Individual neurotoxic compounds typically have one of four targets: the neuron, the axon, the myelinating cell, or the neurotransmitter system.
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.
Table 16–1 Compounds associated with neuronal injury (neuronopathies). ||Download (.pdf)
Table 16–1 Compounds associated with neuronal injury (neuronopathies).
Cellular Basis of Neurotoxicity
Dementia, encephalopathy (humans), learning deficits
Spongiosis cortex, neurofibrillary aggregates, degenerative changes in cortex
Not reported in humans; hind limb paralysis (experimental animals)
Spongy (vacuolar) degeneration in spinal cord, brainstem, cerebellum; axonal degeneration of the peripheral nervous system (PNS)
Encephalopathy (acute), peripheral neuropathy (chronic)
Brain swelling and hemorrhage (acute); axonal degeneration in PNS (chronic)
Insufficient data (humans); convulsions, ataxia (primates)
Neuronal loss in cerebellum and cortex
Emotional disturbances, encephalopathy, myoclonus
Neuronal loss, basal ganglia, and Purkinje cells of cerebellum
Encephalopathy, delayed parkinsonism/dystonia
Neuronal loss in cortex, necrosis of globus pallidus, focal demyelination; blocks oxygen-binding site of hemoglobin and iron-binding sites of brain
Encephalopathy (secondary to liver failure)
Enlarged astrocytes in striatum, globus pallidus
Optic neuritis, peripheral neuropathy
Neuronal loss (retina), axonal degeneration (PNS)
Coma, convulsions, rapid death; delayed parkinsonism/dystonia
Neuronal degeneration, cerebellum, and globus pallidus; focal demyelination; blocks cytochrome oxidase/ATP production
Insufficient data (humans); progressive ataxia (experimental animals)
Degeneration of dorsal root ganglion cells, axonal degeneration (PNS)
Mental retardation, hearing deficits (prenatal exposure)
Microcephaly, cerebral malformations
Encephalopathy (acute), learning deficits (children), neuropathy with demyelination (rats)
Brain swelling, hemorrhages (acute), axonal loss in PNS (humans)
Emotional disturbances, parkinsonism/dystonia
Degeneration of striatum, globus pallidus
Emotional disturbances, tremor, fatigue
Insufficient data in humans (may affect spinal tracts; cerebellum)
Headache, visual loss or blindness, coma (severe)
Necrosis of putamen, degeneration of retinal ganglion cells
Methylazoxymethanol acetate (MAM)
Microcephaly, retarded development (rats)
Developmental abnormalities of fetal brain (rats)
Visual and speech impairment; peripheral neuropathy
Methyl mercury (organic mercury)
Ataxia, constriction of visual fields, paresthesias (adult)
Psychomotor retardation (fetal exposure)
Neuronal degeneration, visual cortex, cerebellum, ganglia
Spongy disruption, cortex, and cerebellum
Parkinsonism, dystonia (acute exposure)
Early onset parkinsonism (late effect of acute exposure)
Neuronal degeneration in substantia nigra
Neuronal degeneration in substantia nigra
Seizures, delayed dystonia/grimacing
Necrosis in basal ganglia
Nystagmus, ataxia, dizziness
Degeneration of Purkinje cells (cerebellum)
Constriction of visual fields
Vacuolization of retinal ganglion cells
Degeneration of inner ear (organ of Corti)
Emotional disturbances, ataxia, peripheral neuropathy
Brain swelling (acute), axonal degeneration in PNS
Tremors, hyperexcitability (experimental animals)
Loss of hippocampal neurons, amygdala pyriform cortex
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.
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.
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.
Table 16–2 Compounds associated with axonal injury (axonopathies). ||Download (.pdf)
Table 16–2 Compounds associated with axonal injury (axonopathies).
Basis of Neurotoxicity
Peripheral neuropathy (often sensory)
Axonal degeneration, axon terminal affected in earliest stages
Axonal degeneration in the peripheral nervous system (PNS) and central nervous system (CNS)
Psychosis (acute), peripheral neuropathy (chronic)
Axonal degeneration, early stages include neurofilamentous swelling
Tremors, in coordination (experimental animals)
Insufficient data (humans); axonal swelling and degeneration
Peripheral neuropathy, weakness
Axonal degeneration, inclusions in dorsal root ganglion cells; also vacuolar myopathy
Encephalopathy (acute), subacute myelooptic neuropathy (subacute)
Axonal degeneration, spinal cord, PNS, optic tracts
Axonal degeneration, neuronal perikaryal filamentous aggregates; vacuolar myopathy
Peripheral neuropathy, predominantly motor
Axonal degeneration (both myelinated and unmyelinated axons)
Peripheral neuropathy (delayed)
Peripheral neuropathy, urinary retention
Axonal degeneration (both myelinated and unmyelinated axons)
Peripheral neuropathy (predominantly sensory)
Peripheral neuropathy (may have psychiatric problems)
Axonal degeneration, some segmental demyelination
Peripheral neuropathy, severe cases have spasticity
Axonal degeneration, early neurofilamentous swelling, PNS, and spinal cord
No data in humans; excitatory movement disorder (rats)
Proximal axonal swellings, degeneration of olfactory epithelial cells, vestibular hair cells
Peripheral neuropathy (sensory), ataxia (high doses)
Lethargy, tremor, ataxia (reversible)
Methyl n-butyl ketone
Axonal degeneration, early neurofilamentous swelling, PNS, and spinal cord
Sensory peripheral neuropathy, ataxia, seizures
Axonal degeneration, mostly affecting myelinated fibers; lesions of cerebellar nuclei
Organophosphorus compounds (NTE inhibitors)
Abdominal pain (acute); peripheral neuropathy
Delayed peripheral neuropathy (motor), spasticity
Axonal degeneration (delayed after single exposure), PNS, and spinal cord
Axonal degeneration; microtubule accumulation in early stages
Movement disorders (tremor, choreoathetosis)
Axonal degeneration (variable)
Vincristine (vinca alkaloids)
Cranial (most often trigeminal) neuropathy
Peripheral neuropathy, variable autonomic symptoms
Axonal degeneration (PNS), neurofibrillary changes (spinal cord, intrathecal route)
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.
