amount of cadmium in the typical adult human body (0.12 mg/kg to 0.5 mg/kg) [9]. Furthermore, cadmium exposure at a CdCl₂ concentration of 0.49 mg/kg of pregnant Wistar rat body weight has been found to increase glycogen accumulation in rat placentae following daily injections until gestational age [122].
这一假设得到了一些实验证据的支持。例如，在大鼠中，发现浓度为 0.3 毫克/千克体重的醋酸镉 (CdAc ₂ ) 中毒会破坏糖酵解酶的功能，导致皮下注射 CdAc ₂时糖原积累增加 20%每周两次，持续三个月[ 121 ]。引人注目的是，本研究中使用的 0.3 mg/kg 浓度完全在典型成人体内镉含量的估计范围内（0.12 mg/kg 至 0.5 mg/kg）[ 9 ]。此外，已发现，在每日注射直至孕龄之前，CdCl ₂浓度为0.49 mg/kg怀孕Wistar大鼠体重的镉暴露会增加大鼠胎盘中糖原的积累[ 122 ]。

Information about the bGP enzyme itself also lends credence to the idea that cadmium could interfere with critical cysteine residues, ultimately disrupting enzyme function. Heavy metals such as cadmium have the ability to disrupt the function of enzymes reliant on cysteine due to heavy metal’s high affinity for sulfhydryl/thiol groups [17,90] (Figure 3(top)). The primary structure of human bGP reveals that there are 14 important cysteine residues of this enzyme, which is notable since 8% of human proteins do not have a single cysteine residue [92,123]. Moreover, the crystal structure of bGP had been solved with high resolution (2.5 Å and 3.4 Å) in 2016, which may help shine more light on this idea [113]. The structure highlights the diffuse nature of bGP’s cysteine residues and the relevance of the thiol group in multiple motifs of the native structure (Figure 3(bottom)). Thus, as a result of bGP’s multiple thiol groups from cysteines and cadmium’s ability to enter into the nervous system, bGP’s impairment is plausibly a result of cadmium interfering with its susceptible cysteine residues. Notably, these cysteine residues are not in the catalytic site nor the allosteric binding site of modulator AMP, though it is feasible that cadmium-induced modification of cysteine residues elsewhere in the protein negatively affects enzymatic activity. The likely mechanism by which this interference occurs is depicted in Figure 3, in which unoxidized cysteines important for the three-dimensional structure of bGP are instead coordinated to a cadmium cation.
有关 bGP 酶本身的信息也证实了镉可能干扰关键半胱氨酸残基，最终破坏酶功能的观点。由于重金属对巯基/硫醇基团的高亲和力，镉等重金属能够破坏依赖半胱氨酸的酶的功能 [ 17 , 90 ]（图 3 （上））。人类 bGP 的一级结构揭示了该酶有 14 个重要的半胱氨酸残基，这一点值得注意，因为 8% 的人类蛋白质没有一个半胱氨酸残基 [ 92 , 123 ]。此外，bGP的晶体结构已于2016年以高分辨率（2.5 Å和3.4 Å）得到解析，这可能有助于进一步阐明这一想法[ 113 ]。该结构突出了 bGP 半胱氨酸残基的扩散性质以及天然结构多个基序中硫醇基团的相关性（图 3 （底部））。因此，由于 bGP 的半胱氨酸具有多个硫醇基团以及镉进入神经系统的能力，bGP 的损伤可能是镉干扰其易受影响的半胱氨酸残基的结果。值得注意的是，这些半胱氨酸残基既不位于调节剂 AMP 的催化位点，也不位于调节剂 AMP 的变构结合位点，尽管镉诱导的蛋白质其他位置半胱氨酸残基的修饰可能会对酶活性产生负面影响。这种干扰发生的可能机制如图 3所示，其中对 bGP 三维结构重要的未氧化半胱氨酸改为与镉阳离子配位。

Figure 3. (top) Cadmium can interact at the sulfhydryl groups of cysteine residues, resulting in a change in enzyme structure. (bottom) bGP protein structure with cysteine residues highlighted (PDB entry: 5IKP).
图 3. （上）镉可以与半胱氨酸残基的巯基相互作用，导致酶结构发生变化。 （底部）bGP 蛋白质结构，突出显示半胱氨酸残基（PDB 条目：5IKP）。

