Peripheral Neurons

Markers of lineage progression Characterization of a number of specific biochemical markers has increased our knowledge on the stages of SC maturation, both in vivo and in vitro. Some of the biochemical markers have been shown to overlap partially (Table 8.3). 

Schwami ceU piecui sor (.SCPs) Cadherml9, AP2a, low level PO, GAP43, F-spondm, SOXIO, BFABP, DHH 

Immature Schwaim cells Sloop, GFAP, low level of PO, SOXIO, 04 antigen, BFABP, DHH 

Signaling Pathways Involved in Survival, Migration and Death of SCs 

The survival of immature SCs in late embryonic and pre-natal nerves is probably controlled by a balance betw een factors that support survival and factors that cause death. Axon-derived neuregulin family (NRG-1, NRG-2, and NRG-3) have been implicated in the biological processes of SCs including fate specification, proliferation, survival, migration, regulating the extent of myelination, and triggering demyelination. It is believed that the interaction between several NRG ligands 

---

Delta receptors are relatively selective for two related penta-peptides, methionine enkephalin and leucine enkephalin (met- and leu-enkephalin), which were isolated from porcine brain (Hughes 1975). Both met- and leu-enkephalin inhibit electrically induced contractions of guinea pig ileum, an effect that mimics those effects seen with opioid drugs, and is naloxone reversible. The enkephalins are processed posttranslational ly from proenkephalin, and secreted from central and peripheral neurons and endocrine cells in the adrenal medulla. 

In the periphery, CB1 is found in the adrenal glands, bone marrow, heart, lung, prostate, testes, thymus, tonsils, spleen, lymphocytes, phagocytes, smooth muscle, vascular endothelium, peripheral neurons (e.g., in the gut), kidneys, uterus, and sperm as reviewed by Schuel et al. (1999). 

Pulliam, M.W., Boyd, L.F., Baylan, N.C., and Bradshaw, R.A. (1975) Specific binding of covalently cross-linked mouse nerve growth factor to responsive peripheral neurons. Biochem. Biophys. Res. Comm. 67, 1281-1289. 

Reserpine blocks vesicular storage of monoamines, prolonging their presence in cytoplasm. There they are degraded by MAO, leading to a depletion of monoamines in synaptic terminals of central and peripheral neurons, so that little or no neurotransmitter is released when the neuron depolarizes (Oates 1996). Reversal of this process requires synthesis of new vesicles, which occurs over a period of days to weeks after discontinuation of the drug. 

Certain organic forms of mercury can elicit specific damage in the main cell body of peripheral neurons. Similar responses are associated with certain natural products called vincristine and vinblastine, both of which have been used as antileukemic medicines. The deadly botulinum toxins, mentioned earlier in this chapter, block transmission of nerve impulses at the synapses of motor neurons. This blockage results in muscular paralysis which, if sufficiently severe, can lead to death, usually because respiration is impaired. The once widely used pesticide, DDT, is an organic chemical that also acts on the nervous system at this site, although it can also mount an attack on areas of the CNS. 

Hemopexin was first identified as a heme binding P-globin in elec-trophoretograms of plasma of patients with hemolysis (17-19). The protein is synthesized and secreted by the liver (20-22), and during secretion the signal peptide is removed and the protein is glycosylated (23). Tissue forms of hemopexin are expected due to the presence of mRNA in brain (24), peripheral neurons (25), and neural retina (26), pointing to a function of hemopexin in barrier tissues. 

Central nervous system effects predominate in acute exposures at massive doses, whereas peripheral neuropathy is more common with lower doses.After cessation of exposure to acrylamide, most cases recover, although the course of improvement can extend over months to years and depends on the severity of exposure. Because peripheral neurons can regenerate and central axons cannot, severely affected individuals may still experience residual ataxia, distal weakness, reflex loss, or sensory disturbance. 

Another complication of diabetes is the loss of peripheral neuronal function. It has recently been shown that camosine and its zinc complex can ameliorated progressive diabetic neuropathy in mice (Kamel et al.,... 

B. Methylxanthines have been proposed to be inhibitors of phosphodiesterase, which would elevate intracellular levels of cAMP. However, the concentration of cAMP that is required for such action is above the threshold of CNS stimulation. Since the methylxanthines are relatively potent antagonists of adenosine and since adenosine has been shown to be a reasonably potent inhibitor of both central and peripheral neurons, the most likely mechanism by which CNS stimulation occurs is through antagonism of adenosine receptors. 

