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039 ASSESSMENT OF THE PROTECTIVE EFFECT OF L-CARNITINE IN HEPATIC ENCEPHALOPATHY BY MULTINUCLEAR NMR SPECTROSCOPY: IMPROVEMENTS OF MUSCLE AND BRAIN MITOCHONDRIAL AND FATTY ACID METABOLISM C Zwingmann, W Jiang, RF Butterworth Hepatic Encephalopathy (HE) in both chronic and acute liver failure is associated with alterations of energy metabolism in brain and peripheral organs. L-carnitine attenuates HE in experimental and clinical chronic liver failure. The mechanisms of L-Carnitine's action have not been systematically investigated. In order to address this issue, 1H- and 13C-Nuclear Magnetic Resonance (NMR) studies (Bruker DRX 600 MHz spectrometer) was used to measure metabolism in brain and muscle following i.p. administration of 13C-glucose (500 mg/kg; 30-60 minutes) to rats 4 weeks following end-to-side portacaval anastomosis (PCA). Sham-operated rats were time-matched to the rats with PCA. Rats with PCA and sham-operated controls were daily administered with either L-carnitine (0.8 mmol/kg; i.p.) or saline. Groups of PCA rats received ammonium acetate (3.8 mmol/kg; i.p.) four weeks after PCA to precipitate encephalopathy; L-carnitine was administered in a single dose (1.6 mmol/kg concomitantly with ammonium acetate. Tissues were snap-frozen in liquid nitrogen and extracted. PCA resulted in >80% impaired locomotor activity (p<0.001). Treatment with L-carnitine resulted in significant improvement in locomotor activity (p<0.001). Treatment with L-carnitine stimulated mitochondrial metabolism by 253 ± 36% and 291 ± 22% as well as de novo synthesis of the Krebs cycle intermediate succinate in muscle and brain, respectively. However, de novo synthesis of glutamine decreased by 62% ± 4% and 54% ± 8% in muscle and brain (glutamine synthesis in the astrocytes), respectively. 1H-NMR spectra of brain lipid extracts showed a 71 ± 4% decrease in the ratio of CH2- to CH3 groups of fatty acids in L-carnitine-treated PCA rats. Concomitant with improved Krebs cycle metabolism, the decrease of the astrocytic osmolyte myo-inositol (66 ± 5%) was normalised in L-carnitine treated PCA rats. After administration of ammonium acetate to rats with PCA, L-carnitine prolonged the time to onset of coma and brain lactate increased by 192 ± 25% (p<0.01). Following L-carnitine, lactate synthesis was significantly attenuated. These data demonstrate that L-carnitine acts both at brain and muscle by improvement of mitochondrial metabolism and fatty acid catabolism. These mechanisms explain L-carnitine's therapeutic benefit in the prevention of mild HE and ammonia-precipitated encephalopathy in cirrhotic patients.
CHUM, Hôpital Saint-Luc, Université de Montréal, Montreal, Quebec
Funded by CIHR