Section 2

A Systems - Affected Approach to Toxicology

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11 Nervous System

INTRODUCTION

The nervous system is a target for an extremely large number of toxic agents including drugs, environmental and industrial chemicals, and “ natural ” products such as bacte-rial toxins and animal venoms (Tables 11.1 – 11.4 ). Many of these agents are able to bypass the nervous system ’ s protective blood - brain barrier and cause neurologic dys-function. Many agents that affect the nervous system, espe-cially psychotropic drugs, exert their effects through biochemical mechanisms that do not leave any telltale clinical pathologic changes or anatomic lesions to aid in diagnosis in animals experiencing a toxicosis. Because the nervous system has a limited number of responses to injury, the clinical effects of toxicoses affecting nervous system function will resemble effects from other causes of neuro-logic dysfunction such as infectious, metabolic, traumatic, and neoplastic injury. Defi nitive diagnosis of nervous system toxicosis can therefore be quite challenging.

ANATOMY AND PHYSIOLOGY

The nervous system encompasses both the central nervous system (CNS) and the peripheral nervous system (PNS). The CNS coordinates the activity of all parts of the body and consists of the brain and spinal cord. The PNS con-nects the CNS with the limbs and organs.

The basic functional unit of the nervous system is the neuron. Neurons initiate and conduct nerve stimuli. The basic structure of a neuron contains the body (soma), den-drites, and axons. The dendrites are short branches off the body that receive stimuli from other neurons and transmit it to the soma. The axon carries impulses away from the

soma, and is often covered by myelin, a fatlike substance that increases the speed of impulse conduction (Spencer 2000 ). Nervous impulses cross the synapses between neurons by the release of chemicals termed neurotransmit-ters (Anthony et al. 2001 ). Neurotransmitters include ace-tylcholine, catecholamines (dopamine, norepinephrine, epinephrine), amino acid derivatives (serotonin, gamma amino butyric acid or GABA, glycine, histamine, aspartic acid, glutamic acid), and various other neuropeptides (substance P, orexins, endorphins, vasopressin, thyroid - releasing hormone) (Beasley 1999 ; Spencer 2000 ).

Neurotransmitters can be excitatory and/or inhibitory. Excitatory neurotransmitters stimulate postsynaptic mem-branes, and inhibitory neurotransmitters decrease (or make less likely) the transmission of an impulse. Acetylcholine is both excitatory and inhibitory. It has inhibitory effects on the heart but stimulatory effects on other organs. The catecholamines are hormones that are released by the adrenal glands in reaction to stress. Epinephrine and nor-epinephrine are associated with the sympathetic nervous system (fi ght or fl ight response). Dopamine is found in the brain and affects muscle control and autonomic functions. GABA is the main inhibitory neurotransmitter. GABA regulates neuronal excitability throughout the nervous system. Glycine is also an inhibitory neurotransmitter found in the spinal cord, brainstem, and retina.

The major protective mechanism in the CNS is the blood - brain barrier. The blood - brain barrier forms a “ wall ” between capillaries in the brain and the nervous tissue. The tight junctions allow small molecules and lipid soluble molecules to enter easily, but keep other substances out of

Small Animal Toxicology Essentials, First Edition. Edited by Robert H. Poppenga, Sharon Gwaltney-Brant.© 2011 John Wiley and Sons, Inc. Published 2011 by John Wiley and Sons, Inc.

Tina Wismer

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Table 11.1. Pesticides

Toxicant Possible Effect on the Nervous System

4 - aminopyridine (Avitrol ® ) Stimulation, tremors, seizures Amitraz Depressant Anticholinesterase insecticides (organophosphates, carbamates) Seizures Avermectins (ivermectin, moxidectin) Weakness, ataxia, tremors, seizures, coma Bromethalin Stimulant at high doses; depressant at low doses 3 - chloro - p - toluidine hydrochloride (Starlicide ® ) Depressant, weakness, paralysis DEET (diethyltoluamide) Seizures Metaldehyde Seizures, tremors Organochlorine insecticides (lindane, DDT) Seizures Pyrethrins Tremors Sodium fl uoroactate (1080) Intermittent seizures, stimulation Strychnine Seizures Zinc phosphide Ataxia, seizures

