Neurotoxicity
Encyclopedia
Neurotoxicity occurs when the exposure to natural or artificial toxic substances, which are called neurotoxin
s, alters the normal activity of the nervous system
in such a way as to cause damage to nervous tissue. This can eventually disrupt or even kill neuron
s, key cells that transmit and process signals in the brain and other parts of the nervous system. Neurotoxicity can result from exposure to substances used in chemotherapy
, radiation treatment, drug therapies, certain drug abuse
, and organ transplant
s, as well as exposure to heavy metals
, certain food
s and food additive
s, pesticide
s, industrial and/or cleaning solvent
s, cosmetics
, and some naturally occurring substances. Symptoms may appear immediately after exposure or be delayed. They may include limb weakness or numbness, loss of memory, vision, and/or intellect, uncontrollable obsessive and/or compulsive behaviors, delusions, headache, cognitive and behavioral problems and sexual dysfunction. Individuals with certain disorders may be especially vulnerable to neurotoxins.
The name implies the role of a neurotoxin
although the term 'neurotoxic' may be used more loosely to describe states that are known to cause physical brain damage
but where no obvious neurotoxin has been identified.
The term neurotoxic is used to describe a substance, condition or state that damages the nervous system
and/or brain
, usually by killing neuron
s. The term is generally used to describe a condition or substance that has been shown to result in observable physical damage. The presence of neurocognitive deficits alone is not usually considered sufficient evidence of neurotoxicity, as many substances exist which may impair neurocognitive
performance without resulting in the death of neurons. This may be due to the direct action of the substance, with the impairment and neurocognitive deficits being temporary, and resolving when the substance is metabolised
from the body. In some cases the level or exposure-time may be critical, with some substances only becoming neurotoxic in certain doses or time periods. Some of the most common naturally occurring brain toxins that lead to neurotoxicity as a result of excessive dosage are: Beta amyloid (Aβ), Glutamate and Oxygen radicals. When present in high concentrations they can lead to neurotoxicity and death (apoptosis
). Some of the symptoms that result from cell death include: loss of motor control, cognitive deterioration and autonomic nervous system dysfunction. Additionally, neurotoxicity has been found to be a major cause of neurodegenerative diseases such as Alzheimer’s disease (AD).
to cause cell death. An example is through the nicotinic acetylcholine receptor
(nAchRs), which is a receptor commonly found along the surfaces of the cells that respond to nicotine stimulation, turning them on or off. Aβ was found manipulating the level of nicotine
in the brain along with the MAP kinase, another signaling receptor, to cause cell death. Another chemical in the brain that Aβ regulates is JNK; this chemical halts the extracellular signal-regulated kinases
(ERK) pathway, which normally functions as memory control in the brain. As a result this memory favoring pathway is stopped and the brain loses essential memory function. The loss of memory is a symptom of neurodegenerative disease, including AD. Another way Aβ cause cell death is through the phosphorylation of AKT
, this occurs as the element phosphate is bound to several sites on the protein. This phosphorylation allows AKT
to interact with BAD, a protein known to cause cell death. Thus an increase in Aβ results in an increase of the AKt/BAD complex, in turn stopping the action of the anti-apoptotic protein Bcl-2
, which normally functions to stop cell death, causing accelerated neuron
breakdown and the progression of AD.
and production of Reactive Oxygen Species
(ROS) via the activation of nitric oxide synthase
, ultimately leading to cell death. Aβ was also found aiding this route to neurotoxicity by enhancing neuron
vulnerability to glutamate.
(NOS) pathway. This reaction occurs as a response to an increase in the Ca2+ concentration inside a brain cell. This interaction between the Ca2+ and NOS results in the formation of the cofactor tetrahydrobiopterin
(BH4), which then moves from the plasma membrane into the cytoplasm. As a final step, NOS is dephosphorylated yielding nitric oxide
(NO), which accumulates in the brain, increasing its oxidative stress
. There are several ROS including: superoxide
, hydrogen peroxide
and hydroxyl
, all of which lead to neurotoxicity. Naturally, the body utilizes a defensive mechanism to diminish the fatal effects of the reactive species by employing certain enzymes to break down the ROS into small, benign molecules of simple oxygen and water. However, this breakdown of the ROS is not completely efficient; some reactive residues are left in the brain to accumulate, contributing to neurotoxicity and cell death. The brain is more vulnerable to oxidative stress
, in comparison to other organs, due to its low oxidative capacity. Because neurons are characterized as postmitotic cells, meaning that they live with accumulated damage over the years, accumulation of ROS is fatal. Thus, increased levels of ROS age neurons, which leads to accelerated neurodegenerative processes and ultimately the advancement of AD.
