ENHANCED ENDOGENOUS ANTIOXIDANT ACTIVITY AND INHIBITION OF CEREBRAL VASOSPASM IN RABBITS BY PRETREATMENT WITH A NONTOXIC ENDOTOXIN ANALOG, MONOPHOSPHORYL LIPID-A

Object. Monophosphoryl lipid A (MPL) and diphosphoryl lipid (DPL) are derivatives of the lipopolysaccharide (endotoxin) of Salmonella minnes ota strain R595. Monophosphoryl lipid A is relatively nontoxic and can stimulate the natural defense or immune system. Diphosphoryl lipid is relatively toxic; however, at higher concentrations, it can also stim ulate an immune response. The purpose of the present study was to dete rmine the effects of these endotoxin analogs on cerebral vasospasm aft er the onset of subarachnoid hemorrhage (SAH) in rabbits. Methods. Int rathecal administration of MPL or DPL (5 mu g/kg) was performed immedi ately before and 24 hours after induction of SAH in New Zealand White rabbits. Forty-eight hours after induction of SAH, the animals were ki lled by perfusion fixation for morphometric analyses of vessels or per fused with saline and assayed for superoxide dismutase (SOD) activity. Additional rabbits were administered MPL or DPL and killed 24 hours l ater for assessment of SOD activity; no SAH was induced in these anima ls. Experimental SAH elicited spasm of the basilar arteries in each gr oup. Vasospasm was markedly attenuated in animals treated with MPL (p < 0.01 compared with vehicle-treated animals), but not in animals trea ted with DPL. A substantial reduction in SOD activity in the basilar a rtery accompanied the vasospasm; this loss of activity was significant ly blocked by treatment with MPL, but not DPL. In animals that were no t subjected to experimental SAH, MPL elicited a significant increase i n SOD activity over basal levels, whereas DPL was ineffective. Conclus ions. These data provide evidence of a marked protective effect of the endotoxin analog MPL against vasospasm. Although the mechanism(s) res ponsible for the protective effect of MPL remains to be verified, an e nhancement of basal antioxidant activity and an inhibition of SAM-indu ced loss of this activity are attractive candidates. An MPL-based ther apy could represent a useful addition to current therapies for SAM-ind uced cerebral injury.