Biochemical Mechanisms of Aluminium Induced Neurological Disorders E-Book
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- Herausgeber: Bentham Science Publishers
- Kategorie: Wissenschaft und neue Technologien
- Sprache: Englisch
- Veröffentlichungsjahr: 2006
Aluminium is a chemical element present in earth’s crust and it is a known environmental toxin which has been found to be associated with various neurological disorders. Aluminium has been found to be a very strong risk factor for the development of Alzheimer’s disease.
Biochemical Mechanisms of Aluminium Induced Neurological Disorders explains the association of aluminium with neurological disorders. The book introduces the reader to sources of aluminium exposure, followed by an explanation of pharmacokinetics of aluminium and the different biochemical pathways that cause neurological effects. Chapters cover the typical mechanisms associated with aluminium neurotoxicity such as synaptic impairment as well as recent topics of interest such as the role of aluminum in impairing blood-brain barrier functions. Separate chapters which cover clinical evidence of aluminium toxicity and its management are also included in the book. Biochemical Mechanisms of Aluminium Induced Neurological Disorders is a concise, yet informative reference on the subject of aluminium neurotoxicity for all readers, whether they are students of biochemistry, pharmacology and toxicology, clinical neurologists, environmentalists interested in metal pollution or general readers who want to learn about the toxic effects of aluminium in humans.
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PREFACE
This book “Biochemical Mechanisms of Aluminium Induced Neurological Disorders” is composed of six chapters contributed by reputed scientists working in the field of metals neurotoxicity and studying the role of metals on various neurological disorders. The salient features of this book which make it unique are– it highlights the basic as well as clinical mechanisms of metals induced neurotoxicity in various neurological disorders, and another unique feature of this book is that it discusses the role of Aluminium induced neurological disorders, alone and in combination with other toxic metals as well as with the high fat diet intake, thus adding diversity and unraveling new features of metals neurotoxicity in real scenarios.
Aluminium is present in the earth’s crust and it is a well known environmental toxin/metal which has been found to be associated with various neurological disorders. Aluminium has been found to be a very strong risk factor for the development of Alzheimer’s disease. It is known to cause neurotoxicity by various mechanisms, which are highlighted in this book. Cholinergic system impairment seems to be prominent; however, other mechanisms and pathways are also discussed and elaborated in this book. This book also covers missing aspects of the blood brain barrier and developmental toxicity, which are not very well studied areas related to Aluminium exposure alone or in combination with other metals. Knowing the pharmacokinetics of Aluminium and other metals are important aspects that can help us to understand the exposure of metals and their brain entry mechanisms, thus, opening up new horizons for the development of therapeutic options. Finally, I would say that this comprehensive book is well balanced and well written in developing understandings of basic and clinical mechanisms of Aluminium induced neurological disorders.
List of Contributors
Biochemical Mechanisms of Aluminium and Other Metals Exposure, Their Brain Entry Mechanisms, Effects on Blood Brain Barrier and Important Pharmacokinetic Parameters in Neurological Disorders
Sara Ishaq1,Amna Liaqat1,Armeen Hameed1,Touqeer Ahmed1,*Abstract
Evolution of life has resulted in a strong association between environmental metals and the biological processes taking place in the human body. Some of these metals are essential for the survival of human life, while many others can pose harmful effects on the body if exposed continuously. These toxic metals include Aluminium (Al), Arsenic (As), Lead (Pb), Mercury (Hg), Cadmium (Cd) etc. Upon entry into the brain, these metals lead to the development of many neurological disorders by increasing the levels of ROS, disturbing calcium ion efflux, causing mitochondrial dysfunction and activating an immunogenic response. These metals also cause a decrease in the levels of certain antioxidants in the brain like glutathione, superoxide dismutase and catalase. Moreover, the decrease in the level of certain genes like brain derived neurotropic factor (BDNF) due to metals neurotoxicity can also cause depletion of the memory and other cognitive functions leading to many neurodegenerative diseases like Alzheimer’s disease (AD), Parkinson’s disease (PD), etc. The following chapter explains the pharmacokinetic mechanisms involved in metals induced neurotoxicity leading to different neurological disorders.
