Chapter 16. Toxic Responses of the Nervous System

• The central nervous system (CNS) is protected from the adverse effects of many potential toxicants by an anatomical blood–brain barrier.
• Neurons are highly dependent on aerobic metabolism because this energy is needed to maintain proper ion gradients.
• Individual neurotoxic compounds typically target the neuron, the axon, the myelinating cell, or the neurotransmitter system.
• Neuronopathy is the toxicant-induced irreversible loss of neurons, including its cytoplasmic extensions, dendrites and axons, and the myelin ensheathing the axon.
• Neurotoxicants that cause axonopathies cause axonal degeneration, and loss of the myelin surrounding that axon; however, the neuron cell body remains intact.
• Numerous naturally occurring toxins as well as synthetic chemicals may interrupt the transmission of impulses, block or accentuate transsynaptic communication, block reuptake of neurotransmitters, or interfere with second-messenger systems.

Several generalities that allow a basic understanding of the actions of neurotoxicants include (1) the privileged status of the nervous system (NS) with the maintenance of a biochemical barrier between the brain and the blood, (2) the importance of the high energy requirements of the brain, (3) the spatial extensions of the NS as long cellular processes and the requirements of cells with such a complex geometry, (4) the maintenance of an environment rich in lipids, (5) the transmission of information across extracellular space at the synapse, (6) the distances over which electrical impulses must be transmitted, coordinated, and integrated, and (7) development and regenerative patterns of the NS.

Blood–Brain Barrier

The central NS (CNS) is protected from the adverse effects of many potential toxicants by an anatomical barrier between the blood and the brain, or a “blood–brain barrier.” To gain entry to the NS, molecules must pass into the cell membranes of endothelial cells of the brain rather than between endothelial cells, as they do in other tissues (Figure 16–1). The blood–brain barrier also contains xenobiotic transporters that transport some xenobiotics that have diffused through endothelial cells back into the blood. If not actively transported into the brain, the penetration of toxicants or their metabolites into the NS is largely related to their lipid solubility. However, spinal and autonomic ganglia as well as a small number of other sites within the brain are not protected by blood–tissue barriers. The blood–brain barrier is incompletely developed at birth and even less so in premature infants. This predisposes the premature infant to brain injury by toxicants that later in life are excluded from the NS.

Energy Requirements

Neurons are highly dependent on aerobic metabolism because they must use this energy to maintain proper ion gradients. The brain is extremely sensitive to even brief interruptions in the supply of oxygen or glucose. Exposure to toxicants that inhibit aerobic respiration (e.g., cyanide) or to conditions that produce hypoxia (e.g., CO poisoning) leads to early signs of neuronal dysfunction.

Axonal Transport

Impulses are conducted over great distances at rapid speed, providing information about the environment to the organism in a coordinated manner that allows an organized response to be carried out at a specific site. However, the intricate organization of such a complex network places an unparalleled demand on the cells of the NS. Single cells, rather than being spherical and a few micrometers in diameter, are elongated and may extend over 1 m in length. Two immediate demands placed on the neuron are the maintenance of a much larger cellular volume requiring more protein synthesis and the transport of intracellular materials over great distances using various mechanisms. These demands require ATP.

Axonal transport moves protein products from the cell body to the appropriate site in the axon. Fast axonal transport carries a large number of proteins from their site of synthesis in the cell body into the axon. Many proteins associated with vesicles migrate through the axon at a rate of 400 mm/day (Figure 16–2). This process is dependent on microtubule-associated ATPase activity and the microtubule-associated motor proteins, kinesin and dynein, that provide both the mechanochemical force in the form of a microtubule-associated ATPase and the interface between microtubules as the track and vesicles as the cargo. Vesicles are transported rapidly in an anterograde direction by kinesin, and they are transported in a retrograde direction by dynein. This mechanism of cytoplasmic transport is amplified within the NS, compared with other cells, by the distances encompassed by the axonal extensions of neurons.

The transport of some organelles, including mitochondria, constitutes an intermediate component of axonal transport, moving at 50 mm/day. The slowest component of axonal transport represents the movement of the cytoskeleton itself (Figure 16–2). The cytoskeleton is composed of microtubules formed by the association of tubulin subunits and neurofilaments formed by the association of three neurofilament protein subunits. Each of the elements of the cytoskeleton moves along the length of the axon at a specific rate. Overall, slow component A (SCa) represents retrograde axonal transport, whereas slow component B (SCb) is composed of the movement of the axonal cytoskeleton in an anterograde direction.

