Neurological Toxicosis:- Impact of poisons on nervous system

Msp 305: Neurological ToxicosisDr. Willis Ochieng

IntroductionCentral and Peripheral Nervous

Systems

1.1 ENTRY OF POISONS IN NERVOUS SYSTEM

CNS and PNS Blood Barriers

• Many poisons cannot easily penetrate CNS, with a few exceptions like anaesthetics, analgesics and others due to their lipophilicity.

• Capillary endothelium is invested with astrocytes presenting a barrier to free access of substances to the neurones in many places.

• Entry is possible in certain areas where capillaries are not wrapped with glial processes.

• Small molecules may pass through to the neurons at the intercellular junctions and cytoplasm of endothelial and glial cells.

• The normal endothelial cells lack pinocytic vesicles in their cytoplasm and pores in luminal endothelia causing blood brain barrier.

• In PNS, the blood neural barrier is present in some places and absent in others.

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1.2 Areas with deficient barriers-

In CNS are: Median eminence with arcuate nucleusMedian preoptic regionChoroid plexusArea postrema

In PNS are:Dorsal root gangliaAutonomic ganglia

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2.1 Influence of Vascularity in Toxicosis

• Toxic substances which can penetrate brain tissues do not affect equally all cells in the brain Different brain areas usually have different

sensitivities to toxicants• Although the brain is highly vascularised, not

all portions are equally supplied with bloodThis variation in degree of vascularity accounts

for some of the variations in sensitivity of brain areas to hypoxia

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2.2 Density of Capillaries in Brain(Poisoning Susceptability)

Brain area Rating of Capillary length

Parietal cortex Layer I 6 Layer II 3 Layer III 4 Layer IV 2 Layer V 8 Layer VI 7

Corpus callosum 12*least vascularity Hippocampal pyramidal layer 9 Dentate gyrus granular layer 10 Caudate nucleus 5 Globus pallidus 11 Thalamic lateral geniculate nucleus 1* highest vascularity

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3.1 Type of toxic effects & cell types affected

Cells can be damaged in the following manner:- Direct contact with various toxicants Indirect effect such as anoxia subsequent to diminished supply of oxygen

Most damage occurs to neuron cells since they have little capability for anaerobic metabolism. their oxygen consumption is also greater than other nerve cells

The sequence of vulnerability to anoxia can be described in order of decreasing sensitivity as given below:- Neurons Oligodendrocyctes Astrocyctes Microglia Cells of capillary endothelium

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3.2 Causes of toxic anoxia• Anoxic anoxia - Primary oxygen lack in the

presence of adequate blood flow.• Ischaemic anoxia is due to a decrease in arterial

blood pressure to a level below that which supplies brain adequately with oxygen.Stagnation of blood in brain may lead to inadequate

supply of needed nutrients and accumulation of metabolic poisons

• Cytotoxic anoxia - Consequence of metabolism interference in the presence of an adequate supply of both blood and oxygen.

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4.1 Reversibility of Toxicity Neuronal cells cannot divide and hence

damage is irreversible. However, normal function may be restored for an individual cell even after considerable damage because of:- When some neurons die, other cells already

having the same function may be adequate to maintain normal activity.

Other neurons may acquire function of dead ones

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4.2 Physiological Recovery Potential

• Nervous system has a considerable redundancy of structure, which may mask functional change until the reserve capacity of the system is exceeded by the magnitude of the damage.

• Nervous system is capable of developing tolerance or adapting to

some types of damage, hence function may return to normal during continuous exposure to a toxic substance.

• Toxicological effects are differentiated from pharmacological effects which are short lasting and are often completely reversible while toxicological effects often include irreversible damage.

• Early indicators of nervous toxicosis---Behavioural parameters like emotional state, visual motor performance, etc. may be the earliest and most sensitive signs of nervous system toxicity.

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5.1 Types of NeuropoisonsPoisons Causing Anoxic Damage

Affect grey matter. Neurons and astrocytes have a variation in pattern of damage depending on type of anoxia involved. Examples of poisons causing toxic anoxia are

barbiturates, carbon monoxide, cyanide, nitrogen trichloride etc

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5.2 Types of NeuropoisonsPoisons Damaging Myelin• Toxicants affecting oligodendroglia and

Schwann cells may cause CNS damage especially the long axons which are usually myelinated.

• The long axons of the PNS are also vulnerableExamples are isonicotinic acid, hydrazide

(isoniazid), hexachlorophene, lead, thallium and many others.