Table 11.2. Biologic agents

Toxicant Possible Effect on the Nervous System

Asclepias spp. (Milkweed) Weakness, tremors, seizures Atropa belladonna (Deadly nightshade, Belladonna) Tremors, paralysis, hallucinations Black widow spider envenomation Flaccid paralysis Blue - green algae (anatoxin - a, anatoxin - a[s]) Tremors, seizures Botulism Flaccid paralysis Brunfelsia spp. (Yesterday, Today, and Tomorrow) Tremors (can last for weeks), seizures Calycanthus spp. (Bubby bush) Seizures Cannabis sativa (Marijuana) Depressant, ataxia, coma; possible agitation Cicuta spp. (Water hemlock) Seizures Conium spp. (Poison hemlock) Initial stimulation, followed by depressive signs Coral snake envenomation Ataxia, tremors, paralysis Datura spp. (Jimsonweed, Angel ’ s trumpet) Tremors, paralysis, hallucinations Essential oils Depressant, ataxia, weakness, tremors; seizures with large doses Eupatorium rugosum (White snakeroot) Tremors, ataxia, stiff gait, weakness Ipomoea spp. (Morning glory) Stimulation, hallucinations Lobelia spp. (Lobelia) Initial stimulation, followed by depressive signs Lupinus spp. (Lupine) Initial stimulation, followed by depressive signs Macadamia nuts Weakness, tremors (dogs only) Mushrooms, isoxazole Alternating CNS stimulation and depression Mushrooms, monomethylhydrazines Tremors, seizures, coma Mushrooms, psychedelic Ataxia, tremors, hallucinations Nerium oleander (Oleander) Tremors, seizures Nicotine (cigarettes, Nicotiana spp.) Initial stimulation, followed by depressive signs Tetanus Muscle rigidity Tick paralysis Weakness, paralysis Tremorgenic mycotoxins (Penitrem A, roquefortine) Tremors, seizures

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Table 11.3. Pharmaceuticals

Toxicant Possible Effect on the Nervous System

Amphetamines (Ritalin ® , Adderall ® , crack, methamphetamine, MDMA)

Stimulation

Antihistamines (diphenhydramine, hydroxyzine, loratadine) Stimulant at high doses; depressant at low doses Atropine Seizures with high doses Barbiturates (phenobarbital) Depressant Benzodiazepines (diazepam, alprazolam) Depressant, ataxia; rarely agitation Bromide Depressant, weakness, ataxia Bupropion (Wellbutrin ® ) Stimulant at high doses; depressant at low doses Buspirone Stimulant at high doses; depressant at low doses Cocaine Stimulation Cyproheptadine Stimulant at high doses; depressant at low doses Decongestants (pseudoephedrine, phenylephrine, Ma huang,

ephedra) Stimulation

5 - fl uorouracil (Efudex ® ) Seizures General anesthetics (isofl urane, halothane, propofol) Depressant Ibuprofen Seizures, coma with high doses Isoniazid Seizures Lithium Seizures Local anesthetics (lidocaine, benzocaine) Seizures with high doses LSD Stimulation, hallucinations MAO inhibitors (Anipryl ® ) Stimulant at high doses; depressant at low doses Methylxanthines (caffeine, theobromine, theophylline) Stimulation Mirtazepine (Remeron ® ) Stimulant at high doses; depressant at low doses Nefazadone, trazodone Stimulant at high doses; depressant at low doses Opiates (hydrocodone, morphine, codeine, butorphanol, tramadol) Depressant; rarely agitation and seizures Phenothiazines (acepromazine, chlorpromazine) Depressant Piperazine Ataxia, tremors Salicylates Seizures with high doses Serotonergic drugs (Prozac ® , Paxil ® , 5 - hydroxytryptophan,

Effexor ® ) Stimulant at high doses; depressant at low doses

Tricyclic antidepressants (amitriptyline, clomipramine) Stimulant at high doses; depressant at low doses

