Delayed treatment of ischemia/reperfusion brain injury: extended therapeutic window with the proteosome inhibitor MLN519.

Autor:	Williams AJ; Department of Neuropharmacology and Molecular Biology, Division of Neurosciences, Walter Reed Army Institute of Research, Silver Spring, MD 20910, USA. anthony.williams@na.amedd.army.mil, Berti R, Dave JR, Elliot PJ, Adams J, Tortella FC
Jazyk:	angličtina
Zdroj:	Stroke [Stroke] 2004 May; Vol. 35 (5), pp. 1186-91. Date of Electronic Publication: 2004 Apr 01.
DOI:	10.1161/01.STR.0000125721.10606.dc
Abstrakt:	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-alpha (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.
Databáze:	MEDLINE
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