Human clinical data also supports the theory regarding glycogen accumulation-mediated neurotoxicity. For instance, in the case of glycogen storage disease type IX, glycogen accumulation results from the inactivity of glycogen phosphorylase and has been observed to result in neurological symptoms such as ataxia and spasticity [124,125]. This rare genetic disease is characterized by a mutation affecting a phosphorylase enzyme responsible for activating GP. Though this disease does not show evidence of cadmium’s involvement in this process, it does show that GP downregulation is sufficient for neurotoxic effects. Other neurodegenerative conditions, such as Pompe disease, are associated with glycogen accumulation as well [126,127].
人类临床数据也支持有关糖原积累介导的神经毒性的理论。例如，在 IX 型糖原贮积病的情况下，糖原积累是由糖原磷酸化酶失活引起的，并已被观察到导致神经系统症状，如共济失调和痉挛 [ 124 , 125 ]。这种罕见的遗传病的特点是影响负责激活 GP 的磷酸化酶的突变。尽管这种疾病没有证据表明镉参与了这一过程，但它确实表明 GP 下调足以产生神经毒性作用。其他神经退行性疾病，例如庞贝病，也与糖原积累有关[ 126 , 127 ]。

7.2. Evidence Contradicting the Original Theory Regarding Cadmium’s Functional Impairment of bGP
7.2.与镉损害 bGP 功能的原始理论相矛盾的证据

While evidence does exist that supports the original hypothesis of cadmium’s glycogen-associated neurotoxicity, there also exists evidence in opposition to this theory. The Roelfzema study, which showed an increase in glycogen accumulation following cadmium exposure, paradoxically demonstrated a cadmium-induced increase in GP activity, indicating that while cadmium may lead to an increase in glycogen accumulation, it may do so in a mechanism not involving GP glycogen phosphorylase inhibition [122]. Furthermore, animal studies explored the effects of cadmium exposure on glycogen, and these studies have largely found that glycogen depletion, not accumulation, is likely the leading cause of cadmium’s glycogen-associated toxicity. For example, in climbing perch, cadmium exposure resulted in a significant reduction in glycogen levels in muscle and liver tissue, demonstrating that cadmium may affect the ability to store glycogen by inhibiting glycogen synthesis [128]. In freshwater bivalve mussel, exposure to CdCl₂ (7.0 ppm and 12.0 ppm in water) increased glycogen degradation in its gastropod organs, thus increasing the rate of energy storage depletion in this species [87]. Furthermore, in rats, CdCl₂ at a concentration of 2.6 and 5.2 mg/kg of body weight was found to reduce glycogen reserves in the liver, revealing that glycogen storage is impacted in mammalian species as well [129].
虽然确实存在证据支持镉与糖原相关的神经毒性的最初假设，但也存在反对这一理论的证据。 Roelfzema 研究表明，接触镉后糖原积累增加，但矛盾的是，镉诱导 GP 活性增加，这表明虽然镉可能导致糖原积累增加，但它可能以不涉及 GP 糖原的机制实现。磷酸化酶抑制[ 122 ]。此外，动物研究探讨了镉暴露对糖原的影响，这些研究在很大程度上发现糖原消耗而不是积累可能是镉糖原相关毒性的主要原因。例如，在攀鲈中，镉暴露导致肌肉和肝脏组织中的糖原水平显着降低，这表明镉可能通过抑制糖原合成来影响储存糖原的能力[ 128 ]。在淡水双壳贝类中，暴露于 CdCl ₂ （水中 7.0 ppm 和 12.0 ppm）会增加其腹足动物器官中糖原的降解，从而增加该物种的能量储存消耗率[ 87 ]。此外，在大鼠中，浓度为 2.6 和 5.2 mg/kg 体重的 CdCl ₂被发现会减少肝脏中的糖原储备，这表明哺乳动物物种中的糖原储存也受到影响 [ 129 ]。

