NEURONAL DAMAGE AFTER REPEATED 5 MINUTES OF ISCHEMIA IN THE GERBIL IS PRECEDED BY PROLONGED IMPAIRMENT OF PROTEIN-METABOLISM

The effect of single or repeated episodes of cerebral ischemia on protein biosynthesis and neuronal injury was studied in halothane-anesthetized gerbils by autoradiography of [C-14]leucine incorporation into brain proteins and light microscopy. For quantification of the protein synthesis rate, the steady-state precursor pool distribution space for labeled and unlabeled free leucine was determined by clamping the specific activity of [C-14]leucine in plasma, and by measuring free tissue leucine in samples taken from various parts of the brain. Control values of protein synthesis were 14.6 +/- 2.2, 5.8 +/-2.3, 14.2 +/- 3.1. and 10.0 +/- 3.8 nmol g-1 min-1 (means +/- SD) in the frontal cortex, striatum, CA1 sector, and thalamus, respectively. Following a single episode of 5 or 15 of ischemia, protein synthesis recovered to normal in all brain regions except the CA1 sector, where it returned to only 50% of control after 6 h and to less than 20% after 3 days of recirculation. After three episodes of 5 min of ischemia spaced at 1 h intervals, protein synthesis remained severely suppressed in all brain regions after both 6 h and 3 days of recirculation. Inhibition of protein synthesis after 6 h predicted histological injury after 3 days of recirculation. In animals submitted to a single episode of 5 or 15 min of ischemia, histological damage was restricted to the CA1 sector but injury occurred throughout the brain after three episodes of 5 min of ischemia. These observations demonstrate that persisting inhibition of protein synthesis following cerebral ischemia is an early manifestation of neuronal injury. Prevention of neuronal injury requires restoration of a normal protein synthesis rate.