Response of the brain to oligemia: gene expression, c-Fos, and Nrf2 localization

Oligemia is blood flow reduction without acute tissue damage that occurs in shock, migraine, and stroke penumbra. We developed a mouse model of oligemia by lowering mean arterial pressure to 30-40 mm Hg, resulting in a 50% reduction in cerebral blood flow as measured by laser Doppler, and reperfusing the blood after 30 min. Control experiments included anesthesia-only and surgery without blood withdrawal. Using immunohistochemistry, we localized the transcription factors Nrf2, which regulates expression of antioxidant and detoxification protein, and c-Fos, a marker of neuronal activation. Nrf2 was found only in oligemia mice and was localized in neurons of the cingulate cortex and cerebellar Purkinje cells. By contrast, c-Fos was found widely expressed in both groups and was localized in neurons in regions associated with response to stress, immunomodulation, and fluid homeostasis, including the periaqueductal gray and periventricular nucleus. These data indicate that c-Fos expression occurs as a result of surgical stress, but Nrf-2 upregulation is specific to oligemia. The CLONTECH Atlas 1.2 Mouse Array was used to assess genes that were up or down-regulated in oligemia versus surgery controls. Of 1176 genes, 29 differed between oligemia and surgery groups. Upregulation of oxidative stress induced (OSI) protein, heat shock protein (HSP) 84 and transthyretin (TTR) precursor in the oligemia group was confirmed with RT-PCR. The expression of HSP 84, transthyretin precursor, and OSI genes adds further evidence that oligemia induces an oxidative stress response in the brain.