Journal
NEUROSCIENCE
Volume 104, Issue 4, Pages 947-955Publisher
PERGAMON-ELSEVIER SCIENCE LTD
DOI: 10.1016/S0306-4522(01)00125-7
Keywords
cerebral protein synthesis; ATP bioluminescence; immediate-early gene; heat-shock gene; p53-activated gene; caspase-3
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The evolution of brain injury was examined in mice subjected to focal cerebral ischemia as induced by 30 min of intraluminar thread occlusion of the middle cerebral artery. followed by 3 h to 3 days of reperfusion. Metabolic dysfunctions were studied by IH-leucine autoradiography for the measurement of cerebral protein synthesis and by regional ATP bioluminescent imaging. Metabolic changes were compared with responses of the genes c-fos, c-jun, heat-shock protein gene (hsp)72, p53-activated gene (pag)608 and caspase-3, which were investigated by in situ hybridization histochemistry and immunocytochemistry, and correlated with the degree of DNA fragmentation, as assessed by the terminal TdT-mediated dUTP-biotin nick end labeling method. Intraluminar thread occlusion led to a reproducible reduction of cerebral laser Doppler flow to 20-30% of control. Thread withdrawal was followed by a short-lasting postischemic hyperperfusion to approximately 120%. In non-ischemic control animals, fractional protein synthesis values of 0.81 +/- 0.26 and 0.94 +/- 0.23 were obtained. Thread occlusion resulted in a suppression of protein synthesis throughout the territory of the middle cerebral artery after 3 h of reperfusion (0.04 +/- 0.08 in caudate-putamen and 0.14 +/- 0.19 in somatosensory cortex. P < 0.05). Protein synthesis partly recovered in the cortex after 24 h and 3 days (0.71 +/- 0.40 and 0.63 +/- 0.26. respectively). but remained suppressed in the caudate-putamen (0.14 +/- 0.22 and 0.28 +/-0.28). Regional ATP levels did not show any major disturbances at the reperfusion times examined. Thread occlusion resulted in a transient increase of c-fos mRNA levels in ischemic and non-ischemic parts of the cortex and caudate-putamen at 3 It after ischemia, which suggests that spreading depressions were elicited in the tissue. At the same time. c-jun and hsp72 mRNAs were elevated only in ischemic, brain areas showing inhibition of protein synthesis. C-fos and c-jun responses completely disappeared within 24 h of reperfusion. Hsp72 mRNA levels remained elevated in the cortex after 24 h, but decreased to basal values in the caudate-putamen. Twenty-four hours after reperfusion, pag608 and caspase-3 mRNA levels increased in the caudate-putamen, where protein synthesis rates were still reduced. and remained elevated even after 3 days. However, pag608 and caspase-3 mRNA levels did not increase in the cortex. where protein synthesis recovered. After 24 h and 3 days, functionally active p20 fragment of caspase-3 was detected in the caudate-putamen, closely associated with the appearance of DNA fragmented cells. Neither activated caspase-3 nor DNA fragmentation were noticed in the cortex. In summary, the suppression of protein synthesis is reversible in the ischemia-resistant cortex following 30 min of thread occlusion in mice, but persists in the vulnerable caudate-putamen, In the caudate-putamen, apoptotic programs are induced, closely in parallel with the manifestation of delayed cell death. Thus, the recovery of protein synthesis may be a major factor influencing tissue survival after transient focal ischemia. (C) 2001 IBRO. Published by Elsevier Science Ltd. All rights reserved.
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