Early onset of lipid peroxidation after human traumatic brain injury: A fatal limitation for the free radical scavenger pharmacological therapy?

Background: On the basis of the contradiction between data on experimental head trauma showing oxidative stress-mediated cerebral tissue damage and fa ilure of the majority of clinical trials using free radical scavenger drugs , we monitored the time-course changes of malondialdehyde (MDA, an index of cell lipid peroxidation), ascorbate, and dephosphorylated ATP catabolites in cerebrospinal fluid (CSF) of traumatic brain-injured patients. Methods: CSF samples were obtained from 20 consecutive patients suffering f rom severe brain injury. All patients were comatose, with a Glasgow Coma Sc ale on admission of 6 +/-1. The first CSF sample for each patient was colle cted within a mean value of 2.95 hours from trauma (SD=1.98), after the ins ertion of a ventriculostomy catheter for the continuous monitoring of intra cranial pressure. During the next 48 hours, CSF was withdrawn from each pat ient once every 6 hours. All samples were analyzed by an ion-pairing high-p erformance liquid chromatographic method for the simultaneous determination of MDA, ascorbic acid, hypoxanthine, xanthine, uric acid, inosine, and ade nosine. Results: In comparison with values recorded in 10 herniated-lumbar-disk, no ncerebral control patients, data showed that all CSF samples of brain-injur ed patients had high values (0.226 mu moL/1,; SD=0.196) of MDA (undetectabl e in samples of control patients) and decreased ascorbate levels (96.25 mu mol/L; SD=31.74), already at the time of first withdrawal at the time of ho spital admission. MDA was almost constant in the next two withdrawals and t ended to decrease thereafter, although 48 hours after hospital admission, a mean level of 0.072 mu mol/L CSF (SD=0.026) was still recorded. The ascorb ate level was normalized 42 hours after hospital admission. Changes in the CSF values of ATP degradation products (oxypurines and nucleosides) suggest ed a dramatic alteration of neuronal energy metabolism after traumatic brai n injury. Conclusions: On the whole, these data demonstrate the early onset of oxygen radical-mediated oxidative stress, proposing a valid explanation for the f ailure of clinical trials based on the administration of oxygen free radica l scavenger drugs and suggesting a possible rationale for testing the effic acy of lipid peroxidation "chain breakers" in future clinical trials.