Neurotoxin
A neurotoxin is a toxin that acts specifically on nerve cells , usually by interacting with membrane proteins such as ion channels. Some sources are more general, and define the effect of neurotoxins as occurring at nerve tissue...
s, alters the normal activity of the nervous system
Nervous system
The nervous system is an organ system containing a network of specialized cells called neurons that coordinate the actions of an animal and transmit signals between different parts of its body. In most animals the nervous system consists of two parts, central and peripheral. The central nervous...
in such a way as to cause damage to nervous tissue. This can eventually disrupt or even kill neuron
Neuron
A neuron is an electrically excitable cell that processes and transmits information by electrical and chemical signaling. Chemical signaling occurs via synapses, specialized connections with other cells. Neurons connect to each other to form networks. Neurons are the core components of the nervous...
s, key cells that transmit and process signals in the brain and other parts of the nervous system. Neurotoxicity can result from exposure to substances used in chemotherapy
Chemotherapy
Chemotherapy is the treatment of cancer with an antineoplastic drug or with a combination of such drugs into a standardized treatment regimen....
, radiation treatment, drug therapies, certain drug abuse
Drug abuse
Substance abuse, also known as drug abuse, refers to a maladaptive pattern of use of a substance that is not considered dependent. The term "drug abuse" does not exclude dependency, but is otherwise used in a similar manner in nonmedical contexts...
, and organ transplant
Organ transplant
Organ transplantation is the moving of an organ from one body to another or from a donor site on the patient's own body, for the purpose of replacing the recipient's damaged or absent organ. The emerging field of regenerative medicine is allowing scientists and engineers to create organs to be...
s, as well as exposure to heavy metals
Heavy metals
A heavy metal is a member of a loosely-defined subset of elements that exhibit metallic properties. It mainly includes the transition metals, some metalloids, lanthanides, and actinides. Many different definitions have been proposed—some based on density, some on atomic number or atomic weight,...
, certain food
Food
Food is any substance consumed to provide nutritional support for the body. It is usually of plant or animal origin, and contains essential nutrients, such as carbohydrates, fats, proteins, vitamins, or minerals...
s and food additive
Food additive
Food additives are substances added to food to preserve flavor or enhance its taste and appearance.Some additives have been used for centuries; for example, preserving food by pickling , salting, as with bacon, preserving sweets or using sulfur dioxide as in some wines...
s, pesticide
Pesticide
Pesticides are substances or mixture of substances intended for preventing, destroying, repelling or mitigating any pest.A pesticide may be a chemical unicycle, biological agent , antimicrobial, disinfectant or device used against any pest...
s, industrial and/or cleaning solvent
Solvent
A solvent is a liquid, solid, or gas that dissolves another solid, liquid, or gaseous solute, resulting in a solution that is soluble in a certain volume of solvent at a specified temperature...
s, cosmetics
Cosmetics
Cosmetics are substances used to enhance the appearance or odor of the human body. Cosmetics include skin-care creams, lotions, powders, perfumes, lipsticks, fingernail and toe nail polish, eye and facial makeup, towelettes, permanent waves, colored contact lenses, hair colors, hair sprays and...
, and some naturally occurring substances. Symptoms may appear immediately after exposure or be delayed. They may include limb weakness or numbness, loss of memory, vision, and/or intellect, uncontrollable obsessive and/or compulsive behaviors, delusions, headache, cognitive and behavioral problems and sexual dysfunction. Individuals with certain disorders may be especially vulnerable to neurotoxins.
The name implies the role of a neurotoxin
Neurotoxin
A neurotoxin is a toxin that acts specifically on nerve cells , usually by interacting with membrane proteins such as ion channels. Some sources are more general, and define the effect of neurotoxins as occurring at nerve tissue...
although the term 'neurotoxic' may be used more loosely to describe states that are known to cause physical brain damage
Brain damage
"Brain damage" or "brain injury" is the destruction or degeneration of brain cells. Brain injuries occur due to a wide range of internal and external factors...
but where no obvious neurotoxin has been identified.
