The role of Akt signaling in oxidative stress mediates NF-kappaB activation in mild transient focal cerebral ischemia.

Abstract

Reactive oxygen species, derived from hypoxia and reoxygenation during transient focal cerebral ischemia (tFCI), are associated with the signaling pathway that leads to neuronal survival or death, depending on the severity and duration of the ischemic insult. The Akt survival signaling pathway is regulated by oxidative stress and is implicated in activation of nuclear factor-kappaB (NF-kappaB). Mild cerebral ischemia in mice was used to induce increased levels of Akt phosphorylation in the cortex and striatum. To clarify the role of Akt activation by NF-kappaB after tFCI, we injected the specific Akt inhibitor IV that inhibits Akt phosphorylation/activation. Inhibition of Akt phosphorylation induced decreases in sequential NF-kappaB signaling after 30 mins of tFCI at 1 h. Furthermore, the downstream survival signals of the Akt pathway were also decreased. Akt inhibitor IV increased ischemic infarct volume and apoptotic-related DNA fragmentation. Superoxide production in the ischemic brains of mice pretreated with the Akt inhibitor was higher than in vehicle-treated mice. In addition, those pretreated mice showed a reduction of approximately 33% in copper/zinc-superoxide dismutase expression. We propose that Akt signaling exerts its neuroprotective role by NF-kappaB activation in oxidative cerebral ischemia in mice.

• Authors: Yun Seon Song, Purnima Narasimhan, Gab Seok Kim, Joo Eun Jung, Eun-Hee Park, Pak H Chan
• Journal: Journal of cerebral blood flow and metabolism : official journal of the International Society of Cerebral Blood Flow and Metabolism (J Cereb Blood Flow Metab) Vol. 28 Issue 12 Pg. 1917-26 (Dec 2008) ISSN: 1559-7016 [Electronic] United States
• PMID: 18628779 (Publication Type: Journal Article, Research Support, N.I.H., Extramural, Research Support, Non-U.S. Gov't)

Chemical References

• NF-kappa B
• Superoxides
• Cyclooxygenase 2
• Proto-Oncogene Proteins c-akt

Topics

• Animals
• Apoptosis
• Blotting, Western
• Cyclooxygenase 2 (biosynthesis)
• DNA Fragmentation
• Disease Models, Animal
• Ischemic Attack, Transient (enzymology, metabolism, pathology)
• Male
• Mice
• Mice, Inbred Strains
• NF-kappa B (metabolism)
• Oxidative Stress
• Phosphorylation
• Proto-Oncogene Proteins c-akt (antagonists & inhibitors, metabolism, physiology)
• Severity of Illness Index
• Signal Transduction
• Superoxides (metabolism)