Uncoupling protein-2 prevents neuronal death and diminishes brain dysfunction after stroke and brain trauma

Mattiasson, Gustav; Shamloo, Mehrdad; Gidö, Gunilla; Mathi, Kavitha; Tomasevic, Gregor; Yi, Sai-Li; Warden, Craig H; Castilho, Roger F.; Melcher, Thorsten; Gonzalez-Zulueta, Mirella; Nikolich, Karoly; Wieloch, Tadeusz

doi:10.1038/nm903

Cited by 470 publications

(424 citation statements)

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“…A possible causal relationship between redox status and cytokine production has been previously suggested in that increased basal GSH levels and SOD activity may result from high NGF levels (Guegan et al, 1998(Guegan et al, , 1999de Bilbao et al, 2004;Arsenijevic et al, 2006). Consistent with their possible role in neuroprotection (Guegan et al, 1999;Mattiasson et al, 2003), the differences in GSH, UCP2 mRNA and NGF levels persisted between infected and non-infected mice after MCAO. In the absence of a specific antibody for brain UCP2, it was not possible to assess the impact of UCP2 mRNA changes on protein levels.…”

Section: Discussionmentioning

confidence: 56%

“…In the absence of a specific antibody for brain UCP2, it was not possible to assess the impact of UCP2 mRNA changes on protein levels. However, previous data using UCP2 transgenic and UCP2 KO mice have shown that UCP2 plays a central role in brain neuroprotection following ischemia (Mattiasson et al, 2003;de Bilbao et al, 2004). …”

Section: Discussionmentioning

confidence: 96%

“…Although both animal models and clinical studies showed that infections promote neuronal death following cerebral ischemic injury (Sacco, 2001;Emsley and Tyrrell, 2002), activation of the immune system can also result in neuroprotection (Bordet et al, 2000). In fact, the effect of infection on ischemic damage may largely depend on the regulation of reactive oxygen species by pro-inflammatory and anti-inflammatory cytokines as well as by the main antioxidant state regulators, namely superoxide dismutase (SOD) (Guegan et al, 1998;Murakami et al, 1998), glutathione (GSH) (Nicholls and Budd, 2000;Schulz et al, 2000;Droge, 2002), uncoupling protein-2 (UCP2) (Arsenijevic et al, 2000b;Mattiasson et al, 2003) and nerve growth factor (NGF) (Brodie, 1996;Guegan et al, 1999;Villoslada et al, 2000). In addition, the newly described suppressor of cytokine signaling (SOCS) proteins are induced in peripheral and central models of inflammation (Lebel et al, 2000;Bates et al, 2001;Larsen and Ropke, 2002;Wang and Campbell, 2002;Huang et al, 2003;Park et al, 2003;Jo et al, 2005).…”

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confidence: 99%

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Decreased infarct size after focal cerebral ischemia in mice chronically infected with Toxoplasma gondii

et al. 2007

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Abstract-To determine whether Toxoplasma gondii infection could modify biological phenomena associated with brain ischemia, we investigated the effect of permanent middle cerebral artery occlusion (MCAO) on neuronal survival, inflammation and redox state in chronically infected mice. Infected animals showed a 40% to 50% decrease of infarct size compared with non-infected littermates 1, 4 and 14 days after MCAO. The resistance of infected mice may be associated with increased basal levels of anti-inflammatory cytokines and/or a marked reduction of the MCAO-related brain induction of two pro-inflammatory cytokines, tumor necrosis factor-alpha and interferon-gamma (IFN␥). In addition, potential anti-inflammatory/neuroprotective factors such as nerve growth factor, suppressor of cytokine signaling-3, superoxide dismutase activity, uncoupling protein-2 and glutathione (GSH) were upregulated in the brain of infected mice. Consistent with a role of GSH in central cytokine regulation, GSH depletion by diethyl maleate inhibited Toxoplasma gondii lesion resistance by increasing the proinflammatory cytokine IFN␥ brain levels. Overall, these findings indicate that chronic toxoplasmosis decisively influences both the inflammatory molecular events and outcome of cerebral ischemia.

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Section: Discussionmentioning

confidence: 56%

Section: Discussionmentioning

confidence: 96%

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confidence: 99%

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Decreased infarct size after focal cerebral ischemia in mice chronically infected with Toxoplasma gondii

et al. 2007

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“…Altered AMPA receptor subunit expression is debated as a factor in ischemic preconditioning (Sommer and Kiessling, 2002;Tanaka et al, 2002;Yamaguchi et al, 1999), but some evidence indicates that, in apparent contrast to the gerbil, preconditioning in the rat may increase expression of the Ca 2 þ impermeable, rapidly desensitizing GluR2 subunit (Alsbo et al, 2001;Kjøller and Diemer, 2000). Recent results have associated increased expression of uncoupling protein-2 (UCP-2) with neuroprotection (Diano et al, 2003;Mattiasson et al, 2003), but its potential impact on ischemic depolarization per se is unclear. Established global ischemia models are characterized by very low residual flow during occlusion (Kågströ m et al, 1983;Pulsinelli et al, 1982), but perfusion effects of preconditioning are also possible.…”

