Pathophysiology of oligodendroglial excitotoxicity

Yoshioka, Akira; Bacskai, Brian J.; Pleasure, David E

doi:10.1002/(sici)1097-4547(19961115)46:4<427::aid-jnr4>3.0.co;2-i

Cited by 125 publications

(46 citation statements)

References 57 publications

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“…The white matter injury may be due to reduced energy generation. Astrocytic glutamate uptake, a protective mechanism against excitotoxic neuronal injury, is coupled with glycolysis and cellular ATP generation [8]. Impairment of cell energy metabolism, which occurs in PDH deficiency, can lead to irreversible excitotoxicity.…”

Section: Discussionmentioning

confidence: 99%

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Neonatal pyruvate dehydrogenase deficiency due to a R302H mutation in the PDHA1 gene: MRI findings

et al. 2008

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Pyruvate dehydrogenase (PDH) deficiency is one of the most common causes of congenital lactic acidosis. Correlations between the genetic defect and neuroimaging findings are lacking. We present conventional and diffusion-weighted MRI findings in a 7-day-old male neonate with PDH deficiency due to a mosaicism for the R302H mutation in the PDHA1 gene. Corpus callosum dysgenesis, widespread increased diffusion in the white matter, and bilateral subependymal cysts were the main features. Although confirmation of PDH deficiency depends on specialized biochemical analyses, neonatal MRI plays a role in evaluating the pattern and extent of brain damage, and potentially in early diagnosis and clinical decision making.

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Section: Discussionmentioning

confidence: 99%

“…Impairment of cell energy metabolism, which occurs in PDH deficiency, can lead to irreversible excitotoxicity. However, the white matter lesions may also be attributable to selective susceptibility of immature oligodendrocytes to injury from free radicals and glutamate [8].…”

Section: Discussionmentioning

confidence: 99%

Neonatal pyruvate dehydrogenase deficiency due to a R302H mutation in the PDHA1 gene: MRI findings

et al. 2008

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“…Several lines of evidence have suggested that glutamate excitotoxicity plays a key role not only in neuronal cell death but also in delayed post traumatic spinal cord white matter degeneration (Faden and Simon, 1988;Wrathall et al, 1994;Agrawal and Fehlings, 1997;Wrathall et al, 1997). Oligodendrocytes are highly vulnerable to excitotoxic signals mediated by glutamate receptors of the AMPA and kainate classes compared to astrocytes (Oka et al, 1993;Yoshioka et al, 1996;Agrawal and Fehlings, 1997;Matute -27 -et al, 1997;McDonald et al, 1998). Our previous experiments showed that excitotoxic injury caused by injection of kainate into the CNS induced expression of neuropsin mRNA in oligodendrocytes (Tomizawa et al, 1999).…”

Section: Discussionmentioning

confidence: 99%

Neuropsin promotes oligodendrocyte death, demyelination and axonal degeneration after spinal cord injury

et al. 2007

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Abbreviations: SCI, spinal cord injury; DIG, digoxigenin; APC, adenomatus polyposis coli; MBP, myelin basic protein; TUNEL, TdT-mediated dUTP-fluorescein nick end labeling -3 - AbstractPrevious studies indicated that the expression of neuropsin, a serine protease, is induced in mature oligodendrocytes after injury to the central nervous system (CNS). The pathophysiology of spinal cord injury (SCI) involves primary and secondary mechanisms, the latter contributing further to permanent losses of function. To explore the role of neuropsin after SCI, histochemical and behavioral analyses were performed in wild-type (WT) and neuropsin-deficient (neuropsin -/-) mice using a crush injury model, a well-characterized and consistently reproducible model of SCI. In situ hybridization revealed that neuropsin mRNA expression was induced in the spinal cord white matter from WT mice after crush SCI, peaking at day 4. Neuropsin -/-mice showed attenuated demyelination, oligodendrocyte death, and axonal damage after SCI.Although axonal degeneration in the corticospinal tract was obvious caudal to the lesion site in both strains of mice after SCI, the number of surviving nerve fibers caudal to the lesion was significantly larger in neuropsin -/-mice than WT mice. Behavioral analysis revealed that the recovery at days 10-42 was significantly improved in neuropsin -/-mice compared to WT mice in spite of the severe initial hindlimb impairments due to SCI in both strains. These observations suggest that neuropsin is involved in the secondary phase of the pathogenesis of SCI mediated by demyelination, oligodendrocyte death, and axonal degeneration.-4 -