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.
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 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.
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.
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.
Diagram of axonopathies. Whereas 2,5-hexanedione results in the accumulation of neurofilaments in the distal regions of the axon, 3,4-dimethyl-2,5-hexanedione results in identical accumulation within the proximal segments. These proximal neurofilamentous swellings are quite similar to those that occur in the toxicity of β,β'-iminodipropionitrile (IDPN), although the distal axon does not degenerate in IDPN axonopathy but becomes atrophic. Pyridinethione results in axonal swellings that are distended with tubulovesicular material, followed by distal axonal degeneration.
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.
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.
Table 16–3 Compounds associated with injury of myelin (myelinopathies). ||Download (.pdf)
Table 16–3 Compounds associated with injury of myelin (myelinopathies).
Basis of Neurotoxicity
Acetylethyltetramethyl tetralin (AETT)
Not reported in humans; hyperexcitability, tremors (rats)
Intramyelinic edema; pigment accumulation in neurons
Axonal degeneration and demyelination; lipid-laden lysosomes in Schwann cells
Not reported in humans; encephalopathy (experimental animals)
Status spongiosis of white matter, intramyelinic edema (early stages); gliosis (late)
Peripheral neuropathy, predominantly sensory
Axonal degeneration, swellings in distal axons
Insufficient data (humans)
Intramyelinic edema, status spongiosis of white matter
Irritability, confusion, seizures
Brain swelling, intramyelinic edema in CNS and PNS, late axonal degeneration
Effects only on direct injection into PNS or CNS (experimental animals)
Demyelinating neuropathy, membrane-bound inclusions in Schwann cells
Hydrocephalus, hind limb paralysis (experimental animals)
Demyelinating neuropathy, lipofuscinosis (experimental animals)
Headache, photophobia, vomiting, paraplegia (irreversible)
Brain swelling (acute) with intramyelinic edema, spongiosis of white matter
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.
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 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 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.
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.
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.
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.
Table 16–4 Compounds associated with neurotransmitter-associated toxicity. ||Download (.pdf)
Table 16–4 Compounds associated with neurotransmitter-associated toxicity.
Basis of Neurotoxicity
Amphetamine and methamphetamine
Tremor, restlessness (acute); cerebral infarction and hemorrhage; neuropsychiatric disturbances
Bilateral infarcts of globus pallidus, abnormalities in dopaminergic, serotonergic, cholinergic systems
Acts at adrenergic receptors (PNS)
Restlessness, irritability, hallucinations
Blocks cholinergic receptors (anticholinergic)
Increased risk of stroke and cerebral atrophy (chronic users); increased risk of sudden cardiac death; movement and psychiatric abnormalities, especially during withdrawal
Decreased head circumference (fetal exposure)
Infarcts and hemorrhages; alteration in striatal dopamine neurotransmission
Structural malformations in newborns
Headache, memory loss, hemiparesis, disorientation, seizures
Neuronal loss, hippocampus and amygdala, layers 5 and 6 of neocortex
Kainate-like pattern of excitotoxicity
Insufficient data in humans; seizures in animals (selective lesioning compound in neuroscience)
Degeneration of neurons in hippocampus, olfactory cortex, amygdala, thalamus
Binds AMPA/kainate receptors
Weakness, movement disorder (monkeys)
Degenerative changes in motor neurons (monkeys)
Excitotoxic probably via NMDA receptors
Nausea, vomiting, headache
Binds muscarinic receptors (cholinergic)
Nausea, vomiting, convulsions
Binds nicotinic receptors (cholinergic) low-dose stimulation; high-dose blocking
Excitotoxic probably via AMPA class of glutamate receptors
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.
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.
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.
Schematic diagram of a synapse. Synaptic vesicles are transported to the axonal terminus, and released across the synaptic cleft to bind to the postsynaptic receptors. Glutamate, as an excitatory neurotransmitter, binds to its receptor and opens a calcium channel, leading to the excitation of the postsynaptic cell.
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
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.
MPTP toxicity. MPP+, either formed elsewhere in the body following exposure to MPTP or injected directly into the blood, is unable to cross the blood–brain barrier. In contrast, MPTP gains access and is oxidized in situ to MPDP+ and MPP+. The same transport system that carries dopamine into the dopaminergic neurons also transports the cytotoxic MPP+.
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.
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.