Neuroprotection in the rat lateral fluid percussion model of traumatic brain injury by SNX-185, an N-type voltage-gated calcium channel blocker.
Overload of intracellular calcium ([Ca(2+)](i)) following traumatic brain injury (TBI) has been implicated in the pathogenesis of neuronal injury and death. Voltage-gated calcium channels (VGCCs) provide one of the major sources of Ca(2+) entry into cells. Therefore, the potential neuroprotective activity of SNX-185, a specific N-type VGCC blocker, was tested in rats using the lateral fluid percussion (LFP) model of TBI. SNX-185 (50, 100, or 200 pmol) or vehicle was injected 5 min after injury into the CA2-3 subregion of the hippocampus ipsilateral to TBI. Acute neuronal degeneration was visualized in brain sections 24 h postinjury using the histofluorescent marker Fluoro-Jade (FJ), and the number of surviving neurons in the CA2-3 subregion of the hippocampus 42 days after injury was determined stereologically. Behavioral outcome after TBI and drug treatment was assessed in the beam walk test and Morris water maze. Direct injection of SNX-185 into the CA2-3 region of the hippocampus reduced neuronal injury 24 h after TBI and increased neuronal survival at 42 days at each of the three drug concentrations. Behavioral outcome in both the beam walk and Morris water maze were also improved by SNX-185, with 100 and 200 pmol, but not 50 pmol SNX-185 providing neuroprotection. These data support previous studies demonstrating substantial neuroprotection after TBI by treatment with N-type VGCC blockers.
Department of Neurological Surgery, University of California-Davis, One Shields Avenue, Davis, CA 95616, USA.
Lillian L
LL
Lee
Ethel
E
Galo
Bruce G
BG
Lyeth
J Paul
JP
Muizelaar
Robert F
RF
Berman
D000818:Animals; D001522:Behavior, Animal / Q000187:drug effects; D001930:Brain Injuries / Q000188:drug therapy* / Q000473:pathology / Q000503:physiopathology; D002121:Calcium Channel Blockers / Q000627:therapeutic use*; D020864:Calcium Channels, N-Type / Q000187:drug effects*; D004195:Disease Models, Animal; D004305:Dose-Response Relationship, Drug; D008297:Male; D018782:Maze Learning / Q000187:drug effects; D009043:Motor Activity / Q000187:drug effects; D018696:Neuroprotective Agents / Q000627:therapeutic use*; D011312:Pressure / Q000009:adverse effects; D051381:Rats; D017207:Rats, Sprague-Dawley; D015996:Survival Rate; D016896:Treatment Outcome; D020960:omega-Conotoxins / Q000627:therapeutic use*
D002121:Calcium Channel Blockers; D020864:Calcium Channels, N-Type; D018696:Neuroprotective Agents; D020960:omega-Conotoxins; C087968:omega-conotoxin TVIA