Current Medicinal Chemistry - Central Nervous System Agents

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The Mitochondriotropic Effects of L-carnitine and its Esters in the Central Nervous System

Author(s): Zbigniew Binienda, Ashraf Virmani.

Abstract:

Mitochondrial defects have been linked to such devastating neurodegenerative diseases as Parkinsons, Huntingtons, amyotrophic lateral sclerosis (ALS), multiple sclerosis (MS) and Alzheimers as well as senile dementias. Mitochondrial metabolic defects could affect the electron transport, the tricarboxylic acid cycle (TCA), and substrate transport. However, it is the escape of oxygen free radicals (superoxide formation) as a result of a disturbed electron transfer within the respiratory chain that is thought to underlie many of the deleterious effects of mitochondrial dysfunction. A therapeutic strategy aimed at ameliorating these effects with supplementation of antioxidants, cofactors, and substrates is becoming prevalent. L-carnitine (LC), a biologically active stereoisomer of trimethylammonium hydroxide, is a highly polar, small zwitterion (inner salt). Ingested, LC is incorporated into the total body carnitine pool that includes unchanged LC, acetyl-L-carnitine (ALC), and other carnitine esters. LC optimises cell energy production by transporting medium and long chain fatty acids into the mitochondria for utilization in metabolism through β-oxidation. Free LC serves then two important intra-mitochondrial functions. It maintains the acetyl-CoA / CoA ratio and scavenges excess potentially toxic, free acyl groups to transport them out of the mitochondria. A lower acetyl-CoA / CoA ratio favors the action of pyruvate dehydrogenase that increases the formation of acetyl-CoA from pyruvate. The increased formation of acetyl-CoA from pyruvate significantly impacts glucose oxidative metabolism by limiting access to the TCA cycle. LC is also important in maintaining cell membrane stability through its involvement in acetylation of membrane phospholipids and amphiphilic actions. The carnitine system plays a role in the mitochondrial elongation-desaturation of the ω-3-polyunsaturated fatty acids to docosahexaenoic acid (DHA). Thus, LC is an endogenous mitochondriotropic substance and its use in therapy is to replace depleted carnitine levels, resulting in restoration of normal cellular and, hence body functions. LC and its acetylated form, acetyl-L-carnitine (ALC), may have antioxidative properties, protecting cells against lipid peroxidation and membrane breakdown. The carnitine system prevents loss of mitochondrial function in isolated liver mitochondria, prevents lipid peroxidation damage associated with energy loss due to hypobaric hypoxia in rat brain cells, and protects against mitochondrial inhibitor-induced toxicity in neurons. Consequently, LC protects against the neurotoxicity induced by mitochondrial inhibitors such as 3-nitropropionic acid (3-NPA) as well as methamphetamine. Supportive findings indicating a protective ability of LC and some of its esters at the mitochondrial level in the CNS have been reported by various groups and are discussed in further detail in this review.

Keywords: carnitine, Esters, Mitochondriotropic, methamphetamine, amphiphilic, nitropropionic, neurotoxicity

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Article Details

VOLUME: 3
ISSUE: 4
Year: 2003
Page: [275 - 282]
Pages: 8
DOI: 10.2174/1568015033477659
Price: $58