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5.3 Types of NeuropoisonsPoisons Causing Peripheral Axonopathies

These cause the so called dying-back neuropathies in which the primary lesion is in the axon and damage progresses from the most distal portions of the axons Examples implicated are alcohol, carbon

disulphide, organophosphorus compounds etc.

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5.4 Types of NeuropoisonsPoisons Causing primary damage to Perikarya of

peripheral neurons• These interfere with the main process of

protein synthesis essential for normal survival of the entire neuron including its long axon and dendrites Many poisons affect the perikaryon of which a few

examples are organomercury compounds and vinca alkaloids containing vincristine and vinblastine

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5.5 Types of NeuropoisonsPoisons at Neuromuscular Junction of Motor

Nerves• Synaptic clefts and terminals of myelinated

axons are vulnerable to toxic chemicals and are exemplified by:Botulinum toxin - Prevents release of acetylcholine

from the terminal Tetrodoxin - Selectively blocks the sodium channels

along the axon, preventing inward sodium current of the action potential while leaving un-affected outward potassium current.

DDT - Repetitive firing at the motor end-plate.

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6.1 Mechanism of ToxicityToxicogenesis

Basically:---A Poison may act directly on cell constituents or

indirectly by changing the cell environment (e.g. metabolism, oxygen supply)An example of a direct acting poison is malathion

combining with postsynaptic membrane receptors Whereas agents causing indirect damage are

numerous since nervous system may be put at risk from reduced availability of oxygen or glucose.

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6.2 ToxicogenesisInterference with Neuronal Oxidative metabolism• Neurons carrying out impulse transmissions requiring

high levels of energy are vulnerable to oxygen deprivation and are unable to sustain adequate ATP production.

• Causes of damage due to ATP inadequacy include production of hypoxia or anoxia,hypoglyceamia or interference with glycolysis, damage to cell membranes.

• The usual response to a loss of energy is central chromatolysis seen microscopically which may eventually progress to neuronal necrosis.

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6.3 ToxicogenesisProtein Synthesis Inhibition & RNA transcription Block• Some toxicants primarily attack cell components

responsible for protein synthesis. The effects may be on the nucleus or on cytoplasmic organelles.

• Loss of Nissl substance, the RER of the neuron, follows a decrease in ribosomal production as a result of inhibition of nucleolar RNA transcription.

• Decreased protein synthesis can also be caused by direct toxic effects on RER.

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6.4 ToxicogenesisPerturbed Cytoskeletal Organization• Increased permeability of the neurons means, as

a common pathway, loss of energy to cell, reduced ATP synthesis, and subsequent accumulation of lactic acid in a glucose rich environment.

• The consequence is damage to the cytoskeleton. When the primary site of damage is the axon or

peripheral nerve, the neuropathy begins distally, causing "dying-back degeneration"

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6.5 ToxicogenesisImpact of poisons on Glial cells--• Poisons may act primarily on glial elements and

indirectly affect neurons • Example--When the blood level of ammonia rises,

astrocytes respond functionally and because these cells contain high levels of glutamine synthetase, which converts glutamate to glutamine, utilising ammonia as a substrate

• This means a prolonged hyperammonemia will cause astrocytic proliferationExample is severe damage of the liver by carbon

tetrachloride resulting in hepatic encephalopathy. • Oligodendroglia may also be sensitive to poisons.

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6.6 ToxicogenesisCapillary Damage • Reduction of blood supply to the brain tissue may be

the result of several types of cardiovascular alterations, including--Generalised hypotention (causing hypoxia)Direct damage to capillaries (causing hypoxia and

ischaemia)• Depending on the extent of capillary damage,

degeneration and necrosis will occur. • Generally, primary damage to capillaries is an acute

response to high levels of cytotoxic agents such as some of the heavy metals.

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7.1 Factors Modifying Toxicogenesis

Specialisation of cells• Even within the same anatomical area there are often

marked differences between the perikarya or between different types of neurons.

Differential distribution of enzymes• There is differential distribution of glycolytic and

pentose shunt enzymes in perikarya and of citric acid cycle and cytochrome oxidase enzymes throughout the brain.

• Where there is high level of pentose shunt enzymes, there is resistance to anoxia. Astrocytes and oligodendroglia are examples.

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7.2 Factors Modifying Toxicogenesis

• Reversibility of toxic effects– When damage is sufficient to cause cell death, the

long term consequence is based on the capacity or compensatory mechanism for reorganising alternative pathways to restore function since adult neurons cannot be replaced by division of the existing cells.