The term neurotoxic is used to describe a substance, condition or state that damages the nervous system
Nervous system
The nervous system is an organ system containing a network of specialized cells called neurons that coordinate the actions of an animal and transmit signals between different parts of its body. In most animals the nervous system consists of two parts, central and peripheral. The central nervous...
and/or brain
Brain
The brain is the center of the nervous system in all vertebrate and most invertebrate animals—only a few primitive invertebrates such as sponges, jellyfish, sea squirts and starfishes do not have one. It is located in the head, usually close to primary sensory apparatus such as vision, hearing,...
, usually by killing neuron
Neuron
A neuron is an electrically excitable cell that processes and transmits information by electrical and chemical signaling. Chemical signaling occurs via synapses, specialized connections with other cells. Neurons connect to each other to form networks. Neurons are the core components of the nervous...
s. The term is generally used to describe a condition or substance that has been shown to result in observable physical damage. The presence of neurocognitive deficits alone is not usually considered sufficient evidence of neurotoxicity, as many substances exist which may impair neurocognitive
Neurocognitive
Neurocognitive is a term used to describe cognitive functions closely linked to the function of particular areas, neural pathways, or cortical networks in the brain substrate layers of neurological matrix at the cellular molecular level...
performance without resulting in the death of neurons. This may be due to the direct action of the substance, with the impairment and neurocognitive deficits being temporary, and resolving when the substance is metabolised
Metabolism
Metabolism is the set of chemical reactions that happen in the cells of living organisms to sustain life. These processes allow organisms to grow and reproduce, maintain their structures, and respond to their environments. Metabolism is usually divided into two categories...
from the body. In some cases the level or exposure-time may be critical, with some substances only becoming neurotoxic in certain doses or time periods. Some of the most common naturally occurring brain toxins that lead to neurotoxicity as a result of excessive dosage are: Beta amyloid (Aβ), Glutamate and Oxygen radicals. When present in high concentrations they can lead to neurotoxicity and death (apoptosis
Apoptosis
Apoptosis is the process of programmed cell death that may occur in multicellular organisms. Biochemical events lead to characteristic cell changes and death. These changes include blebbing, cell shrinkage, nuclear fragmentation, chromatin condensation, and chromosomal DNA fragmentation...
). Some of the symptoms that result from cell death include: loss of motor control, cognitive deterioration and autonomic nervous system dysfunction. Additionally, neurotoxicity has been found to be a major cause of neurodegenerative diseases such as Alzheimer’s disease (AD).
Beta amyloid
Aβ was found to cause neurotoxicity and cell death in the brain when found in high concentrations. Aβ results from a mutation that occurs when protein chains are cut at wrong locations, resulting in chains of different length that are unusable. Thus they are left in the brain until they are broken down, but meanwhile if enough accumulate, they form plaques which are regarded toxic to neurons. Aβ uses several routes in the CNSCentral nervous system
The central nervous system is the part of the nervous system that integrates the information that it receives from, and coordinates the activity of, all parts of the bodies of bilaterian animals—that is, all multicellular animals except sponges and radially symmetric animals such as jellyfish...
to cause cell death. An example is through the nicotinic acetylcholine receptor
Nicotinic acetylcholine receptor
Nicotinic acetylcholine receptors, or nAChRs, are cholinergic receptors that form ligand-gated ion channels in the plasma membranes of certain neurons and on the postsynaptic side of the neuromuscular junction...
(nAchRs), which is a receptor commonly found along the surfaces of the cells that respond to nicotine stimulation, turning them on or off. Aβ was found manipulating the level of nicotine
Nicotine
Nicotine is an alkaloid found in the nightshade family of plants that constitutes approximately 0.6–3.0% of the dry weight of tobacco, with biosynthesis taking place in the roots and accumulation occurring in the leaves...
in the brain along with the MAP kinase, another signaling receptor, to cause cell death. Another chemical in the brain that Aβ regulates is JNK; this chemical halts the extracellular signal-regulated kinases
Extracellular signal-regulated kinases
In molecular biology, extracellular-signal-regulated kinases or classical MAP kinases are widely expressed protein kinase intracellular signalling molecules that are involved in functions including the regulation of meiosis, mitosis, and postmitotic functions in differentiated cells...
(ERK) pathway, which normally functions as memory control in the brain. As a result this memory favoring pathway is stopped and the brain loses essential memory function. The loss of memory is a symptom of neurodegenerative disease, including AD. Another way Aβ cause cell death is through the phosphorylation of AKT
AKT
Akt, also known as Protein Kinase B , is a serine/threonine protein kinase that plays a key role in multiple cellular processes such as glucose metabolism, cell proliferation, apoptosis, transcription and cell migration.-Family members:...
