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PubMed2006

Simulating focal demyelinating neuropathies: membrane property abnormalities.

Membrane properties such as potentials (intracellular, extracellular, electrotonic) and axonal excitability indices (strength-duration and charge-duration curves, strength-duration time constants, rheobasic currents, recovery cycles) can now be measured in healthy subjects and patients with demyelinating neuropathies. They are regarded here in two cases of simultaneously reduced paranodal seal resistance and myelin lamellae in one to three consecutive internodes of human motor nerve fiber. The investigations are performed for 70 and 96% myelin reduction values. The first value is not sufficient to develop a conduction block, but the second leads to a block and the corresponding demyelinations are regarded as mild and severe. For both the mild and severe demyelinations, the paranodally internodally focally demyelinated cases (termed as PIFD1, PIFD2, and PIFD3, respectively, with one, two, and three demyelinated internodes) are simulated using our previous double-cable model of the fiber. The axon model consists of 30 nodes and 29 internodes. The membrane property abnormalities obtained can be observed in vivo in patients with demyelinating forms of Guillain-Barré syndrome (GBS) and multifocal motor neuropathy (MMN). The study confirms that focal demyelinations are specific indicators for acquired demyelinating neuropathies. Moreover, the following changes have been calculated in our previous papers: (1) uniform reduction of myelin thickness in all internodes (Stephanova et al. in Clin Neurophysiol 116: 1153-1158, 2005); (2) demyelination of all paranodal regions (Stephanova and Daskalova in Clin Neurophysiol 116: 1159-1166, 2005a); (3) simultaneous reduction of myelin thickness and paranodal demyelination in all internodes (Stephanova and Daskalova in Clin Neurophysiol 116: 2334-2341, 2005b); and (4) reduction of myelin thickness of up to three internodes (Stephanova et al., in J Biol Phys, 2006a,b, DOI: 10.1007/s10867-005-9001-9; DOI: 10.1007/s10867-006-9008-x). The membrane property abnormalities obtained in the homogeneously demyelinated cases are quite different and abnormally greater than those in the case investigated here of simultaneous reduction in myelin thickness and paranodal demyelination of up to three internodes. Our previous and present results show that unless focal demyelination is severe enough to cause outright conduction block, changes are so slight as to be essentially indistinguishable from normal values. Consequently, the excitability-based approaches that have shown strong potential as diagnostic tools in systematically demyelinated conditions may not be useful in detecting mild focal demyelinations, independently of whether they are internodal, paranodal, or paranodal internodal.

Animals↗
PubMed1981

Demyelination in experimental beta, beta'-iminodipropionitrile and hexacarbon neuropathies. Evidence for an axonal influence.

beta, beta'-Iminodipropionitrile and 2,5-hexanediol are best known for their ability to induce axonal pathology, including formation of giant axonal swellings. During studies of the pathology of rats exposed to these agents for long periods, we found extensive recurrent demyelination in the spinal roots. To determine whether the demyelination occurred in response to the axonal disease or whether it represented a direct toxic effect on Schwann cells, we examined the time course and distribution of axonal changes and demyelination, asking whether demyelination correlated with, or was independent of, axonal pathology. Experimental animals were continuously intoxicated with one of these agents, and groups were taken for pathologic examination at intervals of up to 2 years; in both models, the relationship between axonal pathology and demyelination was systematically studied in multiple regions of the L5 spinal roots. In control rats, mild demyelination was present by 14 months and increased with age. By 24 months, untreated animals showed widespread demyelination in the spinal roots; in these animals, there was no predilection for proximal or distal regions of the roots, nor was their evidence of recurrent demyelination. Administration of beta, beta'-iminodipropionitrile produced giant axonal swellings located primarily in the proximal 10 mm. of the ventral root and the distal 10 mm. of the dorsal root. By 12 months of exposure, intramyelinic vacuoles (myelin bubbles) and demyelinated segments were numerous in the same regions. By 24 months, the affected regions contained elaborate onion bulbs. The regions without axonal swellings showed only mild demyelination. In contrast, in the 2,5-hexanediol group, giant axonal swellings and axonal degeneration began distally and progressed more proximally with time. By 15 months, when axonal swellings were present primarily in the distal ventral root, there were numerous myelin bubbles. By 24 months, onion bulbs, predominantly involving the distal ventral roots, had developed. Semiquantitative analysis of the time course and distribution of demyelination in these toxic models showed a relationship between axonal abnormalities and subsequent development of demyelination. We concluded that changes in the axons contribute to the development of demyelination in these models and determine the distribution of the lesions. These experimental neuropathies provide models for studies of the stimulus and mechanisms of secondary demyelination.

Animals↗
PubMed2006

Role of microglia in the pathogenesis of osmotic-induced demyelination.

Osmotic demyelination is a serious disease caused by rapid correction of hyponatremia. In humans, demyelinative lesions occur preferentially in the central pons, and thus are termed central pontine myelinolysis. Although accumulation of microglia has been reported in such demyelinative lesions, their role in the pathogenesis of osmotic demyelination remains unclear. We examined the expression of cytokines in microglia that accumulated in the demyelinative lesions in a rat model of osmotic demyelination. Hyponatremia was induced in rats by a combination of dDAVP infusion and liquid diet feeding. After 7 days, serum sodium levels were rapidly corrected by hypertonic saline injection. The rats developed severe motor deficits, and marked demyelinative lesions were found in the midbrain and cerebral cortex. In the area of the demyelinative lesions, massive accumulations of microglia were observed that expressed the proinflammatory cytokines TNF-alpha and IFN-gamma as well as iNOS. In contrast, in hyponatremia corrected rats treated with lovastatin, which is known to inhibit microglial infiltration in various animal models of CNS disease, neurological impairments and the degree of demyelination were significantly ameliorated. Lovastatin also reduced the accumulation of microglia and decreased the expression of TNF-alpha in the demyelinative lesions. These results indicate that microglia play a detrimental role in the pathogenesis of osmotic demyelination by producing proinflammatory cytokines, and further suggest that lovastatin may be useful in repressing the demyelination.

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