INTRODUCTION
Metals and their Evolution in Biological Processes
Metals have been associated with biological systems for billions of years and this association has also been known to evolve with time. Many life processes include a variety of naturally occurring metal complexes in different ways [1]. Major metals like iron, zinc, magnesium, manganese etc. and minor metal ions like copper, nickel, cobalt, molybdenum, tungsten, etc., have been incorporated into the living organisms by the interplay of their metabolic pathways with the products of biogeochemical weathering [2]. Organisms are now able to adapt or die due to the natural development of these metals and other chemicals. Many important life processes of current organisms especially, the metabolic processes require redox reactions which are dependent on the presence of these metals as they have a tendency to lose or gain electrons [3].
Metals are so central in the cellular processes that almost 30% of the overall body proteins are metallo-proteins. Almost 40% of all enzymatic reactions require metals and at least one step of all the biological pathways involve a metal [4]. For example, calcium is not only required for strong bones and teeth but is also involved in reducing muscle cramps and triggering a number of cellular processes. Similarly, many of the cellular activities are dependent on magnesium which is the most abundant element inside the cells after potassium. The biological processes taking place in the nucleus involve metals like calcium, magnesium, copper, zinc, iron and manganese which are present there, in detectable amounts, i.e., 10-2-10-4mol. These metals bind to the DNA and RNA in the cells, even RNA’s active configuration is also dependent upon the concentrations of magnesium and manganese [5]. Magnesium is also responsible for providing energy to millions of cells in the animal and plant bodies by the activation of the production of ATP. It is also involved in some other processes like the process of DNA polymer synthesis along with other divalent metal ions like zinc and manganese [6]. Some of the important functions of all of these metals are given in Table 1 in detail. Thus, the metals are considered to be essential for the biological system as without them the system may collapse.
Metals Induced Neurotoxicity
One quarter of 20 top health conditions around the world are neurological diseases. About one million people covering almost 1% of global prevalence are suffering from these diseases. The main cause is poor hygienic conditions. Metals are one of the most common sources of environmental contamination. These metals affect the brain especially in children, mostly by the production of Reactive Oxygen Species (ROS) or by damaging the DNA and proteins structures [55]. Al is the most common neurotoxin leading to neurodegeneration, cognitive dysfunction, Blood Brain Barrier (BBB) disruption, neuroinflammation, impaired cholinergic projections and neuronal death [56-59] as is among the top toxicants and is involved in many neuropathies. It causes demyelination of axons, encephalopathy, cognitive impairments, irritability and headaches [60, 61]. Pb toxicity is another major concern, especially in developed countries, due to its non-biodegradable nature. Its high levels lead to decreased IQ, muscular dysfunctions and irritability, convulsions, hallucinations, dull personality, ataxia, headaches, coma memory loss, etc [62-65]. Hg has also been reported to be involved in many neurological diseases especially in the form of methylmercury interacting with ROS production and release in the brain. Hg has been found to cause fatigue, irritability, tremors, headaches, cognitive dysfunction and loss of hearing, hallucinations, dysarthria and even death [66, 67]. Cd has also been found to be involved in major neurological symptoms. It is found to be associated with hallucinations, headaches, vertigo, Parkinson’s like symptoms, slow vasomotor functions, muscular and learning disabilities [54, 68].
ABSORPTION OF TOXIC METALS IN THE BRAIN
Metals are bliss as well as harmful to the brain. In view of both harmful and nurturing aspects of the brain, there is the development of a variety of protective mechanisms to check the uptake of metals from blood as well as its distribution within brain tissues. The reason for such tight regulation is that brain can regenerate its cellular components up to a limit and metals toxicity can cause irreversible damage to neurons [69]. Metals levels and homeostasis in the brain is maintained to a specific limit by a structural barrier which under normal conditions prevent any infiltration of unwanted substances from blood to cross the barrier and enter the brain. Structurally these barriers are of two kinds: BBB and blood cerebrospinal fluid barrier (BCB). Former is the barrier between systemic circulation and interstitial fluid while later is between systemic circulation and cerebrospinal fluid [70].