There is a notable lack of hypotheses regarding the mechanism by which cadmium induces glycogen depletion. The two general reasons by which cadmium would likely reduce glycogen reserves include (1) the impairment of glycogenesis by interfering with an enzyme involved in glycogen synthesis or (2) the excessive activation of glycogenolysis, which may be achieved by reducing the concentration of an inhibitor of glycogenolysis such as insulin. Interestingly, cadmium has been found to decrease insulin release, which may help explain the data that report reduced glycogen reserves as a result of excessive glycogenolysis in the absence of its insulin inhibitor [130]. Furthermore, glycogenolysis may be excessively activated as a result of cadmium interfering with PI3-kinase/Akt/mTOR signaling, which downregulates FOXO1, a transcription factor that stimulates glycogenolysis, and glycogen synthase kinase-3β, an enzyme that promotes glycogenolysis by inhibiting/phosphorylating glycogen synthase [131,132]. Akt/glycogen synthase kinase-3β signaling impacted by cadmium has also been linked to neuronal cell apoptosis [102]. Another theory simply states that cells in stressed conditions tend to need more energy to address the source of stress, thus increasing glycogenolysis to facilitate ATP-production from glucose stores [76,133]. The true mechanism is likely quite complex, encompassing the involvement of multiple enzymes and cellular processes.
关于镉诱导糖原消耗的机制明显缺乏假设。镉可能减少糖原储备的两个一般原因包括（1）通过干扰参与糖原合成的酶来损害糖原生成，或（2）过度激活糖原分解，这可以通过降低抑制剂的浓度来实现糖原分解作用，例如胰岛素。有趣的是，人们发现镉可以减少胰岛素的释放，这可能有助于解释在没有胰岛素抑制剂的情况下，由于糖原分解过度而导致糖原储备减少的数据[ 130 ]。此外，镉干扰 PI3 激酶/Akt/mTOR 信号传导，从而下调 FOXO1（一种刺激糖原分解的转录因子）和糖原合成酶激酶 3β（一种通过抑制/磷酸化促进糖原分解的酶），从而导致糖原分解过度激活。糖原合成酶 [ 131 , 132 ]。受镉影响的 Akt/糖原合酶激酶 3β 信号传导也与神经元细胞凋亡有关 [ 102 ]。另一种理论简单地指出，处于应激条件下的细胞往往需要更多的能量来解决应激源，从而增加糖原分解以促进葡萄糖储存中的 ATP 生成 [ 76 , 133 ]。真正的机制可能相当复杂，涉及多种酶和细胞过程。

7.3. Human Data Pointing towards Cadmium as a Glycogen-Disruptor
7.3.人类数据表明镉是一种糖原干扰物

Human epidemiological data point towards cadmium exposure as a contributing factor to glycogen metabolism dysregulation. When glycogen metabolism is compromised by heavy metals exposure, including cadmium, there is a higher observed incidence of metabolic syndrome [134]. Furthermore, cadmium exposure also increases the risk of diabetes by affecting the glycogen/insulin pathways, which can lead to symptoms such as diabetic neuropathy [130,135,136].
人类流行病学数据表明，镉暴露是导致糖原代谢失调的一个因素。当糖原代谢因接触重金属（包括镉）而受到损害时，观察到的代谢综合征的发生率较高[ 134 ]。此外，镉暴露还会影响糖原/胰岛素途径，从而增加患糖尿病的风险，从而导致糖尿病神经病变等症状[ 130,135,136 ]。

Neurodegeneration can result from a prolonged period of glycogen metabolism dysregulation. This has been particularly observed in AD [137,138] and genetic diseases such as Lafora disease [139]. In AD pathology, glycogen synthase kinase-3β, which is upregulated as a result of cadmium toxicity, is considered to be a tau kinase, which contributes to the progression of the neurodegenerative disease [140]. Moreover, glycogen metabolism dysfunctions have been linked to schizophrenia, suggesting that cadmium could also lead to neuropsychiatric conditions such as schizophrenia as a result of its own metabolic dysfunction-inducing properties [141].
神经退行性疾病可能是由于长期糖原代谢失调引起的。这在 AD [ 137 , 138 ] 和拉福拉病等遗传性疾病 [ 139 ] 中尤其明显。在 AD 病理学中，由于镉毒性而上调的糖原合酶激酶 3β 被认为是一种 tau 激酶，有助于神经退行性疾病的进展 [ 140 ]。此外，糖原代谢功能障碍与精神分裂症有关，这表明镉由于其自身的代谢功能障碍诱导特性也可能导致精神分裂症等神经精神疾病[ 141 ]。