Neurofilaments and microtubules move at a rate of approximately 1 mm/day and make up the majority of SCa, the slowest moving component of axonal transport. Moving at only a slightly more rapid rate of 2 to 4 mm/day in an anterograde direction is SCb, which is composed of many proteins. Included in SCb are several structural proteins, such as the component of microfilaments (actin) and several microfilament-associated proteins (M2 protein and fodrin), as well as clathrin and many soluble proteins.

This continual transport of proteins from the cell body through the various components of forward-directed, or anterograde, axonal transport is the mechanism through which the neuron provides the distal axon with its complement of functional and structural proteins. Some vesicles are also moving in a retrograde direction and undoubtedly provide the cell body with information concerning the status of the distal axon.

Axonal Degeneration

Following axotomy (cutting of an axon), there is degeneration of the distal nerve stump, referred to as Wallerian degeneration, which is followed by generation of a microenvironment supportive of regeneration. After the axon dies, active proteolysis digests the axolemma and axoplasm, leaving only a myelin sheath surrounding a swollen degenerate axon (Figure 16–3), which is then digested by endogenous proteases. Schwann cells then provide physical guidance to direct the regrowth of a new axon, and also release growth factors to stimulate growth. Schwann cells respond to loss of axons by decreasing synthesis of myelin lipids, down-regulating genes encoding myelin proteins, and dedifferentiating to a premyelinating mitotic Schwann cell phenotype. In addition to providing physical guidance for regenerating axons, Schwann cells provide trophic support from nerve growth factor, brain-derived nerve growth factor, insulin-like growth factor, and corresponding receptors produced by the associated Schwann cells. Resident and recruited macrophages and the denervated Schwann cells clear myelin debris so that a new axon can grow into the space.

Investigations have shown that degeneration of the distal axonal stump after transection is an active, synchronized process that can be delayed through decreasing temperature, preventing the entry of extracellular Ca2+ or inhibiting proteolysis by calpain II.

When the neuronal cell body has been lethally injured, it degenerates, along with all of its cellular processes. This process is a neuronopathy and is characterized by the loss of the cell body and all of its processes, with no potential for regeneration. However, when the injury is at the level of the axon, the axon may degenerate while the neuronal cell body continues to survive, a condition known as an “axonopathy” (Figure 16–4).

Myelin Formation and Maintenance

Myelin is formed in the CNS by oligodendrocytes and in the peripheral NS (PNS) by Schwann cells as concentric layers by the progressive wrapping of their cytoplasmic processes around the axon in successive loops (Figure 16–5). These cells exclude cytoplasm from the inner surface of their membranes to form the major dense line of myelin. In a similar process, the extracellular space is reduced on the extracellular surface of the bilayers, and the lipid membranes stack together.

The maintenance of myelin is dependent on a number of membrane-associated proteins and on metabolism of specific lipids present in myelin bilayers. Some toxic compounds interfere with this complex process of the maintenance of myelin and result in the toxic “myelinopathies” (Figure 16–4). In general, the loss of myelin, with the preservation of axons, is referred to as demyelination.

Neurotransmission

Intercellular communication is achieved in the NS through the synapse. Neurotransmitters released from one neuron act as the first messenger. Binding of the transmitter to the postsynaptic receptor is followed by modulation of an ion channel or activation of a second-messenger system, leading to changes in the responding cell. Various therapeutic drugs and toxic compounds impact the process of neurotransmission.

Development of the Nervous System

Replication, migration, differentiation, myelination, and synapse formation are the basic processes that underlie development of the NS. Neuron and support cell precursors replicate in an area called the neural tube, and then migrate to different destinations throughout the body. Myelination begins in utero and continues through childhood. Synaptic connectivity, the basis of neurologic function, is a dynamic process throughout life.

The immature NS is especially vulnerable to certain agents. The insufficient replacement of damaged neural cells, the slow formation of the blood–brain barrier, and the lack of key metabolic enzymes may influence NS sensitivity. Ethanol exposure during pregnancy can result in abnormalities in the fetus, including abnormal neuronal migration and diffuse abnormalities in the development of neuronal processes. The clinical result of fetal alcohol exposure is often mental retardation, with malformations of the brain and delayed myelination of white matter.

