THE NERVOUS SYSTEM AS A TARGET ORGAN Summary A target organ is an organ or organs of the body which adversely responds to systemic exposure of a chemical. The function of the nervous system is to communicate with different parts of the body and also coordinate both voluntary and involuntary actions. The main parts are the central nervous system and peripheral nervous system. There are different cell types associated with the nervous system, neurones, glial cells. The nervous system communicates by means of generation of an action potential. The electrical signal is conducted from one neuron to another across the synapse by means of chemical transmitters. Chemicals can cause harm to the cells and also affect the neurotransmitters as well as the vascular system. Introduction The nervous system could be considered to be similar to electrical wiring in a house; enabling messages to be transmitted from one area to another. However should a part of it fail then this could have disastrous consequences. Therefore in this session the nervous system will be introduced and in particular how and why it can be a target organ. 1
1. The nervous system The nervous system is the means by which the body is able to respond to changes in its immediate environment. This is undertaken by means of specialised cells which act as receptors (these are in sense organs, such as ears, eyes, touch, etc.) that detect changes in stimuli and, convert the change into an electrical impulse which is sent to the brain via the nerve cells, called neurons. The brain then undertakes the appropriate response to that particular stimulus. It comprises two main parts; the central nervous system (CNS) (brain and spinal chord) and the peripheral nervous system (PNS); which comprise all the other nerves located outside of the brain and spinal cord. 1.1 The neuron This is the functional cell of the nervous system and their role is to carry information in the form of an electrical impulse. It typically comprises a cell body, axon and dendrites. Unlike the glial cells the neurons cannot regenerate. The axon of the neuron can be up to one metre in length and is covered by a lipid rich myelin sheath which both insulates and speeds up the transmission of the electrical signal (or message). The axon structure itself contains neurofibrillary structures as well as mitochondria and smooth endoplasmic reticulum; all of which are susceptible to chemical insult. 2
1.2 Glial cells These are located in the CNS (called oligodendrites, astrocytes and also microglia) and PNS (where called Schwann cells) provide structural support. They are unable to conduct an electrical impulse. Within the CNS the glial cells include astrocytes, oligodendrites and microglia whereas in the PNS it is the Schwann cell which provides the myelin sheath. The blood brain barrier prevents most substances which are present in circulatory system from entering the brain. This also includes hormones which could influence other parts of the body. It also helps maintain a constant environment for the brain. 1.3 Transmission of information The conduction of the electrical signal arises as a result in changes in both the electrical and chemical state of the neuron. In a resting state the neuron has a resting potential of ca 50 to 75 mv across the membrane as a result of having a greater positive charge outside compared to inside the neuron. However upon stimulation this changes as the membrane becomes more permeable which results in sodium ions entering the neuron creating a more positive charge and depolarisation. This effect occurs along the length of the axon and is how the electrical signal or action potential is conducted. The resting state of the neuron is restored once the electrical signal has passed through by means of a sodium pump. 1.4 The synapse This is the gap between two neurons and is where the electrical signal is conducted from one neuron to another across the synapse by means of chemical transmitters. 3
The presynaptic membrane contains vesicles of neurotransmitters and these diffuse across the gap to the post synaptic membrane of the other neuron. Once the transmission has occurred enzymes break down the neurotransmitter which then permits further transmissions to occur. There are numerous neurotransmitters and one of the most common ones is acetyl choline. This is broken down by the enzyme acetyl choline esterase. 2. The nervous system as a target organ The nervous system is susceptible to the effects of chemical exposure and includes the following, 1. Neuropathy Because the neurons are highly dependent on a good supply of oxygen and glucose they are particularly prone to conditions where this is not the case; that is, anoxic and hypoglycaemic conditions. For example, prolonged exposure to carbon monoxide, which will bind with haemoglobin of the red blood cells, will cause permanent effects in the brain as a result of hypoxia. 2. Axonopathy Effects on the axons can be as a result of direct chemical injury on the axon itself or on the cell body which is responsible for synthesising some of the elements which make up the axon (neurofilaments). Distal axonopathy is where degenerative effects are seen on the axon furthermost away from the cell body. Thallium will cause swelling of the mitochondria and degeneration whereas certain organophosphates and organic solvents will cause swelling of the neurofibrillary structures contained within the axon. Delayed distal axonopathy arises as a result of exposure to some types of organophosphates and causes paralysis of the muscles. 4
3. Myelinopathy This can arise as a result of direct effects on the myelin sheath or on the Schwann cells. The overall effect is either a reduction or complete blockage in the conduction of the action potential through the axon. Triethyltin is a substance which will cause effects on the myelin. 4. Interference with chemical transmitters Botulin toxin causes paralysis of the muscles as a result of preventing the release of acetyl choline whereas the venom of black widow spiders will cause an excessive release of acetyl choline resulting in cramping and paralysis. Other agents will act directly on the enzymes which are responsible for breaking down the neurotransmitter; in the case of acetyl cholinesterase it is known as an anticholinesterase agent, such as organophosphates. The result is that increased stimulation occurs as a result of the absence of the enzyme. Some chemicals such as DDT exert their effect by keeping the sodium ion channel open for too long, resulting in repetitive activity at the synapses, as the resting potential is not restored 5