L-Carnitine Reduces Brain Injury after Hypoxia-Ischemia in Newborn Rats

Abstract

Perinatal hypoxia-ischemia remains a significant cause of neonatal mortality and neurodevelopmental disability. Numerous lines of evidence indicate that cerebral ischemic insults disrupt normal respiratory activity in mitochondria. Carnitine (3-hydroxy-4-N-trimethylammonium-butyrate) has an essential role in fatty acid transport in the mitochondrion and in modulating potentially toxic acyl-CoA levels in the mitochondrial matrix. There are no naturally occurring esterases available to reduce the accumulation of acyl-CoA but this process can be overcome by exogenous carnitine. We used a newborn rat model of perinatal hypoxia-ischemia to test the hypothesis that treatment with Lcarnitine would reduce the neuropathologic injury resulting from hypoxia-ischemia in the developing brain. We found that treatment with L-carnitine during hypoxia-ischemia reduces neurologic injury in the immature rat after both a 7-and 28-d recovery period. We saw no neuroprotective effect when L-carnitine was administered after hypoxia-ischemia. Treatment with D-carnitine resulted in an increase in mortality during hypoxia-ischemia. Carnitine is easy to administer, has low toxicity, and is routinely used in neonates as well as children with epilepsy, cardiomyopathy, and inborn errors of metabolism. L-Carnitine merits further investigation as a treatment modality for the asphyxiated newborn or as prophylaxis for the at-risk fetus or newborn. Hypoxic-ischemic injury in the developing brain is characterized by a cascade of cellular events that evolve for hours or days, a distinct clinical syndrome manifest as encephalopathy, a combination of ischemia superimposed on hypoxia, and specific regional brain vulnerability to injury (1-3). Cerebral ischemia in the adult (4) and hypoxia-ischemia in the newborn (5) disrupt mitochondrial function leading to a collapse in cell energy metabolism.The amino acid derivative carnitine (3-hydroxy-4-Ntrimethylammonium-butyrate) is required for the maintenance of normal mitochondrial function. Carnitine has three major functions: facilitating transport of acyl moieties between organs and across the mitochondrial inner membrane and the buffering of potentially toxic intracellular acyl-CoA moieties (6, 7). High levels of acyl-CoA esters impair numerous mitochondrial processes (Fig. 1) (8 -10). There are no endogenous esterases available to reduce the accumulation of acyl-CoA esters. This process can be overcome by the addition of exogenous carnitine. Carnitine may function therefore in acute metabolic crises to trap toxic acyl-CoA moieties that impair fatty acid oxidation, urea cycle function metabolism, and gluconeogenesis (6,7,11).Carnitine has been tested as a neuroprotective therapy in adult animal models of cerebral ischemia (12-14). However, there are no data directly addressing the effect of L-carnitine treatment on cerebral ischemic injury in the newborn. LCarnitine is potentially an attractive therapeutic modality for perinatal asphyxia given the extensive pediatric clinical experience with the use of th...

Carnitine Content and Expression of Mitochondrial β-Oxidation Enzymes in Placentas of Wild-Type (OCTN2+/+) and OCTN2 Null (OCTN2−/−) Mice

“…It has been proposed by others that carnitine may be involved in fetal growth (21) and differential gene regulation of various metabolic pathways (22)(23)(24). Carnitine may also play a protective role for the growing fetus and prevent the free radical damage that causes lipid peroxidation, cell death and apoptosis (25)(26)(27). Homozygous OCTN2 Ϫ/Ϫ placental carnitine content is about 20% of the wild-type OCTN2 ϩ/ϩ placenta.…”

Carnitine Treatment Inhibits Increases in Cerebral Carnitine Esters and Glutamate Detected by Mass Spectrometry After Hypoxia-Ischemia in Newborn Rats

“…10 Rats were anesthetized with isoflurane (3.5% for induction and 1.5% for maintenance) and 50% oxygen-balance nitrogen. The right common carotid artery was ligated, and the animals recovered for 90 minutes with the dam before undergoing hypoxia.…”

“…Drug or diluent was administered via intraperitoneal injection at a dose of 16 mmol/kg 30 minutes before the induction of hypoxia. 10 …”

“…10 L-Carnitine is an attractive therapy for perinatal asphyxia given the extensive pediatric clinical experience and its minimal toxicity. 6 The newborn may be increased risk of cellular injury related to carnitine deficiency because of the immature development of carnitine biosynthetic pathways.…”

The protective effect of L-carnitine on hepatic ischemia-reperfusion injury in rats

“…(9)(10)(11)(12). Administration of L-carnitine or its derivatives were documented to improve I/R injury of the heart, kidney, skeletal muscle, and brain (3,(13)(14)(15)(16).…”