Microdialysis studies of the role of chemical agents in secondary damage upon spinal cord injury

Assorted microdialysis studies of the roles endogenous chemical agents may play in secondary damage upon spinal cord injury (SCI) are described. Issues addressed include the concentrations reached upon injury, mechanisms of release upon injury, and effects of drugs on injury-elicited increases in glutamate concentrations. An important question in identifying an agent of secondary damage upon central nervous system (CNS) trauma is not simply whether the substance is released upon injury, but whether it reaches harmful levels. To resolve this requires establishing the concentration attained and then determining whether administering that level damages neurons. To make microdialysis measurements of amino acids in the CNS more quantitative, we characterized the effects of insertion of a microdialysis fiber on leakage of glutamate from the circulation and explored the effects of depletion by microdialysis on release caused by SCI. Very high glutamate concentrations were found around the fiber for several hours after fiber insertion and 2 days later, and there was substantial leakage of alpha-aminoisobutyric acid from the circulation into the dialysis zone for several hours after fiber insertion. Glutamate concentrations reached upon SCI under nondepleting conditions were similar to those estimated earlier under depleting conditions. Mg2+ release was detectable when microdialysis probes were perfused with Mg2+-free fluid, but not when the concentrations in the perfusing fluid approximated those in the interstitial space. It is concluded (1) that insertion of microdialysis probes into CNS tissue can cause long-lasting leakage of amino acids from the circulation into the space around the fiber, (2) that this leakage can obscure concentration changes that otherwise occur, and (3) that depletion of substances in the fluid around the fiber may cause increases in concentration to be observed that do not normally happen. We also describe demonstrations that administration of methylprednisolone and dihydrokainic acid diminish increases in glutamate concentrations caused by SCI, showing that microdialysis can be used to explore effects of drugs on actions of damaging substances.