Table 11.4. Nonmedicinal agents

Toxicant Possible Effect on the Nervous System

Alcohol Depressant Carbon monoxide Depressant, weakness, ataxia Ethylene glycol Depressant effect, ataxia, tremors, seizures Lead Intermittent stimulation and depression Liver toxicants Secondary to hepatic encephalopathy Organic alkyl mercury Blindness, ataxia, paralysis, coma Phenol Tremors, seizures with large doses Propylene glycol Depressant effects, ataxia, seizures Sodium Tremors, seizures Thiaminase (raw fi sh) Depression, ataxia, paresis Thallium Tremors, weakness, seizures Turpentine Depressant, weakness, ataxia, coma

86 Section 2 / A Systems-Affected Approach to Toxicology

the brain. The PNS is not protected by the blood - brain barrier, leaving it exposed to toxicants.

MECHANISMS OF TOXICOLOGIC INJURY

In small animal toxicology, most toxicants work directly on the neurons or affect the release and/or binding of neurotransmitters. Toxicant - induced alteration of neu-rotransmitters can result in stimulation or inhibition of postsynaptic neurons, resulting in excitatory or depressive clinical effects depending on the type of neurotransmitter affected, type of postsynaptic neuron, and amount of neu-rotransmitter and receptors involved. For instance, CNS stimulation (manifested as hyperactivity, agitation and/or seizures) may be caused by increasing the synaptic levels of an excitatory neurotransmitter (e.g., stimulation of ace-tylcholine release by organophosphorus insecticides) or by decreasing the synaptic levels of an inhibitory neu-rotransmitter (e.g., strychnine - induced decrease in glycine neurotransmission).

The brain is very susceptible to injury because it requires a continual high level of oxygen. It has a high percentage of blood fl ow for an organ of relatively small mass. Hypoxia is a common cause of neuronal injury. It may be secondary to systemic hypotension, cerebral infarction, vascular injury, or oxygen deprivation. Respiratory com-promise leading to hypoxia is the primary life - threatening issue in many toxic exposures causing alterations of con-sciousness (Anthony et al. 2001 ). Brain damage can also occur secondary to hypoglycemia. During periods of low blood sugar, neuronal damage to dentate and granule cells occurs. Hypoglycemia can result in either cerebral cortex or brainstem defi cits. Other mechanisms of toxicologic injury to the nervous system include ion balance disruption (excessive intracellular accumulation of calcium), cyto-skeleton damage, decreased protein synthesis (loss of rough endoplasmic reticulum), and glial cell damage (Anthony et al. 2001 ).

Disruption or dysfunction of the blood - brain barrier may result in normally excluded compounds entering the CNS, resulting in neurologic injury and/or dysfunction.

PATTERNS OF TOXICOLOGIC INJURY

Toxicological insults to the nervous system produce a wide range of clinical signs when compared to other organ systems. Toxicants can affect multiple areas of the nervous system depending on the dose, route of exposure, and

species of animal. To make diagnosis more diffi cult, toxi-cants can cause a progression of clinical signs (e.g., initial CNS depression, followed by CNS stimulation).

Many neurotoxicants effect neurotransmission and leave no obvious lesions. Functional neurotoxicants can affect the CNS, PNS, and autonomic nervous system (ANS). They act by preventing synthesis, storage, release, binding, reuptake, or degradation of neurotransmitters. Functional neurotoxicants may also interfere with axonal transmission via sodium, potassium, chloride or calcium channels, and alter action potentials (Spencer 2000 ).

There are a few structural changes caused by neurotoxi-cants. These include neuronopathy, anoxopathy, and myelinopathy. In neuronopathy, neurotoxicants directly target the cell body, causing cell death and secondary axonal degeneration. The response to the loss of neurons is gliosis, proliferation of astrocytes, and/or microgilial cells (Anthony et al. 2001 ). Neuronopathies can be selec-tive or diffuse.