7.4. Next Steps for Resolving Cadmium’s Effects on Neuronal Glycogen
7.4.解决镉对神经元糖原影响的后续步骤

Overall, considering the evidence both for and against the original hypothesis that functional impairment of bGP leads to glycogen accumulation, it appears that cadmium may interfere with both glycogen synthesis and breakdown. The precise outcome on glycogen reserves, namely whether they are increased or decreased, is dependent on the particular species investigated and the tissue of interest. It is as yet unclear to what extent each of these mechanisms—glycogen depletion or glycogen overabundance—is most clinically and biologically relevant in the context of human cadmium neurotoxicity. However, it is clear from human clinical data that cadmium exposure can profoundly affect human health and disease in a manner that often involves aberrant glycogen metabolism. Future studies that must be performed to settle these discrepancies include neural tissue experiments that directly investigate glycogen reserves in glial cells following cadmium exposure, assays of the biological activity of all enzymes in both the glycogenesis and glycogenolysis pathways in response to cadmium exposure (i.e., not just glycogen phosphorylase), and examination of human histological samples following cadmium poisoning, when available.
总体而言，考虑到支持和反对 bGP 功能损伤导致糖原积累这一最初假设的证据，镉似乎可能会干扰糖原合成和分解。糖原储备的精确结果，即它们是增加还是减少，取决于所研究的特定物种和感兴趣的组织。目前尚不清楚这些机制（糖原耗尽或糖原过多）在多大程度上与人类镉神经毒性最具有临床和生物学相关性。然而，从人类临床数据可以清楚地看出，镉暴露会深刻影响人类健康和疾病，其方式往往涉及异常的糖原代谢。未来必须进行的研究来解决这些差异，包括直接研究镉暴露后神经胶质细胞中糖原储备的神经组织实验，分析糖原生成和糖原分解途径中所有酶对镉暴露的反应的生物活性（即，不只是糖原磷酸化酶），并在镉中毒后检查人体组织学样本（如果有）。

8. Possible Protective Measures against Cadmium Neurotoxicity
8. 针对镉神经毒性的可能保护措施

Cadmium has long been recognized as a potent inducer of oxidative stress, disrupting the balance between ROS and antioxidants within the nervous system, thereby posing a significant threat to neural health. The preceding sections of this review have illuminated the intricate web of mechanisms through which cadmium exerts its neurotoxic effects, from mitochondrial dysfunction to cholinergic neuronal loss. However, a promising avenue of research has emerged, shedding light on the potential protective measures that antioxidants offer against cadmium-induced neurotoxicity.
镉长期以来被认为是氧化应激的有效诱导剂，破坏神经系统内活性氧和抗氧化剂之间的平衡，从而对神经健康构成重大威胁。本综述的前面部分阐明了镉发挥神经毒性作用的复杂机制，从线粒体功能障碍到胆碱能神经元损失。然而，一个有希望的研究途径已经出现，揭示了抗氧化剂对镉引起的神经毒性的潜在保护措施。

Thiol-containing proteins, including glutathione (GSH), bovine serum albumin (BSA), and selenoprotein P, have also emerged as key players in mitigating cadmium-induced neurotoxicity. These proteins, known for their capacity to scavenge free radicals and bind to cadmium, may act as a protective shield against the harmful effects of cadmium on neural tissues [36]. By decreasing the availability of free cadmium to bind to critical thiol groups on mitochondrial proteins, these antioxidants help maintain mitochondrial function and prevent cadmium-induced permeability transition pore (PTP) opening, ultimately preserving neuronal integrity.
含硫醇的蛋白质，包括谷胱甘肽 (GSH)、牛血清白蛋白 (BSA) 和硒蛋白 P，也已成为减轻镉引起的神经毒性的关键因素。这些蛋白质以其清除自由基和与镉结合的能力而闻名，可以作为抵御镉对神经组织有害影响的保护盾[ 36 ]。通过减少游离镉与线粒体蛋白上关键硫醇基团结合的可用性，这些抗氧化剂有助于维持线粒体功能并防止镉诱导的通透性转变孔 (PTP) 打开，最终保持神经元的完整性。