Transport of Toxic Metals Across Blood Brain Barrier
BBB serves as an essential barrier serving both metabolic and physical roles in maintaining the normalized function of central nervous system (CNS). Main targets of this barrier involve restraining the paracellular movement of toxic metals and other hydrophilic molecules from blood [71]. Integrity of the BBB is maintained by certain structural elements such as cerebral endothelial cells (CECs), (Fig. 1).pericytes and glial end-foot [72]. Among these elements, CECs are important, especially the tight junctions (TJs) present in the CECs. These are particularly involved in maintaining vascular permeability. At the molecular level, protein components of TJs include claudin, occludin, and junctional adhesion molecules, and cytosolic proteins. All these serve as transmembrane proteins. Proteins from cellular compartments of neurons interact with these transmembrane proteins and form multi-protein complexes, which in turn are linked to the actin polymers and its associated actin binding protein, collectively called actin cytoskeleton [73].
Fig. (1)) Blood brain barrier shown as under (a) normal physiological conditions and (b) under conditions of metals induced neurotoxicity.Toxic metals can target certain crucial regions of brain by gaining access by imitating the effect of BBB. Generally, toxic metals can be absorbed by the GI tract or through the lungs and then moving to blood circulation. Once into the blood circulation, gaining access to brain regions is entirely dependent upon the structural integrity of BBB. If this barrier is compromised, then metals can get into the choroid plexuses and cerebrospinal fluid [74]. Although there are specific mechanisms to check the flux of metals and other nutrients in and out of the brain and especially of toxic chemicals [75]. Toxic metals can cause poisoning of BBB and resulting in cerebral hemorrhage, vascular damage and, importantly, the destruction of endothelial TJs (Fig. 1). It leads to excessive leakage of metals from the blood into the brain. Most toxic metals are also reported to accumulate in the brain, especially Al, Cd, Hg and As can easily accumulate in the brain at higher concentrations [76]. Another strategy adopted by metals to gain access to brain is by mimicking the behavior of other essential metals or other nutrients and then utilizing the ionic transporters [77].
Transport of Toxic Metals Across Blood Cerebrospinal Fluid Barrier
The primary element of the blood cerebrospinal fluid barrier is the choroid plexus (CP). Physiologically CP is a dense network of capillaries together with ependymal cells and is located in the cerebral ventricles. CP is both the element of BCB and a producer of cerebrospinal fluid. External side of BCB faces the systemic circulation while the inner side is in contact with the cerebral sections. However, the barrier keeps both sides completely out-of-the-way from each other [78]. Hence structural integrity of BCB is also vital for maintaining a normal homeostasis level in brain [79]. Chemical constituents and metals levels are strictly regulated within the brain by balancing the movement of materials across the barrier from blood into the CSF and vice versa. It acts in a bidirectional way and transport substances. It has been studied that if there are any impairments in barrier structure, it leads to leakage of metals and can cause clinical encephalopathies [80]. Metals are also known to accumulate in the CP and then can find their way to other parts of brain, especially the cerebral parts and hippocampus [80].
MAPPING BRAIN REGIONS WITH TOXIC METALS DISTRIBUTION
Brain is the vital organ processing essential functions such as learning, memory formation, movement and other processes. Environmental pollutants and toxins can cause brain damage resulting in compromised brain functions. Toxic metals such as Pb, Cd, As, Al and Hg have shown to be neurotoxic when exposed to higher concentrations. Metals neurotoxic effects are demonstrated when these toxic metals cross BBB and BCB through different mechanisms; moreover, these metals have the tendency to accumulate in the brain. This accumulation in fact, is more lethal to brain. Different toxic metals get accumulated in brain at different concentrations, as indicated in many scientific studies. Even considering the sub cellular organelles of neurons, metals concentrations are variedly accumulated.
