title: The novel compound LOE 908 attenuates acute neuromotor dysfunction but not cognitive impairment or cortical tissue loss following traumatic brain injury in rats.
abstract: Experimental traumatic brain injury (TBI) initiates massive disturbances in Ca2+ concentrations in the brain that may contribute to neuronal damage. Intracellular Ca2+ may be elevated via influx through voltage-operated cation channels, ligand-gated ionotropic channels, and store-operated cation channels (SOCs). In the present study, we evaluated the neurobehavioral and histological effects of acute posttraumatic administration of (R,S)-(3,4-dihydro-6,7-dimethoxy-isoquinoline-1-yl)-2-phenyl-N,N-di[2-(2 ,3,4-trimethoxyphenyl)ethyl]-acetamide (LOE 908), a broad spectrum inhibitor of voltage-operated cation channels and SOCs. Male Sprague-Dawley rats (n = 53) were trained in the Morris water maze, anesthetized (60 mg/kg pentobarbital, i.p.), and subjected to lateral fluid percussion brain injury (2.5-2.7 atm; n = 38) or surgery without injury (n = 15). At 15 min postinjury, animals were randomized to receive intravenous administration of either a high dose of LOE 908 (4 mg/kg bolus followed by 160 mg/kg over 24 h; n = 13), a low dose of LOE 908 (2 mg/kg bolus followed by 80 mg/kg over 24 h; n = 12), or vehicle (n = 13). Uninjured controls received the high dose of LOE 908 (n = 8) or vehicle (n = 7). Treatment with either dose of LOE 908 significantly improved neuromotor function at 48 h postinjury when compared to vehicle treatment. Although a significant deficit in visuospatial memory was observed in brain-injured animals at this timepoint when compared to uninjured animals, neither dose of LOE 908 attenuated injury-induced cognitive dysfunction. Histological evaluation revealed that neither dose of LOE 908 affected cortical lesion size at 48 h postinjury. These data suggest that broad spectrum cation channel blockers may be beneficial in the treatment of neurological motor dysfunction when administered in the acute posttraumatic period.
authors.affiliation: Department of Neurosurgery, University of Pennsylvania, Philadelphia 19104, USA.
authors.forename: J A
authors.initials: JA
authors.lastname: Cheney
authors.forename: A L
authors.initials: AL
authors.lastname: Brown
authors.forename: F M
authors.initials: FM
authors.lastname: Bareyre
authors.forename: A B
authors.initials: AB
authors.lastname: Russ
authors.forename: J D
authors.initials: JD
authors.lastname: Weisser
authors.forename: H A
authors.initials: HA
authors.lastname: Ensinger
authors.forename: A
authors.initials: A
authors.lastname: Leusch
authors.forename: R
authors.initials: R
authors.lastname: Raghupathi
authors.forename: K E
authors.initials: KE
authors.lastname: Saatman
mesh_terms: D000081:Acetamides / Q000008:administration & dosage* / Q000097:blood; D000818:Animals; D001930:Brain Injuries / Q000097:blood / Q000150:complications / Q000188:drug therapy*; D002404:Catheterization; D002540:Cerebral Cortex / Q000187:drug effects* / Q000293:injuries / Q000473:pathology; D003072:Cognition Disorders / Q000188:drug therapy* / Q000209:etiology; D004305:Dose-Response Relationship, Drug; D004334:Drug Administration Schedule; D007546:Isoquinolines / Q000008:administration & dosage* / Q000097:blood; D008297:Male; D008569:Memory Disorders / Q000188:drug therapy / Q000209:etiology; D019957:Motor Skills Disorders / Q000188:drug therapy* / Q000209:etiology; D009460:Neurologic Examination; D051381:Rats; D017207:Rats, Sprague-Dawley; D013997:Time Factors; D014949:Wounds, Nonpenetrating / Q000097:blood / Q000150:complications / Q000188:drug therapy*
chemical_list: D000081:Acetamides; D007546:Isoquinolines; C081356:LOE 908