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(Stroke. 2004;35:1186.)
© 2004 American Heart Association, Inc.

Original Contributions

Delayed Treatment of Ischemia/Reperfusion Brain Injury

Extended Therapeutic Window with the Proteosome Inhibitor MLN519

Anthony J. Williams, PhD; Rossana Berti, PhD; Jitendra R. Dave, PhD; Peter J. Elliot, PhD; Julian Adams, PhD Frank C. Tortella, PhD

From Walter Reed Army Institute of Research (A.J.R., R.B., J.R.D., F.C.T.), Silver Spring, Md; Combinato RX Inc (P.J.E.), Boston, Mass; Millenium Pharmaceuticals (J.A.), Cambridge, Mass.

Correspondence to Anthony J. Williams, Department of Neuropharmacology and Molecular Biology, Division of Neurosciences, Walter Reed Army Institute of Research, Silver Spring, MD 20910. E-mail anthony.williams{at}na.amedd.army.mil

Background and Purpose— Clinical development of novel neuroprotection therapies for the treatment of brain injury has been unsuccessful. One critical limitation is the lack of a viable therapeutic treatment window (TW). In this study, we evaluated the neuroprotection TW for the proteosome inhibitor MLN519 after ischemia/reperfusion brain injury in rats as related to its antiinflammatory mechanism.

Methods— Male Sprague-Dawley rats were subjected to 2 hours of middle cerebral artery occlusion (MCAo), followed by 70 hours of reperfusion and recovery. MLN519 was administered after injury (starting 6 to 12 hours after MCAo) to evaluate the full TW. Brain infarction, neuronal degeneration, neurological recovery, leukocyte infiltration, and inflammatory gene mRNA levels were assessed.

Results— Core infarct volume in vehicle-treated rats (216±25 mm³) was reduced with delayed MLN519 treatments of 6, 8, or 10 hours after injury (45±13, 86±28, and 150±27 mm³, respectively, P<0.05) and was associated with reductions in neuronal and axonal degeneration. MLN519-treated rats had reduced brain mRNA levels of TNF- (46%, P<0.05), ICAM-1 (58%, P<0.05), IL-6 (58%, P<0.05), and E-selectin (72%, P<0.05) at 24 hours after injury. Furthermore, MLN519 treatment reduced leukocyte infiltration by 32% to 80% (P<0.05) in ischemic brain regions.

Conclusions— Neuroprotection treatment with MLN519 provides an extended TW of up to 10 hours after ischemia/reperfusion brain injury, in part by attenuating the inflammatory response. As such, the delayed onset of brain inflammation after an ischemic injury offers a prime target for extending the neuroprotective TW with compounds such as MLN519, used either alone or possibly as an adjunctive therapy with thrombolytic agents.

Key Words: middle cerebral artery occlusion • inflammation • brain injuries • proteasome

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