Aluminium
Al shows up to be highly accumulated in hippocampal areas and corpus striatum and is then followed by other regions in the order of decreasing concentration as brain stem > cerebral cortex > cerebellum [81]. Going one step further and talking about sub cellular structures, then Al even shows different levels in different organelles. Highest levels are present in the nucleus with decreasing levels in other organelles such as cytosol, microsomes and mitochondria (Fig. 2). It can be written comprehensively as nucleus > cytosol > microsomes > mitochondria [81].
Fig. (2)) Comparison of metals accumulation in different brain regions. Labels (1st, 2nd and 3rd) indicate brain regions with the highest, moderate and low levels of toxic metals.Al is a well-known notorious agent causing learning and memory impairments [82] as Al exposures of brain are linked with decreased neuroplasticity as well as increased risks of neurodegeneration. Memory loss (dementia) is the most common clinical manifestation of Al toxicity in brain. Since hippocampus is the main region of brain which is involved in memory formation as well as neural plasticity [83], so higher levels of Al in the hippocampus are highly defensible with memory loss outcomes [84].
Arsenic
Just like Al, As is also known for its highest concentrations in the hippocampus. But along with hippocampus, it has its equal concentrations in cortical areas followed by the cerebellum (Fig. 2). Inorganic As is the preferred chemical form in which As gets accumulated in brain parts [85].
Lead
Pb is one of the most toxic metals on earth crust [86]. Pb induced neurotoxicity is due to its compatibility with calcium (Ca) ions. It acts as a substitute of Ca and can get entry through barriers swiftly. Once in the brain, it affects two key processes of brain i.e. the cell- to- cell signaling and neurotransmission [87]. The most highly affected areas of brain due to Pb toxicity are the cerebrum, cerebellum and hippocampus [87]. Pb accumulation and damage are not uniform throughout the brain but vary from region to region. The highest percentage of Pb is found in hippocampus followed by both cerebrum and cerebellum (Fig. 2). If Pb induced shrinkage of brain parts is taken into consideration, then cerebellum is the most affected area [88]. The levels of Pb induced toxicity in different brain regions can be graded from highest to lowest as, hippocampus > cerebrum > cerebellum [89]. The elevated levels of Pb in the brain are a major risk factor in stimulating pathology and progression of various neurological diseases [83].
Mercury
Hg is highly toxic in its methylmercury form [90] and it is the 3rd most toxic metal for brain [53]. The main target of Hg in the CNS is the hippocampus. Deleterious effects of Hg include impaired motor coordination, along with learning and memory impairment [91]. Distribution of and toxic effects of Hg are different in brain’s hippocampus, cortex and cerebellum (Fig. 2). Hippocampus gets most damaged by Hg due to the high accumulation [92].
Cadmium
Cd is also known for its toxicity in adults and in children. It is notorious for causing mental retardation in children, because children brain barriers are not fully developed. Cd is found throughout the brain regions including hippocampus, cortex and cerebellum [93]. Maximum levels of Cd are usually found in choroid plexus as it is the first defense against metals intake from systemic circulation [94].
TOXIC METALS WITH MULTIPLE TOXICOKINETIC ASPECTS
Recognizing the factors which influence toxicity of metals are of wide consideration (Fig. 3). After getting distributed in different regions of brain, the pharmacokinetic aspects of metals manifests in the form of disrupting calcium signaling, mitochondrial dysfunction, altered neurotransmission, and oxidative stress etc.
Fig. (3)) Pharmacokinetics of Heavy Metals.Bio-absorption
Among toxic metals, Al is least absorbed dermally. The main route to Al entry is through binding to transferrin protein and once it enters the brain, it can keep the concentration levels up to 1-2 mg/kg of brain [95]. Up to 90% of As gets absorbed by the gastrointestinal tract of human body in the form of arsenite and arsenate. In metabolic pathways, it targets certain proteins and enzymes systems that contain sulfhydryl. Availability of As in brain and other regions depends largely upon the chemical form in which it is absorbed, however, an average half-life of As is about 4 days [96] as metabolites halt the processes in brain by inactivating a series of host enzymes involved in crucial cellular processes [96]. Level of Pb retained in brain vary with age and it is widely accepted that Pb poses its risk more in children than adults. And the reason behind it is that adults only retain 5% of total Pb absorbed and the remaining is excreted [97].
