Enhanced endogenous antioxidant activity and inhibition of cerebral vasospasm in rabbits by pretreatment with a nontoxic endotoxin analog, monophosphoryl lipid A.
OBJECTIVE
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 microg/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.
Toyoda
T
T
Department of Neurological Surgery, University of Virginia Health Sciences Center, Charlottesville 22908, USA.
Kwan
A L
AL
Bavbek
M
M
Kassell
N F
NF
Wanebo
J E
JE
Lee
K S
KS
D000276:Adjuvants, Immunologic / Q000008:administration & dosage / Q000627:therapeutic use*; D000818:Animals; D000975:Antioxidants / Q000008:administration & dosage / Q000627:therapeutic use*; D001488:Basilar Artery / Q000187:drug effects / Q000201:enzymology / Q000473:pathology; D004789:Enzyme Activation; D007278:Injections, Spinal; D002546:Ischemic Attack, Transient / Q000201:enzymology / Q000473:pathology / Q000517:prevention & control*; D008050:Lipid A / Q000008:administration & dosage / Q000031:analogs & derivatives* / Q000276:immunology / Q000627:therapeutic use; D014677:Pharmaceutical Vehicles; D011817:Rabbits; D012475:Salmonella / Q000145:classification; D013345:Subarachnoid Hemorrhage / Q000150:complications; D013482:Superoxide Dismutase / Q000032:analysis / Q000187:drug effects
D000276:Adjuvants, Immunologic; D000975:Antioxidants; D008050:Lipid A; D014677:Pharmaceutical Vehicles; C049596:diphosphoryl lipid A; D013482:Superoxide Dismutase; C048436:monophosphoryl lipid A