<i>In Vitro</i>Ischemic Tolerance Involves Upregulation of Glutamate Transport Partly Mediated by the TACE/ADAM17-Tumor Necrosis Factor-α Pathway

Romera, Cristina; Hurtado, Olivia; Botella, Sofia H.; Lizasoaín, Ignacio; Cárdenas, Antonio; Fernández-Tomé, Paz; Leza, Juan C.; Lorenzo, Pedro; Moro, Marı́a A.

doi:10.1523/jneurosci.1596-03.2004

Cited by 117 publications

(101 citation statements)

References 68 publications

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“…Of note, whereas the staining in neurons is clearly located in the membrane, this is not the case in astrocytes. In this context, using an in vitro model of IPC (Romera et al, 2004), we have recently demonstrated that IPC induces a different regulation of TACE in each cell type, with an increase in mature TACE and a decrease in its precursor, consistent with a regulation by processing, in neurons, and an increase in the expression of the precursor form, suggesting a regulation at the transcriptional level, in astrocytes. This is consistent with our new data, because the precursor form of TACE has been described to be located intracellularly, whereas the mature form is predominantly in the plasma membrane (Schlöndorff et al, 2000).…”

Section: Discussionmentioning

confidence: 87%

TNFR1 Upregulation Mediates Tolerance after Brain Ischemic Preconditioning

Pradillo

Romera

Hurtado

et al. 2005

J Cereb Blood Flow Metab

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A short ischemic event (ischemic preconditioning (IPC)) can result in subsequent resistance to severe ischemic injury (ischemic tolerance (IT)). The expression and neuroprotective role of tumor necrosis factor (TNF-a) have been described in models of IPC and we have showed the participation of its processing enzyme, the TNF-a convertase enzyme (TACE) in this process. We have now decided to explore the expression and localization of TNF receptors (TNFR) as well as other signalling mechanisms involved in IT. A period of 10 mins of temporary middle cerebral artery occlusion (tMCAO) was used for focal IPC. To evaluate the ability of IPC to produce IT, permanent MCAO was performed 48 hours after IPC. Ischemic preconditioning produced a reduction in infarct volume, as we showed previously. Ischemic preconditioning caused upregulation of neuronal TNFR1 that was reduced by the selective TACE inhibitor BB1101. Intracerebral administration of TNFR1 antisense oligodeoxynucleotide, which caused a reduction in TNFR1 expression, inhibited the IPC-induced protective effect, showing that TNFR1 upregulation is implicated in IT. Moreover, treatment with BB1101, TNFR1 antisense and lactacystin-a specific proteasome inhibitor-blocked IPC-induced NF-jB. Immunohistochemical studies showed the expression of TACE and TNFR1 in neurons. In summary, these data show that IPC produces neuronal upregulation of TACE and TNFR1, and that the pathway TACE/TNF-a/TNFR1/NF-jB is involved in IT.

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Section: Discussionmentioning

confidence: 87%

TNFR1 Upregulation Mediates Tolerance after Brain Ischemic Preconditioning

Pradillo

Romera

Hurtado

et al. 2005

J Cereb Blood Flow Metab

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“…Finally, it is noteworthy that although proinflammatory cytokines and mediators are clearly associated with tissue damage in autoimmune neuropathies, some of them have been linked to normal function of the nervous system and even neuroprotection in some cases (45). Particularly, TNF-␣ is produced by astrocytes, microglia, and neurons and has been associated both with CNS damage and neuroprotection against excitotoxicity following ischemia or stroke (45)(46)(47)(48)(49). In contrast, IFN-␥ is produced only by infiltrating leukocytes but not by resident cells in the CNS, thus making this cytokine a better target for immunotherapy than TNF-␣.…”

Section: Discussionmentioning

confidence: 99%

Distinct Effector Mechanisms in the Development of Autoimmune Neuropathy versus Diabetes in Nonobese Diabetic Mice

