AGE, AS WELL AS CELL TURNOVER KINETICS, REGULATES BRAIN-GUT REPAIR

The prototypical brain/gut peptide cholecystokinin (CCK) has been used to assess brain and gut repair kinetics following cytotoxic injury in the rat. Studies addressed the effect of repetitive injury as well as aging. Injury was induced by one of the two alkylating agents, one ac tive in the brain, the other systematically. Consistently the response s differ between brain and intestine. Total RNA falls (as predicted) i n the intestine (control 1.5 +/- 1.4 versus cytotoxic 0.21 +/- 0.06 tR NA mg/organ, P less-than-or-equal-to 0.0001), but rises (unexpectedly) in the brain (control 0.79 +/- 0.04 versus cytotoxic 1.02 +/- 0.03 tR NA mg/organ, P less-than-or-equal-to 0.001). CCK mRNA concentration fa lls in the brain (predicted) (control 27 +/- 1 versus cytotoxic 11 +/- 1 pg CCK mRNA/mug tRNA, P less-than-or-equal-to 0.001). but rises in the intestine (unexpectedly) (control 0.18 +/- 0.02 versus cytotoxic 0 .3 +/- 0.04 pg CCK mRNA/mug tRNA, P less-than-or-equal-to 0.001). CCK peptides do not change in the brain (control 39 +/- 4 versus cytotoxic 34 +/- 4 nmol/g, P less-than-or-equal-to NS), but rise (unexpectedly) in the intestine (control 43 +/- 4 versus cytotoxic 250 +/- 27 nmol/g , P less-than-or-equal-to 0.001). We ascribe these observations to dif fering brain/gut cell turnover kinetics. These data indicate that a re bound phenomenon occurs during gut recovery from cytotoxic injury. We additionally show a differential age-related response to cytotoxic inj ury. Younger animals tolerated the injury better than old ones (mortal ity: young 27% (3/11) versus old 66% (8/12), P less-than-or-equal-to 0 .001). Additionally, intestinal recovery is more rapid in younger anim als. These data suggest that with increasing age, chemotherapeutic dos ages may need to be modulated. It is additionally possible that clinic ally applicable algorithms may be developed using our animal model.