Mitochondrial dysfunction after experimental traumatic brain injury: combined efficacy of SNX-111 and U-101033E.
We recently demonstrated that posttraumatic administration of the N-type calcium channel blocker SNX-111 (S) and a novel blood-brain barrier penetrating antioxidant U-101033E (U), significantly alleviated mitochondrial dysfunction induced by traumatic brain injury (TBI) in rats. The present study was designed to determine whether a combination of S and U, which act on different biochemical mechanisms of secondary brain injury, would be more efficacious than either drug alone. Brain mitochondria from injured and uninjured hemispheres were isolated and examined at 12 h post TBI induced by a severe controlled cortical impact injury. S at 1.0 mg/kg significantly increased both State 3 and 4 rates and produced a slight increase in P/O ratio, and there was virtually no change in RCI. U at 1.0 mg/kg did not show any protection. However, the combined treatment of S at 1.0 mg/kg and U at 1.0 mg/kg eliminated the uncoupling effect of S, and restored not only State 3 rates and P/O ratios but also RCI to near sham values. These results provide further evidence that both reactive oxygen species and perturbation of cellular calcium homeostasis participate in the pathogenesis of TBI-induced mitochondrial dysfunction, and support the idea of using combined therapy with lower drug doses.
Department of Biochemistry and Molecular Biology, Wayne State University School of Medicine, Detroit, Michigan 48201, USA.
Y
Y
Xiong
P L
PL
Peterson
B H
BH
Verweij
F C
FC
Vinas
J P
JP
Muizelaar
C P
CP
Lee
D000704:Analysis of Variance; D000818:Animals; D000975:Antioxidants / Q000494:pharmacology*; D001930:Brain Injuries / Q000188:drug therapy* / Q000517:prevention & control; D002118:Calcium / Q000378:metabolism; D002121:Calcium Channel Blockers / Q000494:pharmacology*; D000252:Calcium-Transporting ATPases / Q000187:drug effects; D004195:Disease Models, Animal; D004305:Dose-Response Relationship, Drug; D004347:Drug Interactions; D004579:Electron Transport / Q000187:drug effects; D008297:Male; D008928:Mitochondria / Q000187:drug effects* / Q000502:physiology; D018696:Neuroprotective Agents / Q000494:pharmacology*; D010085:Oxidative Phosphorylation / Q000187:drug effects; D010455:Peptides / Q000494:pharmacology*; D011743:Pyrimidines / Q000494:pharmacology*; D011759:Pyrrolidines / Q000494:pharmacology*; D051381:Rats; D017207:Rats, Sprague-Dawley; D020960:omega-Conotoxins
D000975:Antioxidants; D002121:Calcium Channel Blockers; D018696:Neuroprotective Agents; D010455:Peptides; D011743:Pyrimidines; D011759:Pyrrolidines; C101923:U 101033E; D020960:omega-Conotoxins; C078452:ziconotide; D000252:Calcium-Transporting ATPases; D002118:Calcium