Zvejniece 2023 Biomed Pharmacother

Zvejniece L, Svalbe B, Vavers E, Ozola M, Grinberga S, Gukalova B, Sevostjanovs E, Liepinsh E, Dambrova M (2023) Decreased long-chain acylcarnitine content increases mitochondrial coupling efficiency and prevents ischemia-induced brain damage in rats.

» Biomed Pharmacother 168:115803. PMID: 37924790 Open Access

Zvejniece Liga, Svalbe Baiba, Vavers Edijs, Ozola Melita, Grinberga Solveiga, Gukalova Baiba, Sevostjanovs Eduards, Liepinsh Edgars, Dambrova Maija (2023) Biomed Pharmacother

Abstract: Long-chain acylcarnitines (LCACs) are intermediates of fatty acid oxidation and are known to exert detrimental effects on mitochondria. This study aimed to test whether lowering LCAC levels with the anti-ischemia compound 4-[ethyl(dimethyl)ammonio]butanoate (methyl-GBB) protects brain mitochondrial function and improves neurological outcomes after transient middle cerebral artery occlusion (MCAO). The effects of 14 days of pretreatment with methyl-GBB (5 mg/kg, p.o.) on brain acylcarnitine (short-, long- and medium-chain) concentrations and brain mitochondrial function were evaluated in Wistar rats. Additionally, the mitochondrial respiration and reactive oxygen species (ROS) production rates were determined using ex vivo high-resolution fluorespirometry under normal conditions, in models of ischemia-reperfusion injury (reverse electron transfer and anoxia-reoxygenation) and 24 h after MCAO. MCAO model rats underwent vibrissae-evoked forelimb-placing and limb-placing tests to assess neurological function. The infarct volume was measured on day 7 after MCAO using 2,3,5-triphenyltetrazolium chloride (TTC) staining. Treatment with methyl-GBB significantly reduced the LCAC content in brain tissue, which decreased the ROS production rate without affecting the respiration rate, indicating an increase in mitochondrial coupling. Furthermore, methyl-GBB treatment protected brain mitochondria against anoxia-reoxygenation injury. In addition, treatment with methyl-GBB significantly reduced the infarct size and improved neurological outcomes after MCAO. Increased mitochondrial coupling efficiency may be the basis for the neuroprotective effects of methyl-GBB. This study provides evidence that maintaining brain energy metabolism by lowering the levels of LCACs protects against ischemia-induced brain damage in experimental stroke models. • Keywords: Ischemic stroke, Long-chain acylcarnitines, MCAO, Methyl-GBB, ROS • Bioblast editor: Plangger M • O2k-Network Lab: LV Riga Liepins E

Labels: MiParea: Respiration 

Stress:Ischemia-reperfusion  Organism: Rat 

Preparation: Isolated mitochondria 

Coupling state: LEAK, OXPHOS  Pathway: N, S, CIV, NS, ROX  HRR: Oxygraph-2k, O2k-Fluorometer 

2023-11