Abstract
The molecular mechanism underlying the selective vulnerability of neurons to oxidative damage caused by ischemia—reperfusion (I/R) injury remains unknown. We sought to determine the role of NADPH oxidase 1 (Nox1) in cerebral I/R-induced brain injury and survival of newborn cells in the ischemic injured region. Male Wistar rats were subjected to 90 min middle cerebral artery occlusion (MCAO) followed by reperfusion. After reperfusion, infarction size, level of superoxide and 8-hydroxy-2′-deoxyguanosine (8-oxo-2dG), and Nox1 immunoreactivity were determined. RNAi-mediated knockdown of Nox1 was used to investigate the role of Nox1 in I/R-induced oxidative damage, neuronal death, motor function recovery, and ischemic neurogenesis. After I/R, Nox1 expression and 8-oxo-2dG immunoreactivity was increased in cortical neurons of the peri-infarct regions. Both infarction size and neuronal death in I/R injury were significantly reduced by adeno-associated virus (AAV)-mediated transduction of Nox1 short hairpin RNA (shRNA). AAV-mediated Nox1 knockdown enhanced functional recovery after MCAO. The level of survival and differentiation of newborn cells in the peri-infarct regions were increased by Nox1 inhibition. Our data suggest that Nox-1 may be responsible for oxidative damage to DNA, subsequent cortical neuronal degeneration, functional recovery, and regulation of ischemic neurogenesis in the peri-infarct regions after stroke.
Highlights
Cerebral ischemia occurs because of a local reduction or an arrest of blood supply, and can lead to neuronal cell death in the ischemic region
We found that the expression of Ki67 and uptake of BrdU was regulated and colocalized the ipsilateral subventricular zone (SVZ) and the peri-infarct regions of middle cerebral artery occlusion (MCAO) rats treated with scb short hairpin RNA (shRNA)/associated virus (AAV) or NADPH oxidase 1 (Nox1) shRNA/AAV particles before MCAO (Fig. 6a and c)
We showed that Nox1 mediates oxidative stress, neuronal death, and activation of astrocytes in rats with MCAO
Summary
Cerebral ischemia occurs because of a local reduction or an arrest of blood supply, and can lead to neuronal cell death in the ischemic region. Focal cerebral ischemia is the most common subtype of clinical stroke. Since the establishment of middle cerebral artery occlusion (MCAO)reperfusion, in rats as an animal model of focal ischemia [1], this model has been widely used to study injury and recovery after stroke [2]. The pathophysiological mechanisms of the ischemia —reperfusion (I/R) injury are complex. Cell death progresses within minutes in the ischemic. PLOS ONE | DOI:10.1371/journal.pone.0116814 January 24, 2015
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