A novel inhibitor of inflammatory cytokine production (CNI-1493) reduces rodent post-hemorrhagic vasospasm.
BACKGROUND
Cerebral vasospasm after aneurysmal subarachnoid hemorrhage (SAH) is a devastating complication, yet despite multiple lines of investigation an effective treatment remains lacking. Cytokine-mediated inflammation has been implicated as a causative factor in the development of posthemorrhagic vasospasm. In previous experiments using the rat femoral artery model of vasospasm, we demonstrated that elevated levels of the proinflammatory cytokine interleukin (IL)-6 are present after hemorrhage and that a polyclonal antibody against IL-6 is capable of attenuating experimental vasospasm.


METHODS
In the present study, we tested the ability of a novel selective proinflammatory cytokine inhibitor (CNI-1493) to protect against the occurrence of experimental vasospasm in the same rat femoral artery model. CNI-1493 was administered by injection directly into the blood-filled femoral pouches of animals at the time of their initial surgery (hemorrhage). Control animals received an equal volume of vehicle alone. Animals were killed at 8 days posthemorrhage and degree of vasospasm was assessed by image analysis of artery cross-sectional area. In a separate series of experiments, enzyme-linked immunosorbent assay (ELISA) was used to assess levels of the proinflammatory cytokine IL-6 and the prototypical antiinflammatory cytokine transforming growth factor (TGF)-beta1 after treatment with CNI-1493.


RESULTS
Pretreatment with CNI-1493 provided dose-dependent attenuation of posthemorrhagic vasospasm, with the highest dose (200 microg in 8 microL dH2O) causing complete reversal of vasospasm (vessel cross-sectional area ratio 1.06 +/- 0.04 versus 0.87 +/- 0.06, p < 0.05, one-way analysis of variance). Assessment of cytokine levels by ELISA confirmed the selectivity of CNI-1493 by demonstrating significant reductions in IL-6 levels, but no suppression of TGF-beta1 levels.


CONCLUSIONS
These findings support the conclusion that inflammatory cytokines, in particular IL-6, play an important role in development of vasospasm in the rat femoral artery model. Furthermore, these results suggest that the inhibition of inflammatory cytokines may be an appropriate strategy for the treatment of vasospasm after SAH.
Bowman
George
G
Cerebrovascular Surgery Laboratory, Department of Neurosurgery, Pennsylvania State University College of Medicine - M.S. Hershey Medical Center, Hershey, PA 17033, USA.
Bonneau
Robert H
RH
Chinchilli
Vernon M
VM
Tracey
Kevin J
KJ
Cockroft
Kevin M
KM
D000818:Animals; D000894:Anti-Inflammatory Agents, Non-Steroidal / Q000494:pharmacology*; D004195:Disease Models, Animal; D004305:Dose-Response Relationship, Drug; D006835:Hydrazones / Q000494:pharmacology*; D007269:Injections, Intra-Arterial; D015850:Interleukin-6 / Q000378:metabolism; D008297:Male; D051381:Rats; D017207:Rats, Sprague-Dawley; D013345:Subarachnoid Hemorrhage / Q000276:immunology*; D053773:Transforming Growth Factor beta1 / Q000378:metabolism; D020301:Vasospasm, Intracranial / Q000276:immunology*; D000093242:Interleukin-6 Inhibitors; D000813:Anilides; D006146:Guanidines
D000894:Anti-Inflammatory Agents, Non-Steroidal; D006835:Hydrazones; D015850:Interleukin-6; D053773:Transforming Growth Factor beta1; D000093242:Interleukin-6 Inhibitors; C097256:semapimod; D000813:Anilides; D006146:Guanidines