Bour-Jordan

Thompson

Bluestone

2005

The Journal of Immunology

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NOD mice deficient for the costimulatory molecule B7-2 (NOD-B7-2KO mice) are protected from autoimmune diabetes but develop a spontaneous autoimmune peripheral neuropathy that resembles human diseases Guillain-Barre syndrome and chronic inflammatory demyelinating polyradiculoneuropathy. Similar observations have now been made in conventional NOD mice. We have shown previously that this disease was mediated by autoreactive T cells inducing demyelination in the peripheral nervous system. In this study, we analyzed the molecular pathways involved in the disease. Our data showed that neuropathy developed in the absence of perforin or fas, suggesting that classic cytotoxicity pathways were dispensable for nerve damage in NOD-B7-2KO mice. In contrast, IFN-γ played an obligatory role in the development of neuropathy as demonstrated by the complete protection from disease and infiltration in the nerves in NOD-B7-2KO mice deficient for IFN-γ. This result was consistent with the inflammatory phenotype of T cells infiltrating the peripheral nerves. Importantly, the relative role of perforin, fas, and IFN-γ appears completely different in autoimmune diabetes vs neuropathy. Thus, there are sharp contrasts in the pathogenesis of autoimmune diseases targeting different tissues in the same NOD background.

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“…The proper functioning of glutamate uptake is critical to prevent glutamate-induced damage to oligodendrocytes, and positive regulators of the expression of glutamate transporters have a protective potential, as they contribute to ischaemic tolerance after ischaemic preconditioning. 79 Another set of molecular targets to prevent glutamate insults to oligodendrocytes lie downstream of glutamate receptor activation (see Figure 5). For instance, tetracyclines, which attenuate mitochondrial damage subsequent to insults including excitotoxicity, protect oligodendrocytes and white matter, making these antibiotics promising candidates for the treatment of acute and chronic diseases with oligodendrocyte loss.…”

Section: Mü Ller Cells and Retinopathymentioning

confidence: 99%

Glia: the fulcrum of brain diseases

et al. 2007

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Neuroglia represented by astrocytes, oligodendrocytes and microglial cells provide for numerous vital functions. Glial cells shape the micro-architecture of the brain matter; they are involved in information transfer by virtue of numerous plasmalemmal receptors and channels; they receive synaptic inputs; they are able to release 'glio'transmitters and produce long-range information exchange; finally they act as pluripotent neural precursors and some of them can even act as stem cells, which provide for adult neurogenesis. Recent advances in gliology emphasised the role of glia in the progression and handling of the insults to the nervous system. The brain pathology, is, to a very great extent, a pathology of glia, which, when falling to function properly, determines the degree of neuronal death, the outcome and the scale of neurological deficit. Glial cells are central in providing for brain homeostasis. As a result glia appears as a brain warden, and as such it is intrinsically endowed with two opposite features: it protects the nervous tissue as long as it can, but it also can rapidly assume the guise of a natural killer, trying to eliminate and seal the damaged area, to save the whole at the expense of the part. The sudden emergence of an intellect, and therefore a human being, which materialised only around a million years ago, remains the main mystery for our self-understanding. Similarly, we still do not know by which steps or transitions the human intellect emerged from the animal kingdom and where the fundamental difference between a man and an animal lies. According to the neuronal doctrine, which governs modern neuroscience since the beginning of the twentieth century, 1,2 the neurone is regarded as a basic information processing unit consisting of dendrites and axons with a unidirectional flow of information from the receiving dendrites via the integrating cell body to the terminal branches of the axon. Neuronal networks, connected through synaptic contacts, are generally considered as the substrate of our intellect.The number and size of neural cells increase with the size of the body and of the brain of mammals. This increasing quantity eventually has caused the generation of a new quality, the intellect. Rather amazingly, however, there is a relatively little difference in the morphology and physiology of neurones between humans and beasts; similarly the density of synaptic contacts in the brains of rodents and humans is more or less constant at around 1100-1300 millions/mm 3 . 3 On the contrary, evolution of the nervous system resulted in great changes in the second type of neural cells, the neuroglia. 4 Indeed, phylogenetic advance in brain complexity and capabilities coincided with a remarkable increase in the number of glial cells: in the rodent cortex the glial to neurone ratio is about 0.3 : 1, whereas in humans the same ratio is several times higher being B1.65:1, 5 while the total number of glial cells in the human brain is B10 (or even more) times larger than in lesser mammals. Astrocytes ...

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In VitroIschemic Tolerance Involves Upregulation of Glutamate Transport Partly Mediated by the TACE/ADAM17-Tumor Necrosis Factor-α Pathway

Cited by 117 publications

References 68 publications

TNFR1 Upregulation Mediates Tolerance after Brain Ischemic Preconditioning

TNFR1 Upregulation Mediates Tolerance after Brain Ischemic Preconditioning

Distinct Effector Mechanisms in the Development of Autoimmune Neuropathy versus Diabetes in Nonobese Diabetic Mice

Glia: the fulcrum of brain diseases

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