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“…42 Interestingly, OL vulnerability to glutamate was first shown in culture by Oka et al 43 as mediated by GluTs, but it was later shown that GluRs also mediate OL excitotoxicity. 44,45 Excitotoxic cell death in OLs can be mediated in different ways (reviewed in Matute et al 46 ). In many cases, a calcium influx is generated by AMPA/kainate receptor activity.…”

Section: Ols and Diseasementioning

confidence: 99%

Maturation-dependent sensitivity of oligodendrocyte lineage cells to apoptosis: implications for normal development and disease

2008

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Apoptosis plays a crucial role in brain development by ensuring that only appropriately growing, migrating, and synapse-forming neurons and their associated glial cells survive. This process involves an intimate relationship between cell-cell interactions and developmental cues and is further impacted by environmental stress during neurogenesis and disease. Oligodendrocytes (OLs), the major myelin-forming cells in the central nervous system, largely form after this wave of neurogenesis but also show a selective vulnerability to cell death stimuli depending on their stage of development. This can affect not only embryonic and early postnatal brain formation but also the response to demyelinating pathologies. In the present review, we discuss the stagespecific sensitivity of OL lineage cells to damage-induced death and how this might impact myelin survival and regeneration during injury or disease. Apoptosis is a major form of programmed cell death required for the normal development of metazoan tissues, including the brain. 1 During embryonic development of the brain, many more cells than ultimately needed are generated and then selection occurs, resulting in the apoptotic depletion of the surplus cells. The importance of the apoptotic pathway in early brain development has been demonstrated by the targeted deletion in mice of the death-specific cysteine proteases caspase-3 or caspase-9, or of the co-activator Apaf-1, all of which cause severe brain overgrowth and perinatal death. 2,3 In the adult brain, 90% of the cells belong to the glial lineage, which includes oligodendrocytes (OLs), astrocytes and microglia. The glia ensures proper development, function and repair of the neuronal network. This is possible through continuous cross-talk between the glia and neurons mediated by neurotransmitters, cytokines, growth and trophic factor secretion and signaling in a reciprocal manner. [4][5][6][7] In the central nervous system (CNS), OLs are responsible for axon myelination, which insulates the electrical signals transmitted between neurons. OL and neuron development is tightly regulated and the myelin sheath is constructed only when OLs reach maturity and neurons have grown appropriately. In response to injury or during the course of neurological diseases, the neuron-glia network can be replenished to some extent but the degree of repair is dependent on the developmental stage of the OL. This complexity is compounded by the differential sensitivity of OL lineage cells to apoptotic stimuli. In the present review, we will first briefly examine the stages of differentiation of OL cells and then discuss several diseases that are impacted by OL apoptosis, noting how the stage of cell differentiation governs the sensitivity to apoptosis. Defined Stages of OL DevelopmentOligodendrocyte development can be divided into four distinct stages according to the temporal expression of cell surface markers and morphology (Table 1). 8 In the first stage, OL progenitor cells (OPCs) originate from the neuroepithelium of the ventricul...

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Pathophysiology of oligodendroglial excitotoxicity

Cited by 125 publications

References 57 publications

Neonatal pyruvate dehydrogenase deficiency due to a R302H mutation in the PDHA1 gene: MRI findings

Neonatal pyruvate dehydrogenase deficiency due to a R302H mutation in the PDHA1 gene: MRI findings

Neuropsin promotes oligodendrocyte death, demyelination and axonal degeneration after spinal cord injury

Maturation-dependent sensitivity of oligodendrocyte lineage cells to apoptosis: implications for normal development and disease

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