There is experimental evidence regarding specific antioxidants’ utility for mitigating cadmium-induced neurotoxicity. Branca et al. demonstrated that antioxidants have some combative power against cadmium, as application of the antioxidant α-tocopheryl acetate to rat brain endothelial cells exposed to cadmium prevented upregulation of GRP78, a marker of ER stress responsible for downstream damage to BBB architecture. The prevention of GRP78 upregulation by α-tocopheryl acetate supports that antioxidants have protective power against the oxidant-dependent ER stress response that ultimately disrupts BBB architecture and contributes to cadmium-induced neurotoxicity [100].
有实验证据表明特定抗氧化剂可减轻镉引起的神经毒性。布兰卡等人。证明抗氧化剂对镉具有一定的对抗能力，因为将抗氧化剂 α-生育酚乙酸酯应用于暴露于镉的大鼠脑内皮细胞可防止 GRP78 的上调，GRP78 是 ER 应激的标志物，负责 BBB 结构的下游损伤。 α-生育酚乙酸酯可防止 GRP78 上调，这表明抗氧化剂具有针对氧化剂依赖性 ER 应激反应的保护能力，这种应激反应最终会破坏 BBB 结构并导致镉诱导的神经毒性 [ 100 ]。

In a study utilizing Sprague–Dawley rats, cadmium exposure led to oxidative stress and autophagy within the testes. However, supplementation with the antioxidant quercetin demonstrated a protective ability to counteract Cd-induced testicular injury [142]. This finding highlights the potential of antioxidants to mitigate the adverse effects of cadmium on neural tissues. Furthermore, the neuroprotective potential of quercetin in the context of CdCl₂-induced hippocampal neurotoxicity in male rats revealed that quercetin exerted a beneficial impact by enhancing memory function and mitigating hippocampal damage in CdCl₂-treated rats. Quercetin increased the levels of antioxidants like glutathione (GSH) and manganese superoxide dismutase (MnSOD). Moreover, quercetin upregulated activity of SIRT1, a protein involved in cellular stress response, suppressed the activity of AChE, inhibited generation of ROS, and increased levels of brain-derived neurotrophic factor (BDNF), a protein crucial for neuronal survival and function [143].
在一项利用斯普拉格-道利大鼠的研究中，镉暴露导致睾丸内的氧化应激和自噬。然而，补充抗氧化剂槲皮素显示出对抗镉引起的睾丸损伤的保护能力[ 142 ]。这一发现凸显了抗氧化剂减轻镉对神经组织不利影响的潜力。此外，槲皮素在CdCl ₂诱导的雄性大鼠海马神经毒性中的神经保护潜力表明，槲皮素通过增强CdCl ₂处理的大鼠的记忆功能和减轻海马损伤而发挥有益的影响。槲皮素可提高谷胱甘肽 (GSH) 和锰超氧化物歧化酶 (MnSOD) 等抗氧化剂的水平。此外，槲皮素上调SIRT1（一种参与细胞应激反应的蛋白质）的活性，抑制AChE的活性，抑制ROS的产生，并增加脑源性神经营养因子（BDNF）的水平，脑源性神经营养因子（BDNF）是一种对神经元存活和功能至关重要的蛋白质[ 143 ]。

Another noteworthy antioxidant, beta carotene, has shown promise in safeguarding neuronal health against the onslaught of cadmium-induced toxicity. In a comprehensive study on rats, cadmium exposure led to a significant increase in lipid peroxidation (LPO), indicative of oxidative damage within neural tissues. Cadmium exposure was also associated with elevated serum urea and blood urea nitrogen levels, indicative of renal dysfunction. Pre-treatment with beta carotene ameliorated the cadmium-induced increase in both LPO levels, serum urea, and blood urea nitrogen levels, underscoring its role in countering cadmium-induced oxidative stress and renal health [144].
另一种值得注意的抗氧化剂，β-胡萝卜素，在保护神经元健康免受镉引起的毒性的侵袭方面显示出良好的前景。在一项针对大鼠的综合研究中，镉暴露导致脂质过氧化（LPO）显着增加，表明神经组织内发生氧化损伤。镉暴露还与血清尿素和血尿素氮水平升高有关，表明肾功能障碍。 β-胡萝卜素预处理可改善镉引起的 LPO 水平、血清尿素和血尿素氮水平升高，强调其在对抗镉引起的氧化应激和肾脏健康方面的作用[ 144 ]。