Environmental Factors Relevant to Neurodegenerative Diseases

It has been observed that individuals exposed to 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) at insufficient levels to result in immediate parkinsonism have developed however early signs of the disease years later. Small exposures to MPTP may cause a decrement in the population of neurons within the substantia nigra. Such a loss would most likely be silent until approximately 80 percent of the substantia nigra neurons are lost. These individuals with a diminished number of neurons may be more vulnerable to further loss of dopaminergic neurons.

An epidemic of dialysis-related dementia with some pathologic resemblance to Alzheimer's disease appears to have been related to aluminum in the dialysate, and its removal has prevented further instances of dialysis dementia.

Functional assessment uses functional test batteries as a means for screening potentially neurotoxic compounds. A group of behavioral tests is typically performed to evaluate a variety of neurologic functions. There are two distinct tiers of functional testing of neurotoxicants: a first tier in which tests may be used to identify the presence of a neurotoxic substance and a second tier that involves characterization of the effects of the compound on sensory, motor, autonomic, and cognitive functions. The second tier is critical to the validation of the behavioral tests as behavioral changes are correlated with physiologic, biochemical, and pathologic identification of neurotoxic injury. Ultimately, neurotoxicants identified by behavioral methods are evaluated at a cellular and molecular level to provide an understanding of the events in the NS that cause the neurologic dysfunction detected by observational tests.

Individual neurotoxic compounds typically have one of four targets: the neuron, the axon, the myelinating cell, or the neurotransmitter system.

Neuronopathies

Certain toxicants are specific for neurons, resulting in their injury or death. Neuron loss is irreversible and includes degeneration of all of its cytoplasmic extensions, dendrites and axons, and the myelin ensheathing the axon (Figure 16–4). Features of the neuron that place it at risk for the action of cellular toxicants include a high metabolic rate, a long cellular process that is supported by the cell body, and an excitable membrane that is rapidly depolarized and repolarized.

Although a large number of compounds are known to result in toxic neuronopathies (Table 16–1), all of these toxicants share certain features. Each toxic condition is the result of a cellular toxicant that has a predilection for neurons. The initial injury to neurons is followed by apoptosis or necrosis, leading to permanent loss of the neuron. These agents tend to be diffuse in their action, although they may show some selectivity in the degree of injury of different neuronal subpopulations. The expression of these cellular events is often a diffuse encephalopathy, with global dysfunctions.

Doxorubicin

Doxorubicin (Adriamycin) injures neurons in the PNS, specifically those of the dorsal root ganglia and autonomic ganglia by intercalating with DNA and interfering with transcription. The vulnerability of sensory and autonomic neurons appears to reflect the lack of protection of these neurons by a blood–tissue barrier within ganglia.

Methyl Mercury

The neurons that are most sensitive to the toxic effects of methyl mercury are those that reside in the dorsal root ganglia, perhaps again reflecting the vulnerability of neurons not shielded by blood–tissue barriers. Methyl mercury exposure impairs glycolysis, nucleic acid biosynthesis, aerobic respiration, protein synthesis, and neurotransmitter release. In addition, there is evidence for enhanced oxidative injury and altered calcium homeostasis. Exposure to methyl mercury leads to widespread neuronal injury and subsequently to a diffuse encephalopathy.

Dopamine, 6-Hydroxydopamine, and Catecholamine Toxicity

The oxidation of catecholamines by monoamine oxidase (MAO) yields H2O2, a known cytotoxic metabolite. The metal ion-catalyzed autooxidation of catecholamines, especially dopamine, results in the production of catecholamine-derived quinones as well as superoxide anion.

6-Hydroxydopamine produces chemical sympathectomy in peripheral nerves after systemic administration. Oxidation of this catecholamine analog leads to production of reactive oxygen species with selective destruction of sympathetic innervation. The sympathetic fibers degenerate, resulting in an uncompensated parasympathetic tone, a slowing of the heart rate, and hypermotility of the gastrointestinal system.

