Selective vulnerability

The neuron and the Schwann cell are the principal cell types in the PNS. There are great morphological, biochemical, and functional differences between neurons and Schwann cells, and this is reflected in the considerable variation in their vulnerability to toxic injury. Some toxic neuropathies are characterized primarily by injury of the neuron, its axon, or its terminal, as evidenced by the presence of axonal degeneration in peripheral nerve, while other toxic neuropathies are characterized primarily by Schwann cell injury, as evidenced by the presence of demyelination. Those neuropathies characterized by axonal injury are often categorized as axonal neuropathies, whereas those characterized by demyelination are categorized as demyelinating neuropathies.  

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The differential vulnerability of fine and beaded 5-HT axons, combined with evidence from anterograde transport that fine and beaded fibers arise from the DR and MR nuclei, respectively, led to the proposal that axons from the DR nucleus are selectively vulnerable to the neurotoxic effects of psychotropic amphetamines, while the MR projection is resistant. The prior anterograde transport study (Kosofsky 1985 Kosofsky and Molliver 1987) sampled a relatively small number of neurons in the central portions of the DR and MR nuclei and suggested a predominantly differential origin of the two axon types. In order to determine directly whether the DR and MR projections are differentially sensitive to psychotropic amphetamines,... 

Kirino T, Sano K. 1984. Selective vulnerability in the gerbil hippocampus following transient ischemia. Acta Neuropathol 62 201-208. 

Focal and global ischemia produce different distributions of injury 560 The Selective vulnerability of specific neurons or glial cells is not explained by vascular distribution 562... 

The rate of free fatty acid production in the mammalian brain correlates to the extent of resistance to ischemia. FFA production rate is much lower in the brains of neonatal mammals and poikilothermic animals, organisms that display a greater resistance to cerebral ischemic insults than mature mammals [63]. In addition, within the mammalian brain, FFA release is higher in the gray matter compared with white matter, and there is a greater accumulation of AA in areas of the brain, such as the hippocampus, selectively vulnerable to cerebral ischemic damage. 

Kruse, M., Desjardins, P. and Butterworth, R. F. Increased brain endothelial nitric synthase expression in thiamine deficiency relationship to selective vulnerability. Neurochem. Int. 43 49-56, 2004. 

Williamson, T. L., Bruijn, L. I., Zhu, Q. et al. Absence of neurofilaments reduces the selective vulnerability of motor neurons and slows disease caused by a familial amyotrophic lateral sclerosis-linked superoxide dismutase 1 mutant. Proc. Natl Acad. Sci. U.S.A. 95 9631-9636,1998. 

Axelsen, R.A. (1978) Experimental renal papillary necrosis in the rat the selective vulnerability of medullary structures to injury. Virchows Arch. A. Pathol. Anal, 381,79-84... 

Sato K. and Matsuki N. (2002). A 72 kDa heat shock protein is protective against the selective vulnerability of CA1 neurons and is essential for the tolerance exhibited by CA3 neurons in the hippocampus. Neuroscience 109 745-756. 

Pun, S., Santos, A. F., Saxena, S., Xu, L. and Caroni, P. (2006) Selective vulnerability and pruning of phasic motoneuron axons in motoneuron disease alleviated by CNTF. Nat... 

Besides the variable functional outcome after ischemia in animal models, it is well established that specific neuronal populations within an individual vary substantially in ischemic tolerance. Neurons in the CA1 region of the hippocampus and other distinct cellular populations of the caudate, thalamus, neocortex and cerebellum are selectively vulnerable to relatively brief periods of ischemia (Kirino and Sano 1984 Siesjo 1988). The reasons for this phenomenon are not fully elucidated, but for example in cerebellar Purkinje cells it could be shown that a reduced level of aldolase may trigger energy failure after brief periods of anoxia (Welsh et al. 2002). Changes in microcirculation, as seen in focal stroke,... 

Globus M. Y., Ginsberg M. D., and Busto R. (1991) Excitotoxic index—a biochemical marker of selective vulnerability. Neurosci. Lett. 127, 39-42. 

Some neurons are more sensitive than others to the effects of a variety of toxicants that is, they display a selective vulnerability to neurotoxicants. For example, mitochondrial respiratory complex inhibitors such as cyanide and 3-nitropropionic acid are toxic to all cell types yet within the CNS, neurons in the basal ganglia (a group of regions that collectively control motor behavior) appear to be particularly sensitive to these agents. In most cases, selective vulnerability to neurotoxicants arises because of a unique combination of factors that predispose a cell type or region to particular insults. These factors may include the presence of certain ion channels, receptors or uptake sites, the activity level of xenobiotic metabolizing or antioxidant enzymes, the expression profile of neurotrophic factors or their receptors, and so on. Three CNS sites highly vulnerable to neurotoxicant effects are described separately below. 

Jolitha AB, Subramanyam MV, Asha Devi S (2006) Modification by vitamin E and exercise of oxidative stress in regions of aging rat brain studies on superoxide dismutase isoenzymes and protein oxidation status. Exp Gerontol 41(8) 753-763 Kruse M, Navarro D, Desjardins P, Butterworth RF (2004) Increased brain endothelial nitric oxide synthase expression in thiamine deficiency relationship to selective vulnerability. Neurochem Int45(l) 49-56... 

Although the expanded Qn domains impart a toxic gain of function, this does not explain the selective vulnerability in the various Q/j-expansion diseases. In all cases, the mutated Q domain is expressed throughout the brain. Therefore, the selective vulnerability must reside in a toxic gain of function that somehow involves the non-mutated part of the protein (Cummings and Zoghbi, 2001 Zoghbi and Orr, 2009). 

Among the trinucleotide-expansion diseases, it is still not yet clear what accounts for the sensitivity of nervous tissue to the altered genotype and what accounts for the selective vulnerability of different brain regions among the various diseases. However, some progress is being made. A feature of the Qn-expansion diseases and An-expansion diseases, is the presence of (or propensity to form) aberrant protein deposits in affected brain regions. In this respect, these diseases are similar to the... 

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