TOXIC RESPONSES OF THE NERVOUS SYSTEM

• Central nervous system (CNS)


  • 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
• Targets of neurotoxic compounds

  • Neuron
  • Axon
  • Myelinating cell
  • Neurotransmitter system

  
• Neuronopathy


  Toxicant induced irreversible loss of neurons, including its cytoplasmic extensions, dendrites and axons, and the myelin ensheathing the axon
• Axonopathy


  Toxicant induced axonal degeneration, and loss of the myelin surrounding that axon, while 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
• Blood-brain barrier


  • Molecules must pass into the cell membranes of endothelial cells of the brain rather than between endothelial cells, as they do in other tissues
  • Contains xenobiotic transporters that transport some xenobiotics that have diffused through endothelial cells back into the blood
• Spinal and autonomic ganglia and a small number of other sites within the brain are not protected by blood–tissue barriers
• processes that underlie development of the NS.

  1. Replication

  2. Migration

  3. Differentiation

  4. Myelination

  5. Synapse formation
• The insufficient replacement of damaged neural cells, the slow formation of the blood–brain barrier, and the lack of key metabolic enzymes may influence NS sensitivity
• Aerobic metabolism


  Energy source for neurons to maintain proper ion gradients
• The brain is extremely sensitive to even brief interruptions in the supply of oxygen or glucose
• Exposure to toxicants that inhibit aerobic respiration (e.g., cyanide) or to conditions that produce hypoxia (e.g., CO poisoning) leads to early signs of neuronal dysfunction
• Neurotransmission


  Intercellular communication in the nervous system through the synapse

  
• Axonal transport


  1. Motor proteins actively navigate microtubules to deliver diverse materials, such as organelles, from one end of the axon to the other

  2. Anterograde transport - transporting nutrients, organelles and other molecules towards the presynaptic terminals

  3. Retrograde transport - transporting damaged organelles and recycled plasma membrane back to the neuron cell body
• Mutations in genes encoding key components of the transport machinery, including motor proteins, motor adaptors and microtubules, have been discovered to cause neurological disease
• Disruptions in axonal cargo trafficking have been extensively reported across a wide range of nervous system disorders
• Disruptions to axonal transport

  • Damage to molecular motors
  • Damage to microtubules
  • Damage to cargoes (such as inhibiting their attachment to motors)
  • Damage to mitochondria, which supply energy for molecular motors
• Axonal degeneration


  Degeneration of the distal portion of the severed axon, first described by Augustus Waller in 1850 and termed Wallerian Degeneration
• Axon regeneration


  1. Schwann cells provide physical guidance and release growth factors to stimulate growth

  2. Resident and recruited macrophages and the denervated Schwann cells clear myelin debris so that a new axon can grow into the space
• Dying-back phenomenon


  In motor degenerative diseases and peripheral nerve diseases caused by toxic insults, the axons of the unhealthy neurons develop a 'dying-back' phenomenon, which starts from the distal terminal and progressively spreads toward the cell body, before death of the cell body
• Neuronopathy


  Loss of the cell body and all of its processes, with no potential for regeneration
• Axonopathy


  The axon may degenerate while the neuronal cell body continues to survive
• Myelination


  Myelinating cell (Schwann cells in PNS or oligodendrocytes in CNS) encircles an axon and progressively wraps multiple layers around it, extruding cytoplasm and extracellular space
• The maintenance of myelin is dependent on a number of membrane-associated proteins and on metabolism of specific lipids present in myelin bilayers
• Some toxic compounds interfere with the maintenance of myelin and result in the toxic myelinopathies
• Demyelination


  Loss of myelin, with the preservation of axons
• Mechanisms of neurotoxicity


  • Neuronopathy - toxicant targets the neuron
  • Axonopathy - toxicant targets the axon
  • Myelinopathy - toxicant targets the myelinating cell
  • Neurotransmitter-associated neurotoxicity - toxicant targets the neurotransmitter system

  
• Neurotoxicants causing neuronopathy


  • aluminum, arsenic, bismuth, carbon monoxide, carbon tetrachloride, chloramphenicol, cyanide, dopamine and other catecholamines, doxorubicin, ethanol, lead, manganese, mercury, methanol, phenytoin, quinine, streptomycin, thallium
• Neurotoxicants causing axonopathy


  • acrylamide, carbon disulfide, chloroquine, colchicine, dapsone, ethylene oxide, gold, hexane, hydralazine, isoniazid, lithium, metronidazole, organophosphates, paclitaxel, platinum, vincristine
• Neurotoxicants causing myelinopathy


  • amiodarone, disulfiram, hexachlorophene, lead, tellurium
• Neurotoxicants affecting neurotransmission


  • amphetamines, atropine, cocaine, muscarine, nicotine, glutamate and other excitatory amino acids
• Generalized depression of CNS function

  Produced by a variety of volatile solvents that are small lipophilic molecules, through interactions with ligand gated ion channels and voltage gated calcium channels
• Astrocytes


  • 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
• Effects of neurotoxicants on astrocytes

  • ammonia – astrocytic swelling and morphological changes
  • nitrochemicals – produce gliovascular lesions that target astrocytes in the gray matter of the brainstem
• Functional manifestations of neurotoxicity


  • Tests to identify the presence of a neurotoxic substance
  • Characterization of the effects on sensory, motor, autonomic, and cognitive functions
  • Evaluation at a cellular and molecular level to understand the events in the nervous system that cause the neurologic dysfunction
• Central nervous system (CNS)


  • 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
• Targets of neurotoxic compounds

  • Neuron
  • Axon
  • Myelinating cell
  • Neurotransmitter system

  
• Neuronopathy


  Toxicant induced irreversible loss of neurons, including its cytoplasmic extensions, dendrites and axons, and the myelin ensheathing the axon