Axonopathies

The neurotoxic disorders termed axonopathies are those in which the primary site of toxicity is the axon itself. The axon degenerates, and with it the myelin surrounding that axon; however, the neuron cell body remains intact (Figure 16–4). The toxicant results in a “chemical transection” of the axon at some point along its length, and the axon distal to the transection degenerates.

A critical difference exists in the significance of axonal degeneration in the CNS compared with that in the PNS: peripheral axons can regenerate, whereas central axons cannot. In the PNS, glial cells and macrophages support axonal regeneration. In the CNS, release of inhibitory factors from damaged myelin and astrocyte scarring actually interferes with regeneration. The clinical relevance of the disparity between the CNS and PNS is that partial to complete recovery can occur after axonal degeneration in the PNS, whereas the same event is irreversible in the CNS.

Axonopathies can be considered to result from a chemical transection of the axon. The number of axonal toxicants is large and increasing in number (Table 16–2). As the axons degenerate, sensations and motor strength are first impaired in the most distal extent of the axonal processes, the hands and feet, resulting in a “glove-and-stocking” neuropathy. With time and continued injury, the deficit progresses to involve more proximal areas of the body and the long axons of the spinal cord.

Gamma-Diketones

Humans develop a progressive sensorimotor distal axonopathy when exposed to high concentrations of a simple alkane, n-hexane, day after day in work settings or after repeated intentional inhalation of hexane-containing glues.

The ω-1 oxidation of n-hexane results ultimately in the γ-diketone, 2,5-hexanedione (HD), which reacts with amino groups in all tissues to form pyrroles that derivatize and cross-link neurofilaments, leading to development of neurofilament aggregates of the distal, subterminal axon. The neurofilament-filled axonal swellings distort nodal anatomy and impair axonal transport. The pathologic processes of neurofilament accumulation and degeneration of the axon are followed by the emergence of a clinical peripheral neuropathy.

Carbon Disulfide

Significant exposures of humans to CS2 cause a distal axonopathy that is identical pathologically to that caused by hexane. Covalent cross-linking of neurofilaments occurs and CS2 is itself the ultimate toxicant.

The clinical effects of exposure to CS2 in the chronic setting are very similar to those of hexane exposure, with the development of sensory and motor symptoms occurring initially in a glove-and-stocking distribution. In addition to this chronic axonopathy, CS2 can also lead to aberrations in mood and signs of diffuse encephalopathic disease.

IDPN

β,β′-Iminodipropionitrile (IDPN) causes a bizarre “waltzing syndrome” consisting of excitement, circling, head twitching, and over-alertness, which appears to result from degeneration of the vestibular sensory hair cells. In addition, administration of IDPN is followed by massive neurofilament-filled swellings of the proximal, instead of the distal, axon.

3,4-Dimethyl-2,5-hexanedione (DMHD) is an analog of HD that is 20 to 30 times more potent as a neurotoxicant and the neurofilament-filled swellings occur in the proximal axon, as in IDPN intoxication. DMHD intoxication leads to limb paralysis, whereas IDPN intoxication results in muscle atrophy but not paralysis.

Acrylamide

Acrylamide is a vinyl monomer used widely in water purification, paper manufacturing, mining, and waterproofing. It is also used extensively in biochemical laboratories, and is present in many foods prepared at high temperatures. Studies of acrylamide neuropathy revealed a distal axonopathy characterized by multiple axonal swellings. Repeated dosing results in a more proximal axonopathy, in a “dying back” process. These changes are caused by accumulations of neurofilaments at the nerve terminal. Recently it has been observed that nerve terminal degeneration occurs prior to development of axonopathy, suggesting that this degeneration is the primary lesion.

Organophosphorus Compounds

These compounds, which are used as pesticides and as additives in plastics and petroleum products, inhibit acetylcholinesterase and create a cholinergic excess. However, tri-ortho-cresyl phosphate (TOCP) causes a severe axonopathy without inducing cholinergic poisoning.

Some hydrophobic organophosphorus compounds readily enter the NS, where they alkylate or phosphorylate macromolecules and lead to delayed-onset neurotoxicity. Whereas “nontoxic” organophosphorus esters inhibit most of the esterase activity in the NS, there is another esterase activity, or neuropathy target esterase (NTE), that is inhibited by the neurotoxic organophosphorus esters. Furthermore, there is a good correlation between the potency of a given organophosphorus ester as an axonal toxicant and its potency as an inhibitor of NTE.