In terms of cadmium clearance, Ethylenediaminetetraacetic acid (EDTA) has shown promising results. EDTA serves as a chelating agent extensively employed for the purpose of sequestering divalent and trivalent metal ions. EDTA binds to the metals through four carboxylates and two amine groups and forms especially strong bonds with Mn (II), Cu (II), Fe (III), and Co (III) [145]. Due to this property, EDTA is utilized as a medical treatment for the removal of lead and cadmium to mitigate metal toxicity [146]. Studies such as Waters et al., 2001, have shown beneficial results in EDTA chelation therapy where significantly higher urinary losses of cadmium were observed [147]. Whereas these studies were focused on the loss of cadmium from the body, recent studies by Fulgenzi et al., 2020 have dived into the neurotoxicity aspect of such. EDTA in the use of toxic metal chelation therapy were shown to have beneficial effects on neurodegenerative diseases, showing promising results for the future on protective measures against cadmium [148].
在镉清除方面，乙二胺四乙酸 (EDTA) 已显示出有希望的结果。 EDTA 作为螯合剂广泛用于螯合二价和三价金属离子。 EDTA 通过四个羧酸盐和两个胺基与金属结合，并与 Mn (II)、Cu (II)、Fe (III) 和 Co (III) 形成特别牢固的键 [ 145 ]。由于这种特性，EDTA 被用作去除铅和镉以减轻金属毒性的药物[ 146 ]。 Waters 等人 (2001) 等研究显示 EDTA 螯合疗法具有有益效果，观察到尿液中镉的流失量显着增加 [ 147 ]。虽然这些研究的重点是镉从体内的流失，但 Fulgenzi 等人最近的研究（2020）已深入研究了镉的神经毒性方面。 EDTA 在有毒金属螯合疗法中的使用已被证明对神经退行性疾病具有有益作用，这在未来针对镉的保护措施方面显示出有希望的结果[ 148 ]。

With recent evidence of Cd-induced neurotoxicity associated with increased ROS and mitochondrial-dependent ER stress, Mostafa et al., 2019 investigates the effect of rutin hydrate (RH), an antioxidant flavonoid well known as a neuroprotective substance [149]. Results showed that RH inhibits the mitochondrial permeability transition pore, enhances mitochondrial coupling, and inhibits mitochondrial cytochrome c release in the brain. Furthermore, RH inhibits mitochondrial Bax translocation, and, as previously discussed, Kim et al., 2013 demonstrated that Bax expression induces cell apoptosis, supporting that RH may be a potential protective measure against cadmium-induced neurotoxicity [47].
最近有证据表明镉诱导的神经毒性与 ROS 增加和线粒体依赖性 ER 应激有关，Mostafa 等人于 2019 年研究了水合芦丁 (RH) 的作用，这是一种众所周知的神经保护物质的抗氧化剂黄酮类化合物 [ 149 ]。结果表明，RH抑制线粒体通透性转换孔，增强线粒体偶联，并抑制大脑中线粒体细胞色素c的释放。此外，RH 抑制线粒体 Bax 易位，并且如前所述，Kim 等人，2013 年证明 Bax 表达诱导细胞凋亡，支持 RH 可能是针对镉诱导的神经毒性的潜在保护措施 [ 47 ]。

