Activated phosphorylation of cyclic AMP response element binding protein is associated with preservation of striatal neurons after focal cerebral ischemia in the rat

Phosphorylation of the DNA-binding transcription factor, cyclic AMP respons e element binding protein, has recently been suggested to provide neuroprot ective signals in times of cellular stress. Medium-sized striatal neurons a re among the cells that are most vulnerable to ischemic stress in the brain . In the present study, phosphorylation of cyclic AMP response element bind ing protein was immunohistochemically evaluated in rat striatum in order to examine the ischemic vulnerability of each striatal region from the standp oint of cyclic AMP response element binding protein. Rats were subjected to 90-min focal cerebral ischemia followed by various periods of recirculatio n. Focal ischemia was induced by occlusion of the middle cerebral artery by the intraluminal suture method. Local cerebral blood how measured by the C -14-iodoantipyrine method in the lateral and the medial striatal regions du ring occlusion was 5.0 +/- 7.1 and 42.5 +/- 8.1 ml/100 g/min, respectively. Cerebral blood flow in each region was restored to the control level durin g the recirculation period. The lateral and the medial regions of the stria tum in the sham animals showed hardly any immunoreactivity with the specifi c antibody against phosphorylated cyclic AMP response element binding. prot ein. By contrast, at 3.5 h of recirculation, a number of phosphorylated cyc lic AMP response element binding protein-positive neurons were detected in the medial striatal region on the occluded side, and the increase in the nu mber of immunopositive cells continued until two weeks of recirculation wit h gradual decline. The lateral striatal region on the ischemic side showed only a mild increase in phosphorylated cyclic AMP response element binding protein-positive cells at 3.5 h of recirculation, and the immunoreactivity rapidly disappeared during the subsequent recirculation period. Appreciable increase in immunoreactive cells was also noted in the contralateral stria tum during the early phase of recirculation, and this increase seemed to be associated with spontaneous circling movements of the animals. Cresyl Viol et staining revealed that striatal neurons in the medial region remained in tact until two weeks of recirculation, whereas neurons in the lateral stria tal region soon showed ischemic damage, followed by complete neuronal loss, and evolution of a frank infarct. Immunoreactivity for bcl-2, apoptosis-su ppressive protein, was clearly,detected in many neurons in the medial stria tal region, but no such immunoreactivity was detected in the lateral striat al region. These findings suggest that persistently activated phosphorylation of cycli c AMP response element binding protein in the striatum during post-ischemic recirculation may be closely associated with protection of striatal neuron s on the ischemic side, while it may be associated with spontaneous circlin g movements on the contralateral side. (C) 2000 IBRO. Published by Elsevier Science Ltd. All rights reserved.