Published Online
on April 1, 2004

A more recent version of this article appeared on May 1, 2004

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Submitted on November 6, 2003
Revised on January 23, 2004
Accepted on January 28, 2004

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; and 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.

^* To whom correspondence should be addressed. 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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