title: Mildronate, the inhibitor of L-carnitine transport, induces brain mitochondrial uncoupling and protects against anoxia-reoxygenation.
abstract: 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; 100mg/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.
authors: Latvian Institute of Organic Synthesis, Aizkraukles Str. 21, Riga LV-1006, Latvia; Riga Stradins University, Faculty of Pharmacy, Dzirciema Str. 16, Riga LV-1007, Latvia. Electronic address: makrecka@biomed.lu.lv.
authors: Marina
authors: M
authors: Makrecka
authors: Latvian Institute of Organic Synthesis, Aizkraukles Str. 21, Riga LV-1006, Latvia; University of Latvia, Faculty of Medicine, Sarlotes St. 1a, Riga, LV-1001, Latvia.
authors: Baiba
authors: B
authors: Svalbe
authors: Riga Stradins University, Faculty of Pharmacy, Dzirciema Str. 16, Riga LV-1007, Latvia.
authors: Kristine
authors: K
authors: Volska
authors: Latvian Institute of Organic Synthesis, Aizkraukles Str. 21, Riga LV-1006, Latvia.
authors: Eduards
authors: E
authors: Sevostjanovs
authors: University of Latvia, Institute of Microbiology and Biotechnology, Kronvalda Blvd. 4, Riga LV-1586, Latvia.
authors: Janis
authors: J
authors: Liepins
authors: Latvian Institute of Organic Synthesis, Aizkraukles Str. 21, Riga LV-1006, Latvia.
authors: Solveiga
authors: S
authors: Grinberga
authors: Latvian Institute of Organic Synthesis, Aizkraukles Str. 21, Riga LV-1006, Latvia.
authors: Osvalds
authors: O
authors: Pugovics
authors: Latvian Institute of Organic Synthesis, Aizkraukles Str. 21, Riga LV-1006, Latvia.
authors: Edgars
authors: E
authors: Liepinsh
authors: Latvian Institute of Organic Synthesis, Aizkraukles Str. 21, Riga LV-1006, Latvia; Riga Stradins University, Faculty of Pharmacy, Dzirciema Str. 16, Riga LV-1007, Latvia.
authors: Maija
authors: M
authors: Dambrova
mesh_terms: D000214:Acyl Coenzyme A / Q000378:metabolism; D000255:Adenosine Triphosphate / Q000378:metabolism; D000818:Animals; D001921:Brain / Q000187:drug effects* / Q000378:metabolism; D002331:Carnitine / Q000037:antagonists & inhibitors* / Q000378:metabolism; D002333:Carnitine Acyltransferases / Q000378:metabolism; D019069:Cell Respiration / Q000187:drug effects; D000860:Hypoxia / Q000378:metabolism; D008297:Male; D008763:Methylhydrazines / Q000494:pharmacology*; D008928:Mitochondria / Q000187:drug effects* / Q000378:metabolism; D018696:Neuroprotective Agents / Q000494:pharmacology*; D010100:Oxygen / Q000378:metabolism; D051381:Rats; D017208:Rats, Wistar
chemical_list: D000214:Acyl Coenzyme A; D008763:Methylhydrazines; D018696:Neuroprotective Agents; C050147:3-(2,2,2-trimethylhydrazine)propionate; D000255:Adenosine Triphosphate; D002333:Carnitine Acyltransferases; D002331:Carnitine; D010100:Oxygen
keywords: Anoxia-reoxygenation; L-carnitine; Mildronate; Mitochondria; Uncoupling preconditioning