, this occurs as the element phosphate is bound to several sites on the protein. This phosphorylation allows AKT
AKT
Akt, also known as Protein Kinase B , is a serine/threonine protein kinase that plays a key role in multiple cellular processes such as glucose metabolism, cell proliferation, apoptosis, transcription and cell migration.-Family members:...
to interact with BAD, a protein known to cause cell death. Thus an increase in Aβ results in an increase of the AKt/BAD complex, in turn stopping the action of the anti-apoptotic protein Bcl-2
Bcl-2
Bcl-2 is the founding member of the Bcl-2 family of apoptosis regulator proteins encoded by the BCL2 gene. Bcl-2 derives its name from B-cell lymphoma 2, as it is the second member of a range of proteins initially described in chromosomal translocations involving chromosomes 14 and 18 in...
, which normally functions to stop cell death, causing accelerated neuron
Neuron
A neuron is an electrically excitable cell that processes and transmits information by electrical and chemical signaling. Chemical signaling occurs via synapses, specialized connections with other cells. Neurons connect to each other to form networks. Neurons are the core components of the nervous...
breakdown and the progression of AD.
Glutamate
Glutamate is a chemical found in the brain that poses a toxic threat to neurons when found in high concentrations. This concentration equilibrium is highly sensitive, and it’s usually found in millimolar amounts in the brain. When disturbed, an accumulation of glutamate occurs as a result of a mutation in the glutamate transporters, which act like pumps to drain glutamate from the brain. Naturally, glutamate concentration is several times higher in the blood than in the brain; in turn the body must act to maintain equilibrium between the two concentrations by pumping the glutamate out of the bloodstream and into the brain and vice versa. In the event of a mutation, the glutamate transporters are unable to pump back the glutamate into the blood; thus a higher concentration accumulates in the brain. When released it acts on several receptors that translate its release into an increase in calcium production. Glutamate results in cell death by turning on the N-methyl-D-aspartic acid receptors (NMDA); this receptor causes an increased release of calcium ions (Ca2+) into the cell. As a result, the increased concentration of Ca2+ directly increases the stress on mitochondria, resulting in excessive oxidative phosphorylationOxidative phosphorylation
Oxidative phosphorylation is a metabolic pathway that uses energy released by the oxidation of nutrients to produce adenosine triphosphate . Although the many forms of life on earth use a range of different nutrients, almost all aerobic organisms carry out oxidative phosphorylation to produce ATP,...
and production of Reactive Oxygen Species
Reactive oxygen species
Reactive oxygen species are chemically reactive molecules containing oxygen. Examples include oxygen ions and peroxides. Reactive oxygen species are highly reactive due to the presence of unpaired valence shell electrons....
(ROS) via the activation of nitric oxide synthase
Nitric oxide synthase
Nitric oxide synthases are a family of enzymes that catalyze the production of nitric oxide from L-arginine. NO is an important cellular signaling molecule, having a vital role in many biological processes...
, ultimately leading to cell death. Aβ was also found aiding this route to neurotoxicity by enhancing neuron
Neuron
A neuron is an electrically excitable cell that processes and transmits information by electrical and chemical signaling. Chemical signaling occurs via synapses, specialized connections with other cells. Neurons connect to each other to form networks. Neurons are the core components of the nervous...
vulnerability to glutamate.
Oxygen radicals
The formation of oxygen radicals in the brain is achieved through the nitric oxide synthaseNitric oxide synthase
Nitric oxide synthases are a family of enzymes that catalyze the production of nitric oxide from L-arginine. NO is an important cellular signaling molecule, having a vital role in many biological processes...
(NOS) pathway. This reaction occurs as a response to an increase in the Ca2+ concentration inside a brain cell. This interaction between the Ca2+ and NOS results in the formation of the cofactor tetrahydrobiopterin
Tetrahydrobiopterin
Tetrahydrobiopterin or sapropterin is a naturally occurring essential cofactor of the three aromatic amino acid hydroxylase enzymes, used in the degradation of amino acid phenylalanine and in the biosynthesis of the neurotransmitters serotonin , melatonin, dopamine, norepinephrine ,...
(BH4), which then moves from the plasma membrane into the cytoplasm. As a final step, NOS is dephosphorylated yielding nitric oxide
Nitric oxide
Nitric oxide, also known as nitrogen monoxide, is a diatomic molecule with chemical formula NO. It is a free radical and is an important intermediate in the chemical industry...
