The novel compound LOE 908 attenuates acute neuromotor dysfunction but not cognitive impairment or cortical tissue loss following traumatic brain injury in rats.
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.
Cheney
J A
JA
Department of Neurosurgery, University of Pennsylvania, Philadelphia 19104, USA.
Brown
A L
AL
Bareyre
F M
FM
Russ
A B
AB
Weisser
J D
JD
Ensinger
H A
HA
Leusch
A
A
Raghupathi
R
R
Saatman
K E
KE
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*
D000081:Acetamides; D007546:Isoquinolines; C081356:LOE 908