Therapies Targeted To Metabolic Pathways

Note: The aldose reductase inhibitors are discussed elsewhere (see Chapter 18). Antioxidants

Hyperglycemia has been shown in a number of studies to cause oxidative stress in tissues that are susceptible to the complications of diabetes, including peripheral nerves. In turn, the oxidative stress leads to the generation of free radicals that can attack the lipids, proteins, and nucleic acids of the affected tissues directly, compromising physiological function. The end result is the loss of axons and disruption of the microvascu-lature in the peripheral nervous system (Fig. 2). It has been shown that there is an increased presence of markers of oxidative stress, such as superoxide and peroxynitrite ions, and that antioxidant moieties were reduced in patients with diabetic peripheral

Fig. 2. The interactions of pathways leading to neurovascular and endothelial dysfunction and the actions of drugs that alter those mechanisms and are being tested in models of neuropathy.

neuropathy (4). Therefore, it is reasonable to use therapies that are known to reduce oxidative stress in tissues, and antioxidants. Although a host of antioxidants have been tested in animal models (for review see ref. 5), those that have been tested in human studies will be addressed.

a-Lipoic Acid a-lipoic acid is the best studied antioxidant therapy used in diabetic neuropathy. Lipoic acid (1,2-dithiolane-3-pentanoic acid), a derivative of octanoic acid, is present in food and is also synthesized by the liver. It is a natural cofactor in the pyruvate dehy-drogenase complex where it binds acyl groups and transfers them from one part of the complex to another. a-lipoic acid, also known as thioctic acid, has generated considerable interest as a thiol replenishing and redox modulating agent. In streptozotocin (STZ)-diabetic rats a-lipoic acid has been shown to prevent slowing of peripheral nerve conduction velocity and to maintain peripheral nerve blood flow (6-8). It has also been shown to be effective in ameliorating both the somatic and autonomic neuropathies in diabetes (9-11). It is not clear that the positive effects are limited to the antioxidant properties of a-lipoic acid, and studies are ongoing to determine its range of effects. a-lipoic acid is licensed for use in diabetes in Germany and it is currently undergoing extensive trials in the US as both an antidiabetic agent and for the treatment of diabetic neuropathy.

j-Linolenic Acid

Linoleic acid is an essential fatty acid that is metabolized to di-homo-y-linolenic acid (GLA), which in turn serves as an important constituent of neuronal membrane phospholipids. In addition it can serve as a substrate for prostaglandin E synthesis, which may be important for preservation of nerve blood flow. In diabetes, conversion of linoleic acid to GLA and subsequent metabolites is impaired, possibly contributing to the pathogenesis of diabetic neuropathy (12,13). A multicenter, double-blind placebo-controlled trial using GLA for 1 year demonstrated significant improvements in both clinical measures and electrophysiological testing (14).

Tocopherol (Vitamin E)

The tocopherols, especially the a-tocopherol isoform, have been promoted as effective antioxidant therapy for a number of neurological diseases, including Alzheimer's disease, epilepsy, cerebellar ataxia, and diabetic neuropathy. In studies of patients with diabetes vitamin E has been shown to decrease 8-isoprostane F2a (15), decrease low density lipoprotein-C oxidation at high doses (16), and increase skin blood flow and reduce free radicals in skin with topical application (17). Human studies of vitamin E using combined oral therapy with vitamin C, another well-established antioxidant have shown improved vascular function, but only in type 1 patients (18). Thus, vitamin E appears to exert antioxidant protective effects on neurons in diabetes although efficacy has not yet been demonstrated.

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