Another complication of diabetes is blindness, which is due to blood vessel damage at the back of the eye (proliferative retinopathy), this accounts for about 12% of all blindness. In hyperglycemia, fructose is only slowly metabolized, and sorbitol accumulates in tissues. Because aldose reductase is found in kidneys, optic nerve, and peripheral neurons, retinopathy and painful neuropathies develop in poorly controlled or long-standing diabetes as a result of sugar alcohol (sorbitol) accumulation. Aldose reductase inhibitors, such as tokestat (5.129) or sorbinil (5.130), have been evaluated as agents to ameliorate these additional symptoms of diabetes. 

Methyldopa (l -pathway directly parallels the synthesis of norepinephrine from dopa illustrated in Figure 6-5. Alpha-methylnorepinephrine is stored in adrenergic nerve vesicles, where it stoichiometrically replaces norepinephrine, and is released by nerve stimulation to interact with postsynaptic adrenoceptors. Flowever, this replacement of norepinephrine by a false transmitter in peripheral neurons is not responsible for methyldopa s antihypertensive effect, because the a-methylnorepinephrine released is an effective agonist at the cx adrenoceptors that mediate peripheral sympathetic constriction of arterioles and venules. In fact, methyldopa s antihypertensive action appears to be due to stimulation of central a adrenoceptors by a-methylnorepinephrine or a-methyldopamine. 

L-type Ca2+ channels can be detected in peripheral neurons, central neurons, synaptosomes as well as in non-neuronal cells (review Tsien et al., 1988). In general the following gene products were found to be expressed, at least in part, in the central nervous system (CNS) (Birnbaumer et al., 1994 Alexander and Peters, 2000) ... 

CBt receptors are found in particularly high concentrations within the central nervous system, but also on some peripheral neurons as well as in certain non-neuronal tissues (Herkenham et al., 1990). CB2 receptors mainly occur in immune cells where they can mediate an immunosuppressant effect (Iwamura et al., 2001). Both... 

Most cells of the immune system are ordinarily kept apart from those of the nervous system by means of the blood-brain barrier. However, allergic encephalomyelitis, in which T cells attack the myelin sheath of brain neurons, can easily be induced in mice.506 A similar autoimmune process is thought to be involved in human multiple sclerosis (see Chapter 30, pp. 1769, 1808, and Fig. 30-9).507,508 High levels of circulating IgM are found in some demyelinating diseases of peripheral neurons.508 In Rasmussen s encephalitis, which causes brain inflammation and epilepsy, serum antibodies attack a glutamate receptor subunit GluR3.509... 

L-type calcium channels are the primary trigger for excitation-contraction (EC) coupling in cardiac, skeletal, and smooth muscles (Bean, 1989). They are also found in most central and peripheral neurons where they in part control calcium-dependent gene expression, as well as in endocrine cells and many types of non-excitable cells where they contribute to a variety of processes including exocytotic release. Unlike most synapses in the brain and spinal cord that rely on P/Q- and N-type calcium channels for neurotransmitter release, (Wheeler et al., 1994), the presynaptic terminals in photoreceptor cells rely on the Cav1.4 (a1F) L-type calcium channel for mediating glutamate release (Tachibana et al., 1993 Nachman-Clewner et al., 1999). Photoreceptor neurotransmission is atypical first,... 

Reserpine blocks the ability of aminergic transmitter vesicles to take up and store biogenic amines, probably by interfering with an uptake mechanism that depends on Mg2+ and ATP (Figure 6-4, carrier E). This effect occurs throughout the body, resulting in depletion of norepinephrine, dopamine, and serotonin in both central and peripheral neurons. Chromaffin granules of the adrenal... 

Sutton KG, McRory JE, Guthrie H, Murphy TH, Snutch TP (1999) P/Q-type calcium channels mediate the activity-dependent feedback of syntaxin-lA. Nature 401 800-4 Swartz KJ (1993) Modulation of Ca2+ channels by protein kinase C in rat central and peripheral neurons disruption of G protein-mediated inhibition. Neuron 11 305-20 Swartz KJ, Merritt A, Bean BP, Lovinger DM (1993) Protein kinase C modulates glutamate receptor inhibition of Ca2+ channels and synaptic transmission. Nature 361 165-8 Takahashi SX, Miriyala J, Colecraft HM (2004) Membrane-associated guanylate kinase-like properties of beta-subunits required for modulation of voltage-dependent Ca2+ channels. Proc Natl Acad Sd US A 101 7193-8... 

---