Oligodendrocytes Sensitivity

Conversely, the SAPK/JNK cascade, which is closely associated with apoptosis, is activated by sphingosine (Pyne et al, 1996). Exogenous sphingosine also activates caspase-7in a Bcl-x(L)-sensitive manner wha-eas caspase-8 was unaffected (Nava et al, 2000 Cuvillier et al, 2001). hi addition, sphingosine stimulates p38 MAPK in osteoblast-like cells (Kozawa et al, 2000) but not in oligodendrocytes where is produces lysis (Hida et al, 1999). p38 MAPK is up-stream of MAPKAP kinase-2 and the... 

Alberdi E., Sanchez-Gomez M. V., Torre I., Domercq M., Perez-Samartm A., Perez-Cerda F., and Matute C. (2006). Activation of kainate receptors sensitizes oligodendrocytes to complement attack. J. Neurosci. 26 3220-3228. 

Neural stem cells are known for their sensitivity to the environment. Jan and Kotov reported the differentiation of mouse embryonic neural stem cells on SWNT-polyelectrolyte multilayer thin films [poly(ethylene imine) PEI/SWNT, six layers], which were assembled layer by layer.111 The cells were successfully differentiated to neurons, astrocytes, and oligodendrocytes with a clear formation of neurites. Compared to the widely used poly(L-ornithine) (PLO) substrates, the six-layer PEI/ SWNT thin films exhibited similar properties in terms of biocompatibihty, neurites outgrowth, and the expression of neural markers.111... 

Oligodendrocytes are extremely sensitive to insults that promote oxidative stress, such as inflammation and excessive glutamate signaling. Oligodendrocyte precursors are particularly susceptible to developmental exposure to lead at low doses. 

Coating of axons by myelin sheets produced by oligodendrocytes (in the CNS) and Schwann cells (in the PNS) provide electrical insulation and make transmissions along the axon more rapid [97]. The peak level of myelin synthesis in vivo takes place in the second week postnatally in rats and during the last trimester in humans [10]. However, the process of myelin formation continues during development into adulthood making the nervous system sensitive to myelination disrupters for an exceptionally long period [98]. 

Phenylalanine and related metabolites inhibit activity of 3-hydroxy-3-methylglutaryl coenzyme-A (HMG-CoA) reductase (Fig. 9.2). This aizyme is critical for proper synthesis of cholesterol in phenylalanine-sensitive oligodendrocytes located in the frontal brain, especially in the prefrontal cortex. Locally synthesized cholesterol makes up approximately 30 % of all myelin lipids of the brain tissue. The function of cholesterol is not only structural but is also required for proper neuronal signal transmission [50]. Inhibition of HMG-CoA reductase by phaiylalanine is partially reversible in some individuals. This explains the improvement in myelination observed in MRl scans of poorly controlled patients who have returned to diet and have lowered their blood phenylalanine concentrations. The reduction in phenylalanine allows for proper myelin production in the phenylalanine-sensitive oligodendrocyte population [50,57,58] (Fig. 9.3). 

Fig. 9.3 Hypothesized effect of elevated phenylalanine concentrations on Phe-sensitive oligodendrocyte phenotypes in the forebrain [50]...

The cells of the CNS, ordered according to sensitivity to anoxia, are neuron, oligodendrocyte, astrocyte, microglia, and capillary endothelium. 

The nervous system is a lipid-rich environment. As noted earlier, many elongated axons in the CNS and PNS are insulated by concentric layers of myelin that facilitate conduction of electrical impulses, ause of the density of the lipids, myelinated axons can be more sensitive to lipophilic neurotoxicants. Moreover, axons in adult CNS have a very limited ability to regenerate after injury, at least partially because of myelin-associated inhibitory factors from oligodendrocytes and "glial scars" from reactive astrocytes. In contrast, axons in the PNS have a greater potential to regenerate and regrow after injury under a different environment provided by Schwann cells. 

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