Cysteine has also been observed to reverse cadmium-induced blockade of skeletal neuromuscular neurotransmission [25]. Chick biventer cervicis nerve-muscle preparations exposed to 100 µM cadmium exhibited an 75% reduction in twitch heights within about 20 min of exposure, and application of 1 mM cysteine was able to fully reverse this blockade at the neuromuscular junction. The authors also conducted extracellular recordings of perineural waveforms at the motor nerve terminals of mouse diaphragm nerve-muscle preparations exposed to different concentrations of cadmium (10–100 µM) and reported that cadmium blocked the long-lasting positive deflection associated with calcium current. This cadmium-induced blockade was partially reversed by 300 µM cysteine and fully reversed by 1 mM cysteine. Cysteine may reverse the cadmium-induced block of calcium current by chelating cadmium, as cadmium has been reported to bind the thiol groups on cysteine residues of metallothioneins and the crucial antioxidant glutathione [150]. In a later review, Braga and Rowan stated that cysteine blocks all extracellular effects of cadmium, stressing the importance of developing cysteine therapies to mitigate cadmium neurotoxicity [25]. Combination therapies comprising exogenous chelating agents and antioxidants have been used to treat cadmium toxicity, but much remains to be explored in terms of best practices for the treatment and prevention of cadmium neurotoxicity [151]. Further studies should focus on the interactions between cadmium, cysteine, and other chelating agents in the nervous system to develop efficacious therapies that combat cadmium-induced neurotoxicity for both acute and chronic toxic exposures.
半胱氨酸还被观察到可以逆转镉引起的骨骼神经肌肉神经传递阻断[ 25 ]。暴露于 100 µM 镉的小鸡双腹颈神经肌肉制剂在暴露后约 20 分钟内表现出抽搐高度降低 75%，并且应用 1 mM 半胱氨酸能够完全逆转神经肌肉接头处的这种阻断。作者还对暴露于不同浓度镉（10-100 µM）的小鼠膈神经肌肉制剂的运动神经末梢的神经周围波形进行了细胞外记录，并报告镉阻断了与钙电流相关的长期正向偏转。这种镉诱导的阻断可被 300 µM 半胱氨酸部分逆转，并被 1 mM 半胱氨酸完全逆转。半胱氨酸可以通过螯合镉来逆转镉诱导的钙电流阻断，因为据报道，镉可以与金属硫蛋白和关键抗氧化剂谷胱甘肽的半胱氨酸残基上的硫醇基团结合[ 150 ]。在后来的综述中，Braga 和 Rowan 指出，半胱氨酸可以阻断镉的所有细胞外效应，强调开发半胱氨酸疗法以减轻镉神经毒性的重要性[ 25 ]。包含外源性螯合剂和抗氧化剂的联合疗法已用于治疗镉毒性，但在治疗和预防镉神经毒性的最佳实践方面仍有许多待探索[ 151 ]。进一步的研究应集中于镉、半胱氨酸和其他螯合剂在神经系统中的相互作用，以开发有效的疗法来对抗镉引起的急性和慢性毒性暴露的神经毒性。

Zinc has also been suggested as a protective agent to counter cadmium neurotoxicity. Oral zinc supplementation is thought to prevent free radicals associated with cadmium-induced oxidative stress and alleviate cadmium-induced renal toxicity [151]. Oral supplementation has also been evidenced to slow the progression of neuronal senescence associated with cadmium toxicity and Alzheimer’s disease by reducing Aβ plaque formation in mouse models [152]. However, zinc’s protective functions with respect to neurotoxicity are much more complex and seem to be dose-dependent. Zinc supplementation at low doses protected rat hippocampal neurons from cadmium-induced disruption of neurotransmission but enhanced cadmium neurotoxicity at high doses [32]. More research is necessary to elucidate the intricate relationships between cadmium, zinc, Alzheimer’s disease, and oxidative stress in efforts to develop zinc-based therapies for cadmium neurotoxicity.
锌也被建议作为对抗镉神经毒性的保护剂。口服锌补充剂被认为可以预防与镉诱导的氧化应激相关的自由基，并减轻镉诱导的肾毒性[ 151 ]。口服补充剂也被证明可以通过减少小鼠模型中 Aβ 斑块的形成来减缓与镉中毒和阿尔茨海默氏病相关的神经元衰老的进展 [ 152 ]。然而，锌对神经毒性的保护功能要复杂得多，并且似乎具有剂量依赖性。低剂量的锌补充剂可以保护大鼠海马神经元免受镉引起的神经传递破坏，但高剂量的锌补充会增强镉的神经毒性[ 32 ]。需要进行更多研究来阐明镉、锌、阿尔茨海默病和氧化应激之间的复杂关系，以开发针对镉神经毒性的锌基疗法。

9. Conclusions 9. 结论

Cadmium has several major routes of toxic insult to the nervous system (Figure 4). Cadmium first enters the body either via inhalation, whereby it can accumulate in the olfactory bulb, or, more commonly, via ingestion, eventually making its way to the bloodstream and the central nervous system via the BBB. Cadmium weakens the BBB, thereby increasing the opportunity for further cadmium entry. Cadmium can then enter cells and cellular compartments via calcium and zinc transporters. Intracellular cadmium can profoundly disrupt glycogen metabolism, alter neurotransmitter signaling, and disrupt mitochondrial function, which in turn increases the risk of neurodegenerative outcomes.
镉对神经系统有几种主要的毒性损害途径（图 4 ）。镉首先通过吸入进入人体，从而积聚在嗅球中，或者更常见的是通过摄入，最终通过血脑屏障进入血液和中枢神经系统。镉会削弱血脑屏障，从而增加镉进一步进入的机会。然后镉可以通过钙和锌转运蛋白进入细胞和细胞区室。细胞内镉可以严重破坏糖原代谢，改变神经递质信号传导，并破坏线粒体功能，从而增加神经退行性结果的风险。

