Do these abstracts from PubMed indicate that there are potential uses of drugs to affect the current results of past hexachlorophene exposure?

Hexachlorophene caused damaging changes in oligodendrocytes that involved glutamate exciototoxicity.

These drugs adress oligodendrocytes abnormalities by blocking glutamate receptors. These and other ather articles indicate that drugs such as topiramate and lamictal would therefore be useful for oligdodedrocyte abnormalities.

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Trends Mol Med. 2006 Jul;12(7):289-92. Epub 2006 Jun 5.

Oligodendrocyte NMDA receptors: a novel therapeutic target.

Matute C.

Departamento de Neurociencias, Universidad del País Vasco, 48940-Leioa, Spain. carlos.matute@ehu.es

Excessive glutamate signaling can lead to excitotoxicity, a phenomenon whereby over-activation of glutamate receptors initiates neuronal death. In recent years, it has been shown that glutamate can be toxic to white-matter oligodendrocytes. Up to recently, the prevailing view was that oligodendrocyte excitotoxicity is mediated by alpha-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid (AMPA) and kainate glutamate receptor types. Three recent studies have shown that oligodendrocytes also express N-methyl-D-aspartate (NMDA) receptors, which are activated under pathological conditions. Thus, NMDA receptors seem to be a promising target for the development of new drugs to treat white-matter damage in acute and chronic diseases.

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Neurochem Res. 2008 Apr 26 [Epub ahead of print]Related Articles,

Metabotropic Glutamate Receptors in Glial Cells.

D'Antoni S, Berretta A, Bonaccorso CM, Bruno V, Aronica E, Nicoletti F, Catania MV.

Institute of Neurological Sciences, National Research Council, Vl Regina Margherita 6, 95123, Catania, Italy.

Glutamate is the major excitatory neurotransmitter in the mammalian central nervous system (CNS) and exerts its actions via a number of ionotropic glutamate receptors/channels and metabotropic glutamate (mGlu) receptors. In addition to being expressed in neurons, glutamate receptors are expressed in different types of glial cells including astrocytes, oligodendrocytes, and microglia. Astrocytes are now recognized as dynamic signaling elements actively integrating neuronal inputs. Synaptic activity can evoke calcium signals in astrocytes, resulting in the release of gliotransmitters, such as glutamate, ATP, and D: -serine, which in turn modulate neuronal excitability and synaptic transmission. In addition, astrocytes, and microglia may play an important role in pathology such as brain trauma and neurodegeneration, limiting or amplifying the pathologic process leading to neuronal death. The present review will focus on recent advances on the role of mGlu receptors expressed in glial cells under physiologic and pathologic conditions.

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Glia. 2008 Jan 15;56(2):233-40.Related Articles, Links

Testing NMDA receptor block as a therapeutic strategy for reducing ischaemic damage to CNS white matter.

Bakiri Y, Hamilton NB, Káradóttir R, Attwell D.

Department of Physiology, University College London, London, England.

Damage to oligodendrocytes caused by glutamate release contributes to mental or physical handicap in periventricular leukomalacia, spinal cord injury, multiple sclerosis, and stroke, and has been attributed to activation of AMPA/kainate receptors. However, glutamate also activates unusual NMDA receptors in oligodendrocytes, which can generate an ion influx even at the resting potential in a physiological [Mg2+]. Here, we show that the clinically licensed NMDA receptor antagonist memantine blocks oligodendrocyte NMDA receptors at concentrations achieved therapeutically. Simulated ischaemia released glutamate which activated NMDA receptors, as well as AMPA/kainate receptors, on mature and precursor oligodendrocytes. Although blocking AMPA/kainate receptors alone during ischaemia had no effect, combining memantine with an AMPA/kainate receptor blocker, or applying the NMDA blocker MK-801 alone, improved recovery of the action potential in myelinated axons after the ischaemia. These data suggest NMDA receptor blockers as a potentially useful treatment for some white matter diseases and define conditions under which these blockers may be useful therapeutically. Our results highlight the importance of developing new antagonists selective for oligodendrocyte NMDA receptors based on their difference in subunit structure from most neuronal NMDA receptors. Copyright (c) 2007 Wiley-Liss, Inc.




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J Anat. 2007 Jun;210(6):693-702. Epub 2007 May 15.Related Articles,

Excitotoxic damage to white matter.

Matute C, Alberdi E, Domercq M, Sánchez-Gómez MV, Pérez-Samartín A, Rodríguez-Antigüedad A, Pérez-Cerdá F.

Departamento de Neurociencias, Universidad del País Vasco, Leioa, and Neurotek-UPV/EHU, Parque Tecnológico deBizkaia, Zamudio, Spain. carlos.,matute@ehu.es

Glutamate kills neurons by excitotoxicity, which is caused by sustained activation of glutamate receptors. In recent years, it has been shown that glutamate can also be toxic to white matter oligodendrocytes and to myelin by this mechanism. In particular, glutamate receptor-mediated injury to these cells can be triggered by activation of alpha-amino-3-hydroxy-5-methylisoxazole-4-propionic acid, kainate and N-methyl-D-aspartate glutamate receptor types. Thus, these receptor classes, and the intermediaries of the signal cascades they activate, are potential targets for drug development to treat white matter damage in acute and chronic diseases. In addition, alterations of glutamate homeostasis in white matter can determine glutamate injury to oligodendrocytes and myelin. Astrocytes are responsible for most glutamate uptake in synaptic and non-synaptic areas and consequently are the major regulators of glutamate homeostasis. Activated microglia in turn may secrete cytokines and generate radical oxygen species, which impair glutamate uptake and reduce the expression of glutamate transporters. Finally, oligodendrocytes also contribute to glutamate homeostasis. This review aims at summarizing the current knowledge about the mechanisms leading to oligodendrocyte cell death and demyelination as a consequence of alterations in glutamate signalling, and their clinical relevance to disease. In addition, we show evidence that oligodendrocytes can also be killed by ATP acting at P2X receptors. A thorough understanding of how oligodendrocytes and myelin are damaged by excitotoxicity will generate knowledge that can lead to improved therapeutic strategies to protect white matter.