TY - JOUR
T1 - Mildronate, the inhibitor of l-carnitine transport, induces brain mitochondrial uncoupling and protects against anoxia-reoxygenation
AU - Makrecka, Marina
AU - Svalbe, Baiba
AU - Volska, Kristine
AU - Sevostjanovs, Eduards
AU - Liepins, Janis
AU - Grinberga, Solveiga
AU - Pugovics, Osvalds
AU - Liepinsh, Edgars
AU - Dambrova, Maija
N1 - Funding Information:
This study was supported by The European Regional Development Fund grant No. 2010/0234/2DP/2.1.1.1.0/10/APIA/VIAA/063 , the European Social Fund project No. 2009/0138/1DP/1.1.2.1.2/09/IPIA/VIAA/004 and Riga Stradins University research project No. RSU ZP 09/2013 .
PY - 2014/1/15
Y1 - 2014/1/15
N2 - The preservation of mitochondrial function is essential for normal brain function after ischaemia-reperfusion injury. l-carnitine is a cofactor involved in the regulation of cellular energy metabolism. Recently, it has been shown that mildronate, an inhibitor of l-carnitine transport, improves neurological outcome after ischaemic damage of brain tissues. The aim of the present study was to elucidate the mitochondria targeted neuroprotective action of mildronate in the model of anoxia-reoxygenation-induced injury. Wistar rats were treated daily with mildronate (per os; 100 mg/kg) for 14 days. The acyl-carnitine profile was determined in the brain tissues. Mitochondrial respiration and the activities of carnitine acetyltransferase (CrAT) and tricarboxylic acid (TCA) cycle enzymes were measured. To assess tolerance to ischaemia, isolated mitochondria were subjected to anoxia followed by reoxygenation. The mildronate treatment significantly reduced the concentrations of free l-carnitine (FC) and short-chain acyl-carnitine (AC) in brain tissue by 40-76%, without affecting the AC:FC ratio. The activities of CrAT and TCA cycle enzymes were slightly increased after mildronate treatment. Despite partially induced uncoupling, mildronate treatment did not affect mitochondrial bioenergetics function under normoxic conditions. After exposure to anoxia-reoxygenation, state 3 respiration and the respiration control ratio were higher in the mildronate-treated group. The results obtained demonstrate that mildronate treatment improves tolerance against anoxia-reoxygenation due to an uncoupling preconditioning-like effect. Regulating l-carnitine availability provides a potential novel target for the treatment of cerebral ischaemia and related complications.
AB - The preservation of mitochondrial function is essential for normal brain function after ischaemia-reperfusion injury. l-carnitine is a cofactor involved in the regulation of cellular energy metabolism. Recently, it has been shown that mildronate, an inhibitor of l-carnitine transport, improves neurological outcome after ischaemic damage of brain tissues. The aim of the present study was to elucidate the mitochondria targeted neuroprotective action of mildronate in the model of anoxia-reoxygenation-induced injury. Wistar rats were treated daily with mildronate (per os; 100 mg/kg) for 14 days. The acyl-carnitine profile was determined in the brain tissues. Mitochondrial respiration and the activities of carnitine acetyltransferase (CrAT) and tricarboxylic acid (TCA) cycle enzymes were measured. To assess tolerance to ischaemia, isolated mitochondria were subjected to anoxia followed by reoxygenation. The mildronate treatment significantly reduced the concentrations of free l-carnitine (FC) and short-chain acyl-carnitine (AC) in brain tissue by 40-76%, without affecting the AC:FC ratio. The activities of CrAT and TCA cycle enzymes were slightly increased after mildronate treatment. Despite partially induced uncoupling, mildronate treatment did not affect mitochondrial bioenergetics function under normoxic conditions. After exposure to anoxia-reoxygenation, state 3 respiration and the respiration control ratio were higher in the mildronate-treated group. The results obtained demonstrate that mildronate treatment improves tolerance against anoxia-reoxygenation due to an uncoupling preconditioning-like effect. Regulating l-carnitine availability provides a potential novel target for the treatment of cerebral ischaemia and related complications.
KW - Anoxia-reoxygenation
KW - L-carnitine
KW - Mildronate
KW - Mitochondria
KW - Uncoupling preconditioning
UR - http://www.scopus.com/inward/record.url?scp=84890817398&partnerID=8YFLogxK
U2 - 10.1016/j.ejphar.2013.12.006
DO - 10.1016/j.ejphar.2013.12.006
M3 - Article
C2 - 24333219
AN - SCOPUS:84890817398
SN - 0014-2999
VL - 723
SP - 55
EP - 61
JO - European Journal of Pharmacology
JF - European Journal of Pharmacology
IS - 1
ER -