Published Online
on December 29, 2005

A more recent version of this article appeared on February 1, 2006

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Submitted on July 20, 2005
Revised on October 20, 2005
Accepted on October 27, 2005

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

Mark S. Wainwright MD, PhD^*; Rohit Kohli MD; Peter F. Whitington MD; and Donald H. Chace PhD, MSFS

From the Departments of Pediatrics (M.S.W., R.K., P.F.W.), Molecular Pharmacology and Biological Chemistry (M.S.W.), and Center for Drug Discovery and Chemical Biology (M.S.W.), The Feinberg School of Medicine, Northwestern University, Chicago, Ill; and Pediatrix Analytical (D.H.C.), Bridgeville, Pa.

^* To whom correspondence should be addressed. E-mail: m-wainwright{at}northwestern.edu.

Background and Purpose--Cerebral ischemic insults disrupt normal respiratory activity in mitochondria. Carnitine plays an essential role in mitochondrial metabolism and in modulating excess acyl-coenzyme A (acyl-CoA) levels. The effects of cerebral ischemia on carnitine metabolism are not well understood, although the newborn may be particularly vulnerable to carnitine deficiency. We used a newborn rat model of hypoxia-ischemia (HI) to test the hypothesis that HI alters acyl-CoA:CoA homeostasis and that this effect can be prevented by treatment with carnitine.

Methods--A total of 120 postnatal day 7 rats were subjected to 70 minutes of HI after treatment with 16 mmol/kg intraperitoneal L-carnitine or diluent. Carnitine, acylcarnitines, and excitatory amino acids were measured by mass spectrometry, and carnitine acetyl transferase activity, superoxide, and levels of the mitochondrial phospholipid cardiolipin (CL) were measured at 2- and 24-hour recovery.

Results--HI and hypoxia were associated with a significant increase in the ratio of acyl-CoA:CoA, which was prevented by treatment with carnitine. Carnitine treatment also prevented increases in glutamate, glycine, superoxide, and decrease of CL.

Conclusions--Carnitine metabolic pathways are compromised in HI and hypoxia. The protective effect of carnitine treatment on HI injury may be attributable to maintaining mitochondrial function.

Key words: hypoxia-ischemia, brain • carnitine • animals, newborn • glutamate

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