Chapter 16

• 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.

###### Figure 16–1

Schematic diagram of the blood–brain barrier. Systemic capillaries are depicted with intercellular gaps, or fenestrations, which permit the passage of molecules incapable of crossing the endothelial cell. There is also more abundant pinocytosis in systemic capillaries, in addition to the transcellular passage of lipid-soluble compounds. In brain capillaries, tight junctions between endothelial cells and the lack of pinocytosis limit transport to compounds with active transport mechanisms or those that ...

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