Figure 4. Cadmium’s entry to the nervous system (left). Cadmium gains entry to the nervous system through either inhalation or ingestion. Common sources are food products grown in soil with cadmium contamination. To a lesser extent, inhalation of cadmium fumes from industrial sources or cigarette smoke can enter through the lungs and olfactory bulb. Cadmium’s site of actions within the brain (right). Once in circulation, cadmium decreases the integrity of the blood–brain barrier, allowing further permeance into neural tissue. Cadmium gains entry into cells via cation-permeant integral membrane proteins, such as the voltage-gated calcium channel (VGCC). Once in the cytosol of astrocytes, cadmium disrupts glycogen utilization. Inside neurons, cadmium perturbs mitochondrial function and exocytosis of neurotransmitters via the vesicle cycle.
图 4.镉进入神经系统（左）。镉通过吸入或摄入进入神经系统。常见来源是在受镉污染的土壤中种植的食品。在较小程度上，吸入工业来源的镉烟雾或香烟烟雾可以通过肺部和嗅球进入。镉在大脑内的作用部位（右）。一旦进入循环，镉就会降低血脑屏障的完整性，从而进一步渗透到神经组织中。镉通过阳离子渗透的整合膜蛋白（例如电压门控钙通道（VGCC））进入细胞。一旦进入星形胶质细胞的细胞质，镉就会破坏糖原的利用。在神经元内部，镉通过囊泡循环扰乱线粒体功能和神经递质的胞吐作用。

There are several areas of cadmium neurotoxicity that merit further research. In all cases, more attention must be paid to the cadmium concentrations of these studies, as the current research represents a wide array of concentrations, some of which are orders of magnitude greater than the average human cadmium burden. First, more research is necessary to delineate the molecular relationship between cadmium, the PTP, and weakened ΔΨm. Further research must be conducted to elucidate cadmium’s complex interactions with both glycogenesis and glycogenolysis. Although current research suggests a tentative link between cadmium and neurodegenerative disease pathologies, particularly Alzheimer’s disease, future research should strive to extricate this link. In particular, further work regarding the role of cadmium in the development of neuronal senescence via its disruption of zinc homeostasis is directly relevant to neurodegenerative disease etiology. The identification of biomarkers common to both cadmium exposure and neurodegenerative disease may prove useful in development of targeted therapies for neurodegenerative disease amelioration and prevention. Research may also contribute to development of protective measures and therapies that alleviate neurotoxicity such as antioxidant and chelator combination therapy and oral zinc supplementation.
镉神经毒性的几个领域值得进一步研究。在所有情况下，必须更多地关注这些研究的镉浓度，因为当前的研究代表了广泛的浓度，其中一些浓度比人类平均镉负荷高出几个数量级。首先，需要更多的研究来描述镉、PTP 和弱化 ΔΨm 之间的分子关系。必须进行进一步的研究来阐明镉与糖生成和糖原分解的复杂相互作用。尽管目前的研究表明镉与神经退行性疾病（尤其是阿尔茨海默病）之间存在初步联系，但未来的研究应努力消除这种联系。特别是，关于镉通过破坏锌稳态而在神经元衰老发展中的作用的进一步研究与神经退行性疾病的病因学直接相关。镉暴露和神经退行性疾病共有的生物标志物的鉴定可能有助于开发神经退行性疾病改善和预防的靶向疗法。研究还可能有助于开发减轻神经毒性的保护措施和疗法，例如抗氧化剂和螯合剂联合疗法以及口服锌补充剂。

As global industrialization continues to trend upward, the incidence of cadmium exposure is expected to increase. Physicians and public health officials must be aware of the neurotoxic effects of cadmium, which prove cumulative and potently toxic.
随着全球工业化持续上升，镉暴露的发生率预计将增加。医生和公共卫生官员必须意识到镉的神经毒性作用，事实证明镉具有累积性和强毒性。

Progress in understanding cadmium neurotoxicity will engender an understanding of and therapy development for both neurotoxicity itself and that of closely related, increasingly common neurodegenerative diseases.
了解镉神经毒性的进展将促进对神经毒性本身以及密切相关的、日益常见的神经退行性疾病的理解和治疗开发。