In axonopathy, in contrast to neuronopathy, the neuronal cell body remains intact, but the portion of the axon distal to the lesion degenerates (Wallerian degeneration) (Man-della 2002 ). Histologic changes can be seen in the Nissl substance. These changes include chromatolysis (dissolu-tion of the Nissl substance) as well as movement of the nucleus to the periphery of the cell body. Neurons with axons of the greatest length are most susceptible to axonal damage.

Myelinopathy occurs when toxicants cause a loss of myelin (demyelination) or edema in the myelin sheath and subsequent separation of myelin layers. This slows down nerve transmission.

HEALING AND REPAIR

Damage to the nervous system is frequently irreversible because the adult neuron does not divide. With peripheral neuronopathies the prognosis for at least partial regenera-tion is good. However, this is not true in the CNS. Central neuronopathies, with few exceptions, are not reversible.

In axonopathies, glial cells debride the area. The cell body undergoes central chromatolysis which may lead to cell death. If the cell body does not die, axonal regrowth may occur slowly (approximately 1 mm per day). Second-ary demyelination can be seen with axonal injury (Man-della 2002 ). Remyelination can occur in some cases, more often in the PNS than in the CNS.

Chapter 11 / Nervous System 87

1. Many psychotropic drugs alter nervous system func-tion by changing the brain biochemistry through alterations of a. Hormones b. Neurotransmitters c. Cytokines d. Tight junctions e. Glial cells

2. The functional unit of the nervous system is the _______, composed of ____________ that receive stimuli from other cells, _____________ that carry impulses away from the cell body, and the cell body, also known as the ____________. a. Soma, dendrites, axons, neuron b. Dendrites, soma, axons, neuron c. Neuron, axons, dendrites, soma d. Neuron, dendrites, axons, soma e. Soma, axons, dendrites, neuron

3. GABA is an inhibitory neurotransmitter within the CNS. The most signifi cant effect of inhibition of the action of GABA would be expected to be a. CNS depression and coma b. CNS stimulation and seizures c. Fight or fl ight response d. Corticosteroid release e. Immunosuppression

4. The blood - brain barrier a. Keeps all foreign compounds out of the CNS

regardless of size b. Protects the CNS and PNS from entry of poten-

tially damaging compounds

c. Repels negatively charged compounds, keeping them from entering the nervous system

d. Is readily traversed by infl ammatory cells e. Is composed of tight junctions that allow the

passage of small molecules and lipid - soluble com-pounds but prevent passage of other substances

5. Which of the following is not a potential cause of brain injury? a. Hypoglycemia b. Hypoxia c. Blood - brain barrier disruption d. Disruption of ion balance e. All of the above are potential causes of brain

injury.

CHAPTER 11 STUDY QUESTIONS

ANSWERS

1. b. Neurotransmitters 2. d. The neuron is composed of dendrites that

receive stimuli, axons that transmit impulses, and the soma, or cell body.

3. b. Inhibition of CNS inhibitory neurotransmitters such as GABA and glycine commonly cause CNS stimulation and, potentially, seizures.

4. e. 5. e.

REFERENCES

Douglas C. Anthony , Thomas J. Montine , William M. Valen-tine , Doyle G. Graham . 2001 . Toxic responses of the nervous system. ” In Casarett & Doull ’ s Toxicology: The Basic Science of Poisons , 6th ed. , edited by Curtis D. Klassen , pp. 535 – 563 . New York : McGraw - Hill .

Val R. Beasley . 1999 . Veterinary Toxicology . International Veterinary Information Service. www.ivis.org/advances/Beasley/toc.asp .

Rosemary C. Mandella . 2002 . Applied neurotoxicology . In Handbook of Toxicology , 2nd ed. , edited by Michael J. Derelanko , Mannfred A. Hollinger , pp. 371 – 399 . Boca Raton : CRC Press .

Peter S. Spencer . 2000 . Biological principles of chemical neurotoxicity . In Experimental and Clinical Neurotoxicol-ogy , 2nd edition , edited by Peter S. Spencer , Herbert H. Schaumburg , pp. 3 – 54 . New York : Oxford University Press .