Biochemical Mechanisms of Aluminium and Other Metals Exposure, Their Brain Entry Mechanisms, Effects on Blood Brain Barrier and Important Pharmacokinetic Parameters in Neurological Disorders
Page: 1-32 (32)
Author: Sara Ishaq, Amna Liaqat, Armeen Hameed and Touqeer Ahmed*
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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.
Page: 33-65 (33)
Author: Abida Zulfiqar, Ghazal Iqbal and Touqeer Ahmed*
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Metals are key players in maintaining and regulating gene expression, antioxidant response, cell structure and neurotransmission. Their presence in the human body is required in trace amounts to perform these functions, however, excessive accumulation of these metals in various organs, including the brain, leads to detrimental neurological consequences by altering oxidative stress, protein misfolding, mitochondrial dysfunction, DNA fragmentation and apoptosis. These events over a course of time contribute to mild cognitive impairment, movement related disorders, learning and memory deficits which can further progress to neurodegeneration. According to some epidemiological and clinical findings, there is strong evidence of metal exposure and its correlation with a number of neurological diseases like Alzheimer’s diseases (AD), Huntington’s disease (HD), amyotrophic lateral sclerosis (ALS), Guillain-Barre disease (GBD), Parkinson’s disease (PD) and multiple sclerosis (MS), etc. Moreover, metal ions tend to exacerbate the accumulation of neurotic plaques in AD associated pathologies. It has been observed that metals like iron, zinc, copper and Aluminium are elevated in AD brains, causing damage to the synapses. Such metal ions imbalances are associated with aging related neuropathies and disease progression. Some other factors contributing to neurodegeneration include predisposition to ApoE allele, the interaction and synergistic effect of multiple metals together, the impact of cholesterol, amyloid precursor protein (APP) processing, and increased total tau along with Aβ production play a key role in increased biosynthesis of reactive oxygen species in the brain. Such events tend to reduce neuronal viability and function, thus causing cognitive decline.
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Author: Saadia Zahid*, Sanila Amber and Fatima Javed Mirza
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Increased exposure or elevated levels of aluminium(Al) in humans cause various detrimental pathological processes especially affecting the central nervous system. Al-induced neurotoxicity predominantly leads to impaired motor coordination, cognition and learning and memory deficits. Significant association of chronic Al exposure with several neurological disorders, including Alzheimer’s disease (AD), amyotrophic lateral sclerosis (ALS) Parkinson's disease (PD) and multiple sclerosis (MS) is evident where it instigates aberrant expression of various proteins via alterations in post-translational modifications (PTMs). In depth understanding of mechanism of action of Al, effect of altered PTMs and their detection methods is essential to revert anomalies induced by Al in these neurological disorders. The present chapter will attempt to summarize the role of Al in modulation of significant PTMs including phosphorylation, methylation, oxidation, ubiquitination and provide insights into its involvement in various neurological disorders.
Page: 81-96 (16)
Author: Syeda Mehpara Farhat*
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Aluminium (Al) is the third most abundant metal in the earth’s crust and it has long been associated with the pathogenesis of many neurological disorders. Recently, vast use of this metal in various industries and its elevated leaching from earth reservoirs, due to acid rain, has greatly increased human exposure to this metal. Due to the controversial nature of Al effects on the nervous system, it is important to thoroughly understand the effects of Al on neurological functions. This chapter is focused on understanding the effects of Al on the electrophysiological properties of neurons. The emphasis is on the effects of Al on synaptic plasticity, which is an important underlying mechanism in learning and memory, and voltage-gated ion channels. The evidence indicates that Al affects Long term potentiation (LTP), the most widely studied form of synaptic plasticity, via its effects on various signaling pathways.
Aluminium and other Metals Exposure Cause Neurological Disorders: Evidence from Clinical/ human Studies
Page: 97-146 (50)
Author: Zehra Batool, Laraib Liaquat, Tuba Sharf Batool, Rida Nisar and Saida Haider*
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Exposure to Aluminium and other heavy metals has become a serious concern in today’s modern life. Due to excessive use and improper disposal of heavy metals, the entire food chain is being contaminated, which is imposing various health risks for humans and other living organisms. These heavy metals particularly induce oxidative stress through different mechanisms which can ultimately interfere with the normal physiological activities. Brain is highly prone to oxidative stress due to its rich polyunsaturated content and high oxygen consumption than the periphery. Therefore, emphasis has been given to neurotoxicological effects produced by exposure to heavy metals. In this regard, the effects of both essential and non-essential heavy metals have been investigated in various clinical studies which are demonstrating them as a serious threat to normal brain function. This chapter summarizes the neurotoxicological effects of heavy metals which have been revealed in various human studies.
Page: 147-177 (31)
Author: Laraib Liaquat, Zehra Batool* and Saida Haider
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Reproduction and developmental damage has irreversible consequences compared to other body functions and may have adverse effects throughout life. In some circumstances, the damage passes from generation to generation. Many environmental agents contribute to developmental toxicities such as toxic metals, insecticides or pesticides, commercial or industrial pollutants, and air pollutants. Increased urbanization and industrialization have led to the accumulation of toxic metals in the environment. Widespread use of heavy metals in different fields such as agriculture, domestic, medical, industrial, and technological applications have resulted in increased exposure of heavy metals to the human population. Environmental exposure to heavy metals is extensively linked to toxic effects on mammalian embryos. Metals such as lead, cadmium, mercury and arsenic are known developmental toxicants that intensely affect fetal and embryonic development and cause certain malformations in developing embryo even at low concentrations. Other metals such as uranium, cobalt, lithium, Aluminium, manganese, and copper are also reported to induce developmental consequences, including neurobehavioral abnormalities, neural tube defects, fetal growth retardation, skeletal deformation, preterm or delayed birth, and still birth or postnatal death. Heavy metal developmental toxicity depends on different factors, including dose, duration, and route of exposure. Hence, heavy metals are known to be toxic to fetal and embryonic tissues and can produce serious teratogenicity in mammals; however, not much attention has been given to this topic. This chapter, therefore, summarizes the developmental toxicity of heavy metals on the mammalian system and their teratogenic mechanism in growing embryos.
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.