Enhanced endogenous antioxidant activity and inhibition of cerebral vasospasm in rabbits by pretreatment with a nontoxic endotoxin analog, monophosphoryl lipid A

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Object. Monophosphoryl lipid A (MPL) and diphosphoryl lipid (DPL) are derivatives of the lipopolysaccharide (endotoxin) of Salmonella minnesota 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 stimulate an immune response. The purpose of the present study was to determine the effects of these endotoxin analogs on cerebral vasospasm after the onset of subarachnoid hemorrhage (SAH) in rabbits.

Methods. Intrathecal administration of MPL or DPL (5 µg/kg) was performed immediately before and 24 hours after induction of SAH in New Zealand White rabbits. Forty-eight hours after induction of SAH, the animals were killed by perfusion fixation for morphometric analyses of vessels or perfused with saline and assayed for superoxide dismutase (SOD) activity. Additional rabbits were administered MPL or DPL and killed 24 hours later for assessment of SOD activity; no SAH was induced in these animals.

Experimental SAH elicited spasm of the basilar arteries in each group. Vasospasm was markedly attenuated in animals treated with MPL (p < 0.01 compared with vehicle-treated animals), but not in animals treated with DPL. A substantial reduction in SOD activity in the basilar artery accompanied the vasospasm; this loss of activity was significantly blocked by treatment with MPL, but not DPL. In animals that were not subjected to experimental SAH, MPL elicited a significant increase in SOD activity over basal levels, whereas DPL was ineffective.

Conclusions. These data provide evidence of a marked protective effect of the endotoxin analog MPL against vasospasm. Although the mechanism(s) responsible for the protective effect of MPL remains to be verified, an enhancement of basal antioxidant activity and an inhibition of SAH-induced loss of this activity are attractive candidates. An MPL-based therapy could represent a useful addition to current therapies for SAH-induced cerebral injury.

Article Information

Address reprint requests to: Kevin S. Lee, Ph.D., Department of Neurological Surgery, Box 420, Health Sciences Center, University of Virginia, Charlottesville, Virginia 22908. email: ksl3h@virginia.edu.

© AANS, except where prohibited by US copyright law.

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Figures

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    Photomicrographs showing the effect of MPL on basilar arteries. Basilar artery cross sections are shown for animals from the following groups: SAH only (A), SAH plus vehicle (B), and SAH plus MPL (C). Bar = 250 µm.

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    Bar graph displaying the effect of endotoxin analogs on cross-sectional areas of basilar arteries. The average luminal area (mean ± SEM) of cross sections of rabbit basilar arteries is shown for each group of animals. The degree of vasospasm was reduced significantly in the group treated with 5 µg/kg MPL (SAH plus MPL) (p < 0.01, for comparisons with the vehicle-treated group [SAH plus vehicle] using ANOVA with Fisher's protected LSD test [F4,35 = 18.739]). DPL = SAH plus DPL group.

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    Left: Bar graph showing the effects of endotoxin analogs on basal SOD activity 24 hours after intracisternal drug administration. The SOD activity was elevated 5.9-fold (p < 0.05 compared with vehicle) in rabbits receiving 5 µg/kg MPL. The increase in the DPL-treated group was only slight (1.8-fold) and nonsignificant. Values are expressed as the mean SOD activity ± SEM. Significance was determined by ANOVA with Fisher's protected LSD test (F2,21 = 3.914). There were eight rabbits in each group. Right: Bar graph showing the effects of endotoxin analogs on SOD activity 48 hours after induction of SAH. The level of SOD activity was markedly reduced 48 hours after SAH (1/166-fold, p < 0.01 using the Mann—Whitney U-test between two vehicle groups). Treatment with 5 µg/kg MPL (SAH plus MPL group) significantly enhanced SOD activity (p < 0.05 using ANOVA with Fisher's protected LSD test (F2,15 = 3.291). No elevation in the DPL-treated (SAH plus DPL) group was observed. There were six animals in each group.

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