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Volume 17, Number 23, Issue of December 1, 1997 pp. 9172-9182

Apoptosis-Suppressor Gene bcl-2 Expression after Traumatic Brain Injury in Rats

Received June 18, 1997; revised Aug. 15, 1997; accepted Sept. 22, 1997.

Robert S. B. Clark^{1, 2}, Jun Chen³, Simon C. Watkins⁴, Patrick M. Kochanek^{1, 2}, Minzhi Chen¹, R. Anne Stetler³, J. Eric Loeffert⁴, and Steven H. Graham^{3, 5}

Departments of ¹ Anesthesiology and Critical Care Medicine, ² Pediatrics, ³ Neurology, and ⁴ Cell Biology and Physiology, and the Safar Center for Resuscitation Research and the Brain Trauma Research Center, University of Pittsburgh, Pittsburgh, Pennsylvania 15261, and ⁵ Neurology Service, Department of Veterans Affairs Medical Center, Pittsburgh, Pennsylvania 15261

Neuronal death after experimental traumatic brain injury (TBI) has features of both apoptosis and necrosis. Neurons in the peritrauma cortex, hippocampus, and dentate gyrus are particularly vulnerable. The apoptosis-suppressor gene bcl-2 is induced in brain after ischemia and epilepsy-induced injury and may serve to regulate neuronal death. We studied expression of bcl-2 mRNA and protein after experimental TBI in rats. To determine whether bcl-2 protein expression occurred in cells with evidence of apoptosis, triple-labeling studies were performed using (1) antibody against bcl-2, (2) bis-benzimide dye to examine gross nuclear morphology, and (3) terminal deoxynucleotidyl transferase-mediated biotin-dUTP nick-end labeling (TUNEL) to assess for DNA fragmentation. At 6 and 24 hr, bcl-2 mRNA was induced in ipsilateral peritrauma cortex, hippocampus, and dentate gyrus. By 72 hr the increase in bcl-2 mRNA was detected only in cortex. bcl-2 protein was induced at 8, 24, 72, and 168 hr in ipsilateral cortex and hippocampus. Cells expressing bcl-2 protein included neurons in the peritrauma cortex, hippocampus, hilus, and dentate gyrus. The gross nuclear morphology of neurons expressing bcl-2 appeared normal. Furthermore, biochemical evidence of DNA fragmentation, in a pattern characteristic of either apoptosis or necrosis, was seldom seen in neurons expressing bcl-2 protein (bcl-2 colocalized with TUNEL in 0-2% of TUNEL-positive cells observed). These data suggest that bcl-2 may play an important role in the regulation of neuronal death after TBI, and they support a role for bcl-2 as an inducible neuroprotective gene.

Key words: apoptosis; bcl-2; hippocampus; neuron; rat; traumatic brain injury

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