Section: Changes In Depolarization Kinetics Associated With Preconditmentioning

confidence: 99%

Protective Preconditioning by Transient Global Ischemia in the Rat: Components of Delayed Injury Progression and Lasting Protection Distinguished by Comparisons of Depolarization Thresholds for Cell Loss at Long Survival Times

Ueda

Nowak²

2005

J Cereb Blood Flow Metab

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Robust ischemic preconditioning has been shown in rodent brain, but there are concerns regarding the persistence of neuron protection. This issue was examined in rat hippocampus following 4-vessel occlusion (4-VO) ischemia, using DC shifts characteristic of ischemic depolarization to reproducibly define insult severity. Preconditioning ischemia producing 2 to 3.5 mins depolarization was followed at intervals of 2, 5, or 7 days by test insults of varied duration, after which CA1 counts were obtained at 1, 2, 4, or 12 weeks. Neuron loss in naive animals increased with depolarization time longer than 4 mins regardless of postischemic survival interval. Preconditioning 2, 5, or 7 days before test insults prolonged the injury threshold evaluated at 1 week survival to 15, 9, or 6 mins, respectively, showing robust protection and a rapid decay of the protected state. However, by 2 weeks survival after preconditioning at a 2-day interval, the injury threshold dramatically regressed from 15 to 9 mins. Thereafter protection remained relatively stable through 1 month, but slight progression of neuron injury was evident at 3 months. Inflammatory responses were seen in both naive and preconditioned hippocampi throughout this interval, appropriate to the extent of neuron injury. These studies show distinct components of transient and lasting protection after ischemic preconditioning. Finally, it was found that ischemic depolarization was delayed by approximately 1 min in optimally preconditioned rat hippocampus, in contrast to previous results in the gerbil, identifying one specific mechanism by which insult severity is reduced in this model.

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“…As mitochondrial ROS production is dependent on the mitochondrial potential, mild uncoupling could effectively decrease ROS generation. Therefore, UCP2 activation by ROS could be considered as a protective feed-back loop, as suggested by studies in neurons or cardiomyocytes [22,23].…”

Section: Introductionmentioning

confidence: 99%

Increasing uncoupling protein-2 in pancreatic beta cells does not alter glucose-induced insulin secretion but decreases production of reactive oxygen species

Produit-Zengaffinen¹,

Davis-Lameloise²,

Perreten³

et al. 2006

Diabetologia

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Aims/hypothesis Levels of uncoupling protein-2 (UCP2) are regulated in the pancreatic beta cells and an increase in the protein level has been associated with mitochondrial uncoupling and alteration in glucose-stimulated insulin secretion. However, it is not clear whether an increase in uncoupling protein-2 per se induces mitochondrial uncoupling and affects ATP generation and insulin secretion. Materials and methods Transgenic mice with beta cell-specific overexpression of the human UCP2 gene and INS-1 cells with doxycycline-inducible overproduction of the protein were generated and the consequences of increased levels of UCP2 on glucose-induced insulin secretion and on parameters reflecting mitochondrial uncoupling were determined.Results In transgenic mice, an increase in beta cell UCP2 protein concentration did not significantly modify plasma glucose and insulin levels. Glucose-induced insulin secretion and elevation in the ATP/ADP ratio were unaltered by an increase in UCP2 level. In INS-1 cells, a similar increase in UCP2 level did not modify glucose-induced insulin secretion, cytosolic ATP and ATP/ADP ratio, or glucose oxidation. Increased levels of UCP2 did not modify the mitochondrial membrane potential and oxygen consumption. Increased UCP2 levels decreased cytokine-induced production of reactive oxygen species. Conclusion/interpretation The results obtained in transgenic mice and in the beta cell line do not support the hypothesis that an increase in UCP2 protein per se uncouples the mitochondria and decreases glucose-induced insulin secretion. In contrast, the observation that increased UCP2 levels decrease cytokine-induced production of reactive oxygen species indicates a potential protective effect of the protein on beta cells, as observed in other cell types.

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Uncoupling protein-2 prevents neuronal death and diminishes brain dysfunction after stroke and brain trauma

Cited by 470 publications

References 48 publications

Decreased infarct size after focal cerebral ischemia in mice chronically infected with Toxoplasma gondii

Decreased infarct size after focal cerebral ischemia in mice chronically infected with Toxoplasma gondii

Protective Preconditioning by Transient Global Ischemia in the Rat: Components of Delayed Injury Progression and Lasting Protection Distinguished by Comparisons of Depolarization Thresholds for Cell Loss at Long Survival Times

Increasing uncoupling protein-2 in pancreatic beta cells does not alter glucose-induced insulin secretion but decreases production of reactive oxygen species

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