• Functional recovery potential– Once the immediate damage from cell death is

resolved, growth of neuropil, which includes capillaries, glial and neuronal processes may take place. This may take a long period of time..

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8.0 Response to Toxic Injury• The inability of neurons to divide restricts the type of

regeneration possible following toxic injury. • Axons and dendrites can regenerate if damage to

neuronal cell body is reversible. • If the lesion ends in neuronal death, repair occurs

and is brought about by astrocytes, perivascular mesenchymal cells, or both.

• Astrocytes proliferate following neuronal and tissue loss. Specific responses are elicited according to the class or type of poison.

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9.1 Classic disorders due to toxicosis

Neuronopathies• The consequence of a cell body injury is axonal and

dendritic breakdown described as secondary or Wallerian degeneration. Myelin of these axons may also disintegrate. This is either diffuse or selective.Diffuse neuronopathy is caused by mercury as an example.

Methylmercury causes neuronal degeneration which may progress to necrosis resulting into axonal dystrophy.

Selective neuronopathy is exemplified by adriamycin (doxorubicin). This drug is used in cancer chemotherapy. Since it does not pass the blood-brain barrier, it does not enter CNS. Distribution of neuronal degeneration is in the PNS and is limited to areas where blood-neural barrier is absent

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Axonopathies • There is no structural difference recognisable

between the proximal and distal axon. • However, a selective vulnerability exists for the

proximal axon. This vulnerability is due to:Capability of proximal axon to generate and

propagate action potentials.Ability to synthesize.

• Not all of distal axonopathies are described as "dying-back degeneration" because some chemicals may not affect the terminal axon before ascending to the proximal axon.

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Myelinopathies• Myelination of axons occurs in a segmental fashion, the

segments being separated by the nodes of Ranvier. Pulse transmission, therefore, is greatly enhanced because it occurs from node to node rather than by depolarisation of the total length of the axonal membrane.

• Destruction of myelin results in severe impairment or loss of pulse transmission. Destruction may be caused by direct damage of oligondendrocytes or Schwann cells.

• These cells are responsible for the synthesis and maintenance of myelin in the CNS and PNS.

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Vasculopathies • Functions of the vessels to nervous tissue are -

Supply of oxygen and essential nutrients Clearance of waste products Protection of nervous tissue from harmful substances circulating in blood

• The vessels are an integral part of the blood-brain barrier. A number of toxicants impair the blood-brain barrier at different degrees by increasing vascular permeability (dysoria).

• Dysoria is caused for example by exposure to inorganic lead--- It is the ionic form which is absorbed. Lesions are found in the CNS (neuropathy) characterised by cerebral and

cerebella oedema, endothelial swelling and proliferation, and sometimes capillary endothelial necrosis, hyalinisation and thrombus formation.

Lead neuropathy is manifested by Wallerian axonal degeneration and segmental demyelination affecting primarily motor nerves.

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Neuroteratogenicity• Affect the unborn during the embryonal or

foetal stages of development. • The development of immune and nervous

systems extend beyond parturition and anomalies can therefore occur for a limited period after birth.

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Toxins Interfering with CNS Metabolism

GABA Cycle Metabolic Pathway in CNS Glutamic Dehydrogenase

Glutamine-Ketoglutarate Glutamic acid Krebs Cycle GABA Cycle Glutamic Acid Decarboxylase

(Pyridoxine Co-enzyme)

GABA Succinate Glutamic Acid GABA Transaminase

Dehydrogenase

Succinic Semialdehyde

Effects of GABA-mimetic Poisons Toxicants interfering with GABA metabolism may lead to epileptic seizures. GABA cycle is a specific pathway in the CNS. When GABA is not synthesised, depending on the

degree of deficiency, epileptic seizures may be the consequence. Probably the most important factor in GABA synthesis next to glutamic acid decarboxylase (GAD) is vitamin B6 (pyridoxine) which is a co-enzyme of GAD and, as such, essential for the synthesis of GABA. GABA function becomes severely affected by selective loss of "inhibitory" neurons. Such a loss creates an imbalance between excitatory and inhibitory neuronal actions in favour of excitation, which may lead to uncontrolled neuronal discharges. Loss of GABA-ergic terminal have been described in human epileptogenic foci.

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Neurological Toxicosis:- Impact of poisons on nervous system

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