ABSTRACT
Introduction........................................................................................................ 58 Pharmacokinetics of a-Lipoic Acid................................................................... 60 a-Lipoic Acid-Based Derivatives and Pro-Drugs ............................................. 62 Seleno-a-Lipoic Acid Derivatives ................................................................. 62 Amide and Ester Derivatives of Bis-a-Lipoic Acid...................................... 63 Morpholine-a-Lipoic Acid Derivative........................................................... 65 Fluorinated Amphiphilic-a-Lipoic Acid Derivative ...................................... 65 Indole-a-Lipoic Acid Derivatives.................................................................. 66 LA-Plus: N,N-Dimethyl, N0-2-Amidoethyl-Lipoate ...................................... 67 Lipoamide ...................................................................................................... 68
a-Lipoic Acid in Co-Drugs ............................................................................... 69 Trolox=a-Lipoic Acid Co-Drug..................................................................... 69 Tacrine=a-Lipoic Acid Co-Drug (Lipocrine) ................................................ 70 L-DOPA=a-Lipoic Acid Co-Drug.................................................................. 71 NOS Inhibitor=a-Lipoic Acid Co-Drug......................................................... 72 Thiazolidinedione=a-Lipoic Acid Co-Drug................................................... 72 g-Linoleic Acid=a-Lipoic Acid Co-Drug ...................................................... 74 Chlorambucil-and Cromolyn=a-Lipoic Acid Co-Drugs............................... 75 Other a-Lipoic Acid-Based Co-Drugs .......................................................... 76
Summary ............................................................................................................ 76 Acknowledgments.............................................................................................. 77 References .......................................................................................................... 77
Two cellular systems combine to protect cells against damaging effects of free radicals that are generated under normal metabolic conditions or in excess in pathological processes: Antioxidant enzymes (i.e., superoxide dismutase, catalase) eliminate free radicals by enzymatic reactions whereas low-molecular weight antioxidants neutralize radicals by direct chemical interactions (i.e., vitamin C, vitamin E, glutathione). a-Lipoic acid [LA, CAS 62-46-4, thioctic acid, 5-(1,2-dithiolan-3-yl), pentanoic acid] which belongs to the second group, is an endogenous cofactor for several 2-oxoacid dehydrogenase multienzyme complexes. For instance, it is covalently linked to a lysine residue of dihydrolipoamide acetyltransferase in the pyruvate dehydrogenase (PDH) complex to accept an acyl intermediate from the dehydrogenase components and transfer it to coenzyme-A. The resulting reduced form of LA, dihydrolipoic acid (DHLA), is then reoxidized by lipoamide dehydrogenase (Reed et al. 1958; Loffelhardt et al. 1995; Biewenga et al. 1996). Free LA is considered a therapeutically potent thiol antioxidant due to its reductive power (Packer et al. 1995). The low oxidation potential (0.29 V) of the reduced form of DHLA results from the two vicinal thiol groups within the molecule that enable efficient scavenging of free radicals, such as superoxide, hydroxyl, and peroxyl radicals (Packer et al. 1995; Biewenga et al. 1997; Bustamante et al. 1998). These interactions also contribute to the regeneration of other low-molecular weight antioxidants, such as vitamin C, glutathione, and vitamin E (Packer et al. 1995; Biewenga et al. 1997). In addition, the metal-chelating activity of LA also contributes to its antioxidative activity through the inhibition of metal ion-dependent formation of free radicals in cells (Muller and Menzel 1990; Packer et al. 1995). Another mechanism suggests that dihydrolipoamide dehydrogenase that reduces LA to DHLA consumes cellular NAD(P)H, which is an essential cofactor to several free radicalproducing enzymes (e.g., nitric oxide synthase) (Guo et al. 2001). Many reports and trials have suggested that by virtue of these antioxidative interactions LA may ameliorate various symptoms associated with oxidative stress, such as diabetes-induced neuropathy (Packer et al. 1995; Nickander et al. 1996; Bustamante et al. 1998; Packer et al. 2001; Ziegler 2004; Ziegler et al. 2004; Bilska and Wlodek 2005).
