Cyclosporin A improves brain tissue oxygen consumption and learning/memory performance after lateral fluid percussion injury in rats.
Traumatic brain injury (TBI) triggers a complex pathophysiological cascade, leading to cell death. A major factor in the pathogenesis of TBI is neuronal overloading with calcium, causing the opening of mitochondrial permeability transition pores (MPTP), which consequently inhibit normal mitochondrial function. The immunosuppressant Cyclosporin A (CsA) has been shown to block MPTPs, and to be neuroprotective in ischemia and TBI. However, the translation of these effects on mitochondrial function, into behavioral endpoints has not been investigated thoroughly. Therefore, we tested the effect of a low, clinically evaluated, CsA dose of 0.125 mg/kg (infused for 3 h) and a higher "known" neuroprotective dose of 18.75 mg/kg on brain tissue O(2) consumption, and on motor and cognitive performance following lateral fluid percussion injury (FPI) in rats. CsA at both concentrations abolished the 25% decrease in O(2) consumption (VO(2)), seen in saline-treated animals at 5 h post-FPI. Furthermore, the lower dose of CsA also ameliorated acute motor deficits (days 1-5 post-FPI) and learning and memory impairments in a Morris water maze test on days 11-15 post-FPI. Although, the higher dose of CsA improved cognitive performance, it worsened acute motor functional recovery. These results suggest, that the CsA-induced preservation of mitochondrial function, as assessed by tissue O(2) consumption, directly translated into improvements in motor and cognitive behavior.
Department of Neurosurgery, Medical College of Virginia, Virginia Commonwealth University, Richmond, Virginia 23298, USA.
Beat
B
Alessandri
Ann C
AC
Rice
Joseph
J
Levasseur
Michelle
M
DeFord
Robert J
RJ
Hamm
M Ross
MR
Bullock
D000818:Animals; D001921:Brain / Q000187:drug effects* / Q000378:metabolism; D001930:Brain Injuries / Q000188:drug therapy* / Q000378:metabolism; D003071:Cognition / Q000187:drug effects / Q000502:physiology; D016572:Cyclosporine / Q000494:pharmacology* / Q000627:therapeutic use*; D007858:Learning / Q000187:drug effects* / Q000502:physiology; D008297:Male; D008928:Mitochondria / Q000187:drug effects / Q000378:metabolism; D010101:Oxygen Consumption / Q000187:drug effects* / Q000502:physiology; D051381:Rats; D017207:Rats, Sprague-Dawley
D016572:Cyclosporine