Effects on Myelin

Reseeirch on the effects of Pb on myelin have examined either its effects on myelin formation in young animals or segmented demyelination in adults. 

In developing animals, Pb exposure produces a retardation in myelination. Biochemiced analyses have shown a reduction of myelin basic protein, phospholipids, cholesterol, galactolipids, and sulfatides. With the exception of myelin basic protein, which is reduced by 60%, most of the other myelin-rich chemiceds 

In adult animals the most consistent effect of Pb is segmental demyelination. This effect is found in rats and guinea pigs, but not in humans and several other animals. It is characterized by progressive demyelination and remyelination, but precedes the development of endoneurial edema.  

Pb appears to disrupt the normal formation of myelin when exposure occurs during development, rmd causes segmental demyelination when exposure occurs in adulthood. It is not known whether different species show different demyelinating effects of Pb, or whether these differences are the result of differences in methodology, exposure levels, or sensitivity. 

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MPTP is one example of a toxicant that causes direct structural damage to neurons, resulting in loss of function. In the following sections, other types of structural and functional effects of neurotoxicants are described. Structural effects are divided into three primary types effects on myelin formation, primary damage to axons, and direct promotion of cell death. Neurons may also be secondarily affected by neurotoxicants... 

Since iron is involved in many central nervous system processes that could affect infant behaviour and development, iron deficiency has adverse effects on brain development, both pre- and post-natal. In various epidemiological studies, it is reported that children with iron-deficiency anaemia have poorer performances on tests of some specific cognitive function. Animal experiments have identified some of the defects of reduced iron availability on brain function, which include post-translational changes (which result in a failure of iron incorporation into protein structures which are subsequently degraded), vulnerability of the developing hippocampus (with loss of the neuronal metabolic marker cytochrome c oxidase), and altered dendritic stmcture. Iron deficiency will also have a direct effect on myelin, including a decrease in myelin lipids and proteins, as well as neurotransmitter systems, since iron... 

The mechanism of isoniazid-induced neurotoxicity is believed to be reduced concentrations of GABA by inhibition of pyridoxine (vitamin Be) metabolism. Human studies describing white matter changes in isoniazid toxicity have also corroborated a potential toxic effect on myelin. Rapid resolution of diffusion-restricted lesions in this patient suggested a similar process of intramyeUnic edema. In addition, the half-Ufe of isoniazid was 3.9 hours, suggestive of the slow acetyla-tor phenot, with increased susceptibility to adverse effects of isoniazid. 

The class III cytokine receptor family includes two TNE receptors, the low affinity NGE receptor and 7-ceU surface recognition sites that appear to play a role in proliferation, apoptosis, and immunodeficiency. TNE-a (- 17, 000 protein) is produced by astrocytes and microglia and can induce fever, induce slow-wave sleep, reduce feeding, stimulate prostaglandin synthesis, stimulate corticotrophin-releasing factor and prolactin secretion, and reduce thyroid hormone secretion. TNE-a stimulates IL-1 release, is cytotoxic to oligodendrocytes, and reduces myelination this has been impHcated in multiple sclerosis and encephalomyelitis. Astrocyte TNE-a receptors mediate effects on IL-6 expression and augment astrocytic expression of MHC in response to other stimulants such as lEN-y. 

Myelin affects axonal structure. The presence of a myelin sheath affects the structure of the axon that it surrounds [5], presumably optimizing its properties for transmission of action potentials by saltatory conduction. Generally, one of the effects of myelin is to increase axonal diameter by inducing biochemical changes in components of the axonal cytoskeleton such as neurofilaments (see Ch. 8). The effects of myelin on axonal structure imply... 

MBP) holds membranes together at the inner cytoplasmic surfaces in the CNS. Although MBP is also present in the PNS, it is much less abundant than in the CNS and its absence does not have a dramatic effect on PNS myelin compaction. 

Animals continually exposed to concentrations between 100 and 600 ppm developed signs of peripheral neuropathy after 4-8 weeks in cats, the conduction velocity of the ulnar nerve was less than one-half of normal after exposure for 7-9 weeks. In these animals, histologic examination revealed focal denudation of myelin from nerve fibers with or without axonal swelling. In rats and monkeys, adverse effects on neurophysiological indicators of nervous system integrity were found with 9-month exposures to 100 ppm, 6 hours/day, 5 days/week. MBK neuropathies, however, occurred only after 4-month exposure at 1000 ppm. Four months of intermittent respiratory exposure of rats to 13 00 ppm caused severe symmetric weakness in the hind limbs. ... 

Handlers of methyl methacrylate cement have developed paresthesia of the fingers. Dental technicians who use bare hands to mold methyl methacrylate putty had significantly slower distal sensory conduction velocities from the digits, implicating mild axonal degeneration in the area of contact with methyl methacrylate. The toxic effect on the nervous tissues may be due to diffusion into the nerve cells causing lysis of the membrane lipids and destruction of the myelin sheath. 

The results on the effect of thyroid hormone on myelin lipid synthesis correlate well with the in vivo changes induced under altered thyroid functions, proving, thereby, the direct influence of T on brain maturation. Another in vitro system used to demonstrate such a direct effect of thyroid hormone on myelination was an explant culture of cerebella obtained from newborn rats. 

In another drinking water study, both single and repeated doses of triethyltin bromide produced performance decrements in a series of behavioral toxicity tests in rats (Reiter et al. 1980). The effects were rapid in onset but reversible 1 month after exposure was discontinued. Such findings correlate well with the effects on the myelin sheath (i.e., demyelination). These changes also illustrate the characteristic effects of the triethyltins as compared to trimethyltins. The authors estimated that a behavioral threshold for the rat is between 8-10 mg/kg/day triethyltin bromide for a 3-week exposure. 

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