(NO), which accumulates in the brain, increasing its oxidative stress
Oxidative stress
Oxidative stress represents an imbalance between the production and manifestation of reactive oxygen species and a biological system's ability to readily detoxify the reactive intermediates or to repair the resulting damage...
. There are several ROS including: superoxide
Superoxide
A superoxide, also known by the obsolete name hyperoxide, is a compound that possesses the superoxide anion with the chemical formula O2−. The systematic name of the anion is dioxide. It is important as the product of the one-electron reduction of dioxygen O2, which occurs widely in nature...
, hydrogen peroxide
Hydrogen peroxide
Hydrogen peroxide is the simplest peroxide and an oxidizer. Hydrogen peroxide is a clear liquid, slightly more viscous than water. In dilute solution, it appears colorless. With its oxidizing properties, hydrogen peroxide is often used as a bleach or cleaning agent...
and hydroxyl
Hydroxyl
A hydroxyl is a chemical group containing an oxygen atom covalently bonded with a hydrogen atom. In inorganic chemistry, the hydroxyl group is known as the hydroxide ion, and scientists and reference works generally use these different terms though they refer to the same chemical structure in...
, all of which lead to neurotoxicity. Naturally, the body utilizes a defensive mechanism to diminish the fatal effects of the reactive species by employing certain enzymes to break down the ROS into small, benign molecules of simple oxygen and water. However, this breakdown of the ROS is not completely efficient; some reactive residues are left in the brain to accumulate, contributing to neurotoxicity and cell death. The brain is more vulnerable to oxidative stress
Oxidative stress
Oxidative stress represents an imbalance between the production and manifestation of reactive oxygen species and a biological system's ability to readily detoxify the reactive intermediates or to repair the resulting damage...
, in comparison to other organs, due to its low oxidative capacity. Because neurons are characterized as postmitotic cells, meaning that they live with accumulated damage over the years, accumulation of ROS is fatal. Thus, increased levels of ROS age neurons, which leads to accelerated neurodegenerative processes and ultimately the advancement of AD.
Prognosis
The prognosis depends upon the length and degree of exposure and the severity of neurological injury. In some instances, exposure to neurotoxins can be fatal. In others, patients may survive but not fully recover. In other situations, many individuals recover completely after treatment.See also
- BatrachotoxinBatrachotoxinBatrachotoxins are extremely potent cardiotoxic and neurotoxic steroidal alkaloids found in certain species of frogs , melyrid beetles, and birds...
- CytotoxicityCytotoxicityCytotoxicity is the quality of being toxic to cells. Examples of toxic agents are a chemical substance, an immune cell or some types of venom .-Cell physiology:...
- Multiple chemical sensitivityMultiple chemical sensitivityMultiple chemical sensitivity is a chronic medical condition characterized by symptoms the affected person attributes to exposure to low levels of chemicals. Commonly suspected substances include smoke, pesticides, plastics, synthetic fabrics, scented products, petroleum products and paints...
- NephrotoxicityNephrotoxicityNephrotoxicity is a poisonous effect of some substances, both toxic chemicals and medication, on the kidneys. There are various forms of toxicity. Nephrotoxicity should not be confused with the fact that some medications have a predominantly renal excretion and need their dose adjusted for the...
- Neurotoxic drugs
- OtotoxicityOtotoxicityOtotoxicity is damage to the ear , specifically the cochlea or auditory nerve and sometimes the vestibular system, by a toxin. It is commonly medication-induced; ototoxic drugs include antibiotics such as the aminoglycoside gentamicin, loop diuretics such as furosemide, and platinum-based...
- Penitrem APenitrem APenitrem A is a fungal neurotoxin found on ryegrass. It is produced by certain species of Aspergillus, Claviceps, and Penicillium. It inhibits potassium channels in smooth muscles...
- ExcitotoxicityExcitotoxicityExcitotoxicity is the pathological process by which nerve cells are damaged and killed by excessive stimulation by neurotransmitters such as glutamate and similar substances. This occurs when receptors for the excitatory neurotransmitter glutamate such as the NMDA receptor and AMPA receptor are...
- ToxicityToxicityToxicity is the degree to which a substance can damage a living or non-living organisms. Toxicity can refer to the effect on a whole organism, such as an animal, bacterium, or plant, as well as the effect on a substructure of the organism, such as a cell or an organ , such as the liver...