The degeneration of axons does not commence immediately after acute organophosphorus ester exposure but is delayed for 7 to 10 days between the acute high-dose exposure and the clinical signs of axonopathy. The axonal lesion in the PNS appears to be readily repaired, and the peripheral nerve becomes refractory to degeneration after repeated doses. By contrast, axonal degeneration in the long tracks of the spinal cord is progressive.

Pyridinethione

Zinc pyridinethione has antibacterial and antifungal properties and is a component of shampoos that are effective in the treatment of seborrhea and dandruff. Only the pyridinethione moiety is absorbed following ingestion, with the majority of zinc eliminated in the feces. Pyridinethione appears to interfere with the fast axonal transport systems, impairs the turnaround of rapidly transported vesicles, and slows the retrograde transport of vesicles. Aberration of the fast axonal transport systems most likely contributes to the accumulation of tubular and vesicular structures in the distal axon (Figure 16–6). As these materials accumulate in one region of the axon, the axon degenerates in its more distal regions beyond the accumulated structures. The earliest signs are diminished grip strength and changes of the axon terminal, leading to a peripheral neuropathy.

Microtubule-associated Neurotoxicity

The vinca alkaloids and colchicine, which bind to tubulin and inhibit the association of this protein subunit to form microtubules, produce peripheral neuropathies in patients. Although generally mild, they are often accompanied by a disabling myopathy that can lead to the inability to walk. Paclitaxel (Taxol), which stabilizes the assembled polymerized form of tubules, causes sensorimotor axonopathy and autonomic neuropathy in high doses.

The morphology of the axon is, of course, different in the two situations. In the case of colchicine, the axon appears to undergo atrophy and there are fewer microtubules within the axons. In contrast, following exposure to paclitaxel, microtubules are present in great numbers and are aggregated in arrays. Both situations probably interfere with the process of fast axonal transport, and both result in a peripheral neuropathy.

Myelinopathies

Myelin provides electrical insulation of neuronal processes, and its absence leads to a slowing of conduction and aberrant conduction of impulses between adjacent processes. Exposure to toxicants can result in either separation of the myelin lamellae, termed intramyelinic edema, or the selective loss of myelin, termed demyelination. Remyelination in the CNS occurs to only a limited extent after demyelination. However, Schwann cells in the PNS are capable of remyelinating the axon.

All the compounds in Table 16–3 lead to a myelinopathy.

Hexachlorophene

Hexachlorophene, or methylene 2,2′- methylenebis(3,4,6-trichlorophenol), caused neurotoxicity when newborn infants were bathed with the compound to avoid staphylococcal skin infections. Following skin absorption of this hydrophobic compound, hexachlorophene enters the NS and results in intramyelinic edema, which leads to the formation of vacuoles creating a “spongiosis” of the brain. Hexachlorophene causes intramyelinic edema that leads to segmental demyelination. Swelling of the brain causes increased intracranial pressure, axonal degeneration, along with degeneration of photoreceptors in the retina. Humans exposed acutely to hexachlorophene may have generalized weakness, confusion, and seizures. Progression may occur, to include coma and death.

Tellurium

The neurotoxicity of tellurium in young rats alters the synthesis of myelin lipids in Schwann cells, because of various lipid abnormalities. As biochemical changes occur, lipids accumulate in Schwann cells, which eventually lose their ability to maintain myelin in the PNS.

Lead

Lead exposure in animals results in a peripheral neuropathy with prominent segmental demyelination. In young children, acute massive exposures to lead result in severe cerebral edema, perhaps from damage to endothelial cells. Children absorb lead more readily, and the very young do not have the protection of the blood–brain barrier. Chronic lead intoxication in adults results in peripheral neuropathy, gastritis, colicky abdominal pain, anemia, and the prominent deposition of lead in particular anatomical sites, creating lead lines in the gums and in the epiphyses of long bones in children. Lead in the peripheral nerve of humans slows nerve conduction. The basis of lead encephalopathy is unclear, although an effect on the membrane structure of myelin and myelin membrane fluidity has been shown.

