Damage to the CNS is often due to either lipophilic compounds which readily cross the blood brain barrier or to compounds that damage the blood brain barrier, its pores, or permeability, which then permits the entry of hydrophilic compounds into the CNS.

The mechanisms involved in CNS and nerve toxicity are similar to those discussed previously (direct irritation, chemical irritation, biochemical lesions, et c.).  A common feature to many types of CNS and/or neuronal toxicity is anoxia.  RECALL that anoxia is normally interpreted as a state resulting from ischaemia or reduced blood flow to a specific area, thus depriving the area of oxygen.  HOWEVER, ALSO RECALL that certain chemicals may produce a chemical anoxia by uncoupling oxidative phosphorylation (or other biochemical lesions) that produce the same effect as the absence of oxygen would produce.  The former type of anoxia is termed ISCHAEMIC ANOXIA while the later is referred to as ANOXIC ANOXIA (the classic uncoupling of oxidative phosphorylation seen with cyanide or the nitrophenols is a good example of anoxic anoxia).  Neurones are extremely sensitive to states of anoxia.  If neuronal death occurs, it is incapable of repair (recall that if the injury is not lethal to the neurone, it may repair, via various nerve growth factors) and the damage is done.  HOWEVER, ALSO RECALL that the CNS is redundant and there exists many neurones that are not fully utilised.  IF neuronal death does occur on a limited basis; existing, undamaged neurones may "learn" the function of the lost neurones, thus preserving at least some of the function lost to the toxic effect.  Therefore, there is a reserve capacity within the CNS.

The types of damage that are produced within the CNS may present as different signs or symptoms.
Sensory function deficits may occur if sensory neurones or that area of the brain innervated by them suffers toxic insult.  This type of damage often presents as impairment of sight, hearing, temperature discrimination, pain perception, or non-specific paraesthesias.  Damage of this type is often the result of central demyelination or neuropathy that decreases conduction velocity of the neurone.  Conversely, toxic insult resulting in increased neuronal excitability could increase the perception of sensory input from these neurones.  Lead, methylmercury, and organophosphate insecticides may all produce a type of sensory function deficit by this mechanism.

Motor function deficits present as weakness and paralysis and are most often due to motor fibre demyelination.  The anti-tuberculotic isoniazid is a classic example of drug-induced motor neuropathy (RECALL that this toxicity may be at least partially prevented by the co-administration of vitamin B₆, pyridoxine).   Similar to the converse above, over-excitation could cause mild tremors and other, more pronounced, motor dysfunction.

In some cases of toxicity to peripheral neurones, the damage may progress in a retrograde fashion back to the cord/CNS, ultimately causing neuronal death within the brain.  This occurs with the organochlorine insecticides DDT and kepone.
 

The specific neurotoxins are classified by the distinct type/mechanism of neuronal toxicity they produce.
Type I Agents -- Produce anoxic anoxia or a chemically-induced ischaemic type toxicity.
Carbon monoxide (CO) produces ischaemia by the formation of carboxyhaemoglobin, which reduces the oxygen-transport capability of haemoglobin.  The signs and symptoms of CO toxicity include a sudden onset of bizarre behaviour, confusion, disorientation, pyrexia, ataxia, incoordination, and weakness.  It typically affects the white matter of the CNS.

Cyanide inhibits the cytochrome oxidase pathways to uncouple oxidative phosphorylation, as previously discussed.  It typically effects the gray striatum and substantia nigra of the CNS.
 

Type II Agents -- Cause the demyelination of Schwann Cells and Oligodendroglia
Trimethyl Tin specifically inhibits Na/K ATPase, causing a cleft in the myelin sheath.

Lead (Pb) produces an encephalopathy.

Thallium (Tl) toxicity presents with ataxia, painful paraesthesias and produces its effect by competition with potassium at the ATPase pump.
 

Type III Agents -- Damage the peripheral neurones (or the myoneural junction, see Type V neurotoxins below) This toxicity usually results from chronic exposure with a delayed onset of signs and symptoms.
Ethanol is a classic example of this type of neuronal toxicity.  EtOH alters the permeability of the cellular membrane, increases its fluidity (the cell membrane looses some of its structural integrity).

Organophosphate insecticides (NOTE that ADULTS are more sensitive to these effects of the OPs than are children).  These agents will phosphorylate neuronal proteins, inhibiting their function.

Type IV Agents -- Damage the cell body of peripheral neurones. (RECALL that the soma or cell body of all peripheral nerves lie either in the CNS, cord, or ganglia of the nervous system.)
Organic mercury (e.g. methylmercury) affects the cell bodies in the dorsal root ganglia, disrupting the rough endoplasmic reticula, thus decreasing protein synthesis.

Vinca alkaloids (vincristine, vinblastine) cause a polyneuropathy that presents as sensory disturbances and motor muscle atrophy.
 

Type V Agents -- Damage the myoneural junction (MNJ) specifically
Botulinum toxin prevents the release of acetylcholine by binding irreversibly to the synaptic vesicles of the neurone.  The MNJ is essentially destroyed and new ones must be synthesised to counter the toxicity of the poison.

Tetrodotoxin (from puffer fish) and sejudotoxin (from dinoflagellates, commonly known as "red tide") both block Na channels, thus inhibiting neuronal function.

Synthetic pyrethroid insecticides (derived from naturally occurring pesticides found in chrysanthemums) open and prolong the activated state of Na channels, thus causing neuronal fatigue.

Lead will depress nerve end-plate potential, thus reducing synaptic function.
 

Type VI Agents -- Cause localised anatomical lesions within the CNS
Gold thioglucose will affect the hypothalamus.

Methylmercury produces lesions within the cerebellum and cortex.

MPTP -- this well characterised toxin specifically targets the substantia nigra, causing a Parkinsonian like state.

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