Mitochondrial Dysfunction
Timely generation of the action potential in neurons is necessary for proper signaling. Energy for such robust processes is provided by mitochondria present along the length of axons and throughout the cell body. Oxidative phosphorylation is the key process in regulating the functioning of mitochondria which requires highly regulated membranous systems. Metals toxicity disrupts this process by interfering with the membrane permeability as Al in its ionic form causes excessive leakiness of the membrane [98]. Not only do metals disrupt the membrane permeability but also interact with certain pathways in mitochondria. As interferes with and decreases the activity of mitochondrial complexes I, II-III, and IV. Such alteration can directly lead to disease manifestation such as Parkinson’s disease [99]. Mitochondrial swelling is also one of the outcomes of metals toxicity [99]. Ca2+ release from the mitochondrial membranes is also compromised due to Pb toxicity. Excess abnormal Ca2+ flux causes development of transition pores leading to programmed cell death events [100]. Hg and Cd absorption also leads to the mitochondrial swelling as well as enhanced production of ROS [101].
Effects of Metals Induced Toxicity on Neurotransmission
Human CNS is comprised of around hundred billion neurons. The neurons in the brain are not working individually but are interconnected to one another. This interconnection of neurons is precise and well defined. Communication and coordination of body functions are possible through these neuronal connections. These connection points are called synapses. Synapse is thus the junction between two neurons. Structurally, one neuron can have more than one synaptic connection and, in some cases, even Upton 7000 connections. Presynaptic chemical processes in collaboration with post synaptic signal transduction lead to necessary changes in the brain. Neurotransmitters are the key elements regulating this signal transmission. Any alteration in this process can halt neuron functioning with harmful and destructive disorders ranging from dementia to Parkinson’s disease and multiple sclerosis [102]. The presence of toxic metals can affect the process of transmission drastically (Table 3). In the neurons, toxic metals affect both the signal transmission at the synaptic junction as well as synaptic plasticity resulting in clinical manifestation of impaired learning and memory. Cam kinase pathway is one of the important signaling processes in brain. This pathway is involved in the activation of certain neuronal proteins causing neuronal plasticity. The pathway starts with the Ca2+ influx under the influence of certain neurotransmitters mediated by protein, PSD 95. This Ca+ flux causes activation of another protein, calmodulin which ultimately activates camK protein (signaling protein) [103]. This camK pathway is also affected by certain metals which mimic the Ca2+ signaling to block the signaling mechanism [104].
Another strategy adopted by metals is that often more than one metal target these cellular pathways and show a synergistic effect in deteriorating the neuronal structure and function [105]. Talking more specifically, Al shows its toxic effect by blocking the neuronal Ca2+ channels [106]. Blockage of Ca2+ channels means less signal transmission and less activity of CamK and ultimately, the cellular activity shift from long-term potentiation (LTP) to long-term depression (LTD) (Table 3). If these conditions prevail, then these may consequently lead to neurodegeneration [107]. Cd toxicity is also manifested in the form of the destruction of Ca2+signaling [108]. Often Cd toxicity is characterized by abnormal transmitter’s release. Presence of Cd causes an excessive release of excitatory neurotransmitters, such as, glutamate and aspartate and also an increased release of inhibitory neurotransmitters such as gamma- aminobutyric acid (GABA) [109]. Similarly, As is also found to manifest its toxicity by blocking Ca2+signaling pathway [110].
Cellular Oxidative Stress Induction by Toxic Metals
Toxic metal signaling in brain is carried out importantly by their interactions with the metabolic activities going on in the cellular compartments. Other way to impose their effect is by the production of massive amounts of metals’ free radicals in certain parts of the brain, causing neuronal damage by increased oxidative stress [86]. Hence metals are also involved in the production of ROS in the brain (Fig. 4). The mechanism behind these metals induced oxidative stress is that owing to metals accumulation in the brain there is no more equilibrium between the production and elimination of ROS [118]. At cellular level, oxidative stress is more appropriately defined as a situation when the concentration of ROS is higher. It may be higher at acute or at chronic level with the outcome in the form of impaired cellular metabolic processes and physical damage to cellular components [119]. Adding to the curse of toxic metals, these cause impairment of antioxidant defense. There is an overall unstable and impaired cellular environment which results in damage to important organelles and disrupts biomolecules such as lipids, proteins and sometimes even genetic material [120].
