Effect of propionyl-L-carnitine on experimental models of peripheral arteriopathy in the rat

Abstract

A common feature of several different vascular pathologies is an imbalance of energy metabolism in vascular and muscular tissues in the area affected, independent of the cause of the disease (vascular obstruction, diabetic status, sickle cell anemia, etc.). The energy production in these tissues is strongly dependent on the oxidation of fatty acids via the Krebs cycle. The crucial role of L-carnitine (L-C) in this process has been recognized for many years and explained by many authors [1–3]. L-C is a fundamental cofactor for fatty acid oxidation within the mitochondria; fatty acids, free or CoA-activated, cannot penetrate the mitochondrial membrane, while carnitine esters are transported through the membrane into the mitochondria by carnitine translocase. A beneficial effect of L-C in patients with peripheral vascular diseases (PVD) has already been shown in different clinical studies, as well as, secondary carnitine deficiency in the skeletal muscles of these subjects [4–6]. During the search for new derivatives with an improved activity in comparison to the original compound, an acyl-derivative of L-C, propionyl-L-carnitine (PLC), has been selected. Biochemical studies have indicated that PLC presents some advantages over L-C, mainly due to its better transport into the cells, related to the presence of the propionyl group [7–9]. PLC can be converted to propionyl-CoA by carnitine acetyltransferase (CAT) and further to methylmalonyl-CoA by mitochondrial propionyl-CoA carboxylase. Whereas methyl malonyl-CoA remains in the matrix for further conversion to succinyl-CoA and subsequently to succinate (thereby entering the Krebs cycle), PLC may move across the mitochondrial inner membrane by a reversible transport mechanism. As a consequence, PLC administration could result in an activation of the Krebs cycle through an “anaplerotic effect” with a subsequent increase of energy supply [10, 11]. This enhancement of energy production should be particularly useful in all those conditions in which a reduced oxygen availability is involved.

“Propionyl-L-carnitine and pentoxifylline both provided protection against vascular damages caused by ergotamine tartrate administration, as evidenced by lower frequencies of epithelial tissue damage, at the site of injection, and a lower degree of ulceration and tissue necrosis. Propionyl-L-carnitine treatment (120mg/kg per os) significantly restored the walking ability of the rats when the treatment started one week after streptozotocin injection, and lasted up to 9 weeks.”