Astrocytes

Astrocytes perform and regulate a wide range of physiologic functions in the CNS. The astrocyte appears to be a primary means of defense in the CNS following exposure to neurotoxicants, as a spatial buffering system for osmotically active ions, and as a depot for the sequestration and metabolic processing of endogenous molecules and xenobiotics.

Ammonia

At high CNS concentrations, ammonia produces seizures, resulting from its depolarizing action on cell membranes, whereas at lower concentrations, ammonia produces stupor and coma, consistent with its hyperpolarizing effects. Ammonia intoxication is associated with astrocytic swelling and morphological changes. Increased intracellular ammonia concentrations have also been implicated in the inhibition of neuronal glutamate precursor synthesis, resulting in diminished glutamatergic neurotransmission, changes in neurotransmitter uptake (glutamate), and changes in receptor-mediated metabolic responses of astrocytes to neuronal signals.

Nitrochemicals

Organic nitrates are used for peripheral vasodilatation and reduction of blood pressure (nitroglycerine) in treatment of cardiovascular disease. Other members of the class have neurotoxic properties: (1) 1,3-dinitrobenzene (DNB) produces gliovascular lesions that target astrocytes in the periaqueductal gray matter of the brainstem and deep cerebellar roof nuclei and (2) metronidazole is associated with peripheral neuropathy characterized by paresthesias and dysesthesias.

Neurotransmission-Associated Neurotoxicity

Numerous naturally occurring toxins as well as synthetic chemicals interact with intercellular communication via the process of neurotransmission (Table 16–4). This group of compounds may interrupt the transmission of impulses, block or accentuate synaptic communication, block reuptake of neurotransmitters, or interfere with second-messenger systems. As the targets of these drugs are located throughout the body, the responses are not localized; however, the responses are stereotyped in that each member of a class tends to have similar biological effects. In terms of toxicity, most of the side effects of these drugs may be viewed as short-term interactions that are easily reversible. However, long-term use is associated with irreversible tardivedyskinesias, or facial grimaces.

Nicotine

Nicotine exerts its effects by binding to a subset of nicotinic cholinergic receptors. Smoking and “pharmacologic” doses of nicotine accelerate heart rate, elevate blood pressure, and constrict blood vessels within the skin as a result of stimulation of the ganglionic sympathetic NS.

The rapid rise in circulating levels of nicotine after acute overdose leads to excessive stimulation of nicotinic receptors, a process that is followed rapidly by ganglionic paralysis. Initial nausea, rapid heart rate, and perspiration are followed shortly by marked slowing of heart rate with a fall in blood pressure. Somnolence and confusion may occur, followed by coma; if death results, it is often the result of paralysis of the muscles of respiration.

Exposure to lower levels for longer duration, in contrast, is very common. The complications of smoking include cardiovascular disease, cancers, and chronic pulmonary disease. Chronic exposure to nicotine has effects on the developing fetus. Along with decreased birth weights, attention-deficit disorders are more common in children whose mothers smoke cigarettes during pregnancy.

Cocaine and Amphetamines

The euphoric and addictive properties of cocaine derive from enhanced dopaminergic neurotransmission, by blocking the dopamine reuptake transporter (DAT). Acute toxicity due to excessive intake, or overdose, may result in unanticipated death.

Although cocaine increases maternal blood pressure during acute exposure in pregnant animals, the blood flow to the uterus actually diminishes. Depending on the level of the drug in the mother, the fetus may develop marked hypoxia. Women who used cocaine during pregnancy had more miscarriages and placental hemorrhages (abruptions) than drug-free women.

In addition to deleterious effects on fetal growth and development, cocaine abuse is associated with an increased risk of cerebrovascular disease, cerebral perfusion defects, and cerebral atrophy in adults, along with neurodegenerative changes.

Like cocaine, amphetamines exert their effects in the CNS, altering catecholamine neurotransmission by competing for uptake via plasma membrane transporters and by disrupting the vesicular storage of dopamine. Amphetamines have been associated with an increased risk of abnormal fetal growth and development, increased risk of cerebrovascular disease, and increased risk of psychiatric and neurologic problems in chronic abusers.

Excitatory Amino Acids

Glutamate and certain other acidic amino acids are excitatory neurotransmitters within the CNS. The toxicity of glutamate can be blocked by certain glutamate antagonists, and the concept has emerged that the toxicity of excitatory amino acids may be related to such conditions as hypoxia, epilepsy, and neurodegenerative diseases.

