title: Recovery from ischemic brain injury in the rat following a 10 h delayed injection with MLN519.
abstract: In the present study, we evaluated delayed treatment effects of the proteasome inhibitor and anti-inflammatory agent MLN519 (initiated 10 h post-injury) to improve recovery following ischemic brain injury in rodents. Male rats were exposed to 2 h of middle cerebral artery occlusion (MCAo) and treated with MLN519 (1.0 mg/kg, i.v. @ 10, 24, and 48 h post-occlusion) or vehicle. By 2 weeks post-injury, 60% (6/10) of vehicle animals survived, which was improved (although non-significantly) to 78% (7/9) following MLN519 treatment. The percent loss of tissue in the ipsilateral brain hemisphere (at 2 weeks) was significantly reduced from 27+/-4% (vehicle) to 15+/-4% (MLN519). MLN519 treated animals also lost significantly less body weight (39%) and showed significant improvement in overall neurological function across the 2-week recovery period. However, no significant treatment effects were observed to reduce foot-fault deficits (balance beam) or improve recovery of operant performance (active avoidance test). Overall, delayed treatment with MLN519 provided significant improvement in 3 of 6 test metrics (histopathology, body weight, and neurological dysfunction) supporting improved outcome for brain-injured subjects.
authors.affiliation: Department of Applied Neurobiology, Division of Psychiatry and Neuroscience, Walter Reed Army Institute of Research, 503 Robert Grant Ave, Room 2A40, Silver Spring, MD 20910, USA. anthony.williams@na.amedd.army.mil
authors.forename: Anthony J
authors.initials: AJ
authors.lastname: Williams
authors.forename: Todd M
authors.initials: TM
authors.lastname: Myers
authors.forename: Scott I
authors.initials: SI
authors.lastname: Cohn
authors.forename: Keith M
authors.initials: KM
authors.lastname: Sharrow
authors.forename: Xi-Chun M
authors.initials: XC
authors.lastname: Lu
authors.forename: Frank C
authors.initials: FC
authors.lastname: Tortella
mesh_terms: D000111:Acetylcysteine / Q000008:administration & dosage / Q000031:analogs & derivatives*; D000818:Animals; D002545:Brain Ischemia / Q000188:drug therapy* / Q000473:pathology / Q000503:physiopathology; D007276:Injections, Intraventricular; D008297:Male; D051381:Rats; D017207:Rats, Sprague-Dawley; D020127:Recovery of Function / Q000187:drug effects* / Q000502:physiology; D013997:Time Factors
chemical_list: C411422:PS519; D000111:Acetylcysteine