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

Abstract

Whereas uncoupling protein 1 (UCP-1) is clearly involved in thermogenesis, the role of UCP-2 is less clear. Using hybridization, cloning techniques and cDNA array analysis to identify inducible neuroprotective genes, we found that neuronal survival correlates with increased expression of Ucp2. In mice overexpressing human UCP-2, brain damage was diminished after experimental stroke and traumatic brain injury, and neurological recovery was enhanced. In cultured cortical neurons, UCP-2 reduced cell death and inhibited caspase-3 activation induced by oxygen and glucose deprivation. Mild mitochondrial uncoupling by 2,4-dinitrophenol (DNP) reduced neuronal death, and UCP-2 activity was enhanced by palmitic acid in isolated mitochondria. Also in isolated mitochondria, UCP-2 shifted the release of reactive oxygen species from the mitochondrial matrix to the extramitochondrial space. We propose that UCP-2 is an inducible protein that is neuroprotective by activating cellular redox signaling or by inducing mild mitochondrial uncoupling that prevents the release of apoptogenic proteins.

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

“…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.…”

“…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). …”

“…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).…”

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

“…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.…”

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

“…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].…”