Al and other toxic metals use oxidative stress as the primary pathway for induction of toxicity in the brain. These cause tissue damage in the brain with a high impact on hippocampus and cerebral parts. Damage in parts is carried out by lipid peroxidation, protein depletion, altered gene expression and pathways, and neurodegeneration. An altered expression can have an effect on the signaling pathways in brain such as CamK pathway, which in turn will affect the plasticity, especially LTP [121].
Fig. (4)) Metals induced neurotoxicity causes increase in production of ROS and decreased levels of antioxidants, resulting in oxidative stress.Events of Cellular Signaling in the Nervous System
Most cell signaling occurs through chemicals that may be metallic in nature or neurotransmitters. The most widely distributed chemical in signal transduction is Ca2+. Ca2+signaling in brain maintains the normal processes of synapses. Toxic metals interact with signaling processes by either blocking or decreasing the process or by mimicking the behavior of calcium. Al interferes with the kinetics of cell signaling by altering Ca2+metabolism and increasing its concentration. At secondary level, Al toxicity also interferes with calmodulin which is an essential Ca2+regulator and hence causing huge damage to Ca2+signaling [122]. Similarly, other metals (Hg, As, Cd) also interfere with Ca2+signaling and disrupt the normal process of Ca2+homeostasis [123].
METAL EXCRETION FROM THE BODY
As is mainly excreted through the urine. About 50 - 80% of the consumed inorganic As (having a half-life of approximately 10 hours), is excreted in 3 days. Methylated As takes longer to get excreted from the body as it has a biological half-life of almost 30 hours (three times more than inorganic As). As is also excreted during excessive sweating and by the shedding or removal of skin layer as it is known to have a predilection for the skin [124].
In age 10-15 of the population, the critical concentration for Cd to cause renal dysfunction is approximately 30.2 mg, while in about 50% of the population, the amount is 38.4-42.3 mg. The concentration of Cd increases in the kidney and liver simultaneously, until the final renal cortex concentration reaches 40-50 mg and Cd levels in the liver reach about 70 ppm, depicting a regular pattern [125]. However, this pattern is broken once higher Cd levels are achieved in the liver, thus showing a disproportionate relationship with a metal concentration in the kidney, i.e. when then Cd concentration increases in the liver, it significantly decreases in the renal cortex due to excretion [126]. An epidemiological study conducted in the late 1980s showed the dose dependent relationship of Cd intake showed the total consumption of Cd over a period of lifetime that caused health defects and bodily dysfunctions was 2000 mg for both genders [1]. Proteinuria is the presence of protein in the urine at abnormal quantities, and is hence used as an indicator of renal tubular dysfunction. For renal tubular dysfunction, proteinuria mainly consists of proteins with a lower molecular weight due to impaired reabsorption by proximal tubular lining cells, caused by Cd exposure. Till date, the pathogenesis of the glomerular lesion in Cd nephropathy is not understood completely [127].
Once Al enters the body, via gastrointestinal absorption, it travels to the liver where, most of it is cleared from the bloodstream [128]. In an experiment conducted on a volunteer (41 yr. old male), it was observed that only 10-15% of Al remained in the body while the rest was excreted the first day. Nonetheless, 7% of Al remained in the body for 170 days after it was initially injected [129]. At the time, the authors had expected its clearance half-life to be less than a year. Pharmacokinetic analysis of the study’s results showed the terminal clearance half-life of Al in blood to be 7 days, and whole body to be 170 days. However, in contrast to these results due to sample size taken into consideration, another study [130] determined biliary excretion accounts for less than 1% of Al excretion while excretion via urine accounts about 9-17%. Within two weeks, more than 80% of the Al was excreted via urine and less than 2% was detected in the feces [129].
At least two kinetic pools can be devised for Pb, which have different turnover rates [131