Glutamate is the main excitatory neurotransmitter of the brain and its effects are mediated by several subtypes of receptors (Figure 16–7) called excitatory amino acid receptors (EAARs). The two major subtypes of glutamate receptors are those that are ligand-gated directly to ion channels (ionotropic) and those that are coupled with G proteins (metabotropic). Ionotropic receptors may be further subdivided by their specificity for binding kainate, quisqualate, α-amino-3-hydroxy-5-methylisoxazole-4-propionic acid (AMPA), and N-methyl-D-aspartate (NMDA). The entry of glutamate into the CNS is regulated at the blood–brain barrier, and glutamate exerts its effects in the circumventricular organ of the brain in which the blood–brain barrier is least developed. Within this site of limited access, glutamate injures neurons, apparently by opening glutamate-dependent ion channels, ultimately leading to neuronal swelling and neuronal cell death. The only known related human condition is the “Chinese restaurant syndrome,” in which consumption of large amounts of monosodium glutamate as a seasoning may lead to a burning sensation in the face, neck, and chest.

The cyclic glutamate analog kainate, isolated from a seaweed in Japan, is extremely potent as an excitotoxin, being a hundredfold more toxic than glutamate, and is selective at a molecular level for the kainate receptor. Like glutamate, kainate selectively injures dendrites and neurons and shows no substantial effect on glia or axons. Injected into a region of the brain, it can destroy the neurons of that area without disrupting all of the fibers that pass through the same region. Kainate has become a tool for neurobiologists to explore the anatomy and function of the NS. Kainate, through its selective action on neuronal cell bodies, has provided a greater understanding of the functions of cells within a specific region of the brain, whereas previous lesioning techniques addressed only regional functions. This void in understanding and the epidemiologic evidence that some neurodegenerative diseases may have environmental contributors inspire a heightened desire to appreciate more fully the effects of elements of our environment on the NS.

Development of permanent neurologic deficits occurred in individuals accidentally exposed to high doses of the EAAR agonist domoic acid, an analog of glutamate. The acute illness most commonly presented as gastrointestinal disturbance, severe headache, and short-term memory loss. A subset of the more severely afflicted patients had chronic memory deficits and motor neuropathy. Neuropathologic investigation of patients who died within 4 months of intoxication showed neurodegeneration that was most prominent in the hippocampus and amygdala.

Models of Neurodegenerative Disease

MPTP

A contaminant formed during meperidine synthesis, 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) (Figure 16–8), produces over hours to days the signs and symptoms of irreversible Parkinson's disease. Autopsy studies have demonstrated marked degeneration of dopaminergic neurons in the substantia nigra, with degeneration continuing many years after exposure. It appears that MPTP is metabolized to a molecule that enters the dopaminergic neurons of the substantia nigra, resulting in their deaths.

Although not identical, MPTP neurotoxicity and Parkinson's disease are strikingly similar. The symptomatology of each reflects a disruption of the nigrostriatal pathway: masked facies, difficulties in initiating and terminating movements, resting “pill-rolling” tremors, rigidity, and bradykinesias are all features of both conditions.

Manganese

As an essential trace metal that is found in all tissues, manganese (Mn) is required for normal metabolism of amino acids, proteins, lipids, and carbohydrates, acting as a cofactor of synthesis enzymes. Excessive exposure to Mn produces neurotoxicity resulting in psychologic and neurologic disturbances, including delusions, hallucinations, depression, disturbed equilibrium, compulsive or violent behavior, weakness, and apathy, followed by extrapyramidal motor system defects such as tremors, muscle rigidity, ataxia, bradykinesia, and dystonia. Mn toxicity causes a loss of dopamine neurons in the substantia nigra, and as in Parkinson's disease, oxidative stress appears to play a significant role in the disorder.

Generalized depression of CNS function is produced by a variety of volatile solvents that are small lipophilic molecules. Human exposures range from chronic low-level concentrations encountered in environmental or occupational setting to high-level concentrations intentionally generated through solvent abuse. Recent research has implicated interactions with ligand-gated ion channels as well as voltage-gated calcium channels as the mechanism of generalized depression.