metallothionein and Diabetic-Neuropathies

Epalrestat is the only aldose reductase inhibitor that is currently available for diabetic peripheral neuropathy. Oxidative stress impairs endothelial cells, thereby leading to numerous pathological conditions. Increasing antioxidative ability is important to prevent cellular toxicity induced by reactive oxygen species. Epalrestat increases antioxidant defense factors such as glutathione and γ-glutamylcysteine ligase in vascular endothelial cells through activation of the transcription factor nuclear factor erythroid 2-related factor 2 (Nrf2). This increases suppression of oxidative stress-induced cellular toxicity. Cadmium is an industrial and environmental pollutant that targets the vascular endothelium. The vascular system is critically affected by cadmium toxicity. Therapeutic treatment against cadmium toxicity is chelation therapy that promotes metal excretion; however, cadmium chelators can cause renal toxicity. Therefore, safe and efficient therapeutic agents are required. Epalrestat suppresses cadmium-induced cytotoxicity in vascular endothelial cells through activation of Nrf2. In addition, epalrestat affects the intracellular levels of cadmium, cadmium transporter Zrt-Irt-like protein 8 (ZIP8), and metallothionein (MT). The upregulation of ZIP8 and MT may be involved in the suppression of cadmium-induced cytotoxicity by epalrestat. Drug repurposing is a new strategy for drug discovery in which the pharmacological action of existing medicines whose safety and pharmacokinetics have already been confirmed clinically and whose use has been approved is examined comprehensively at the molecular level. The results can be applied to the development of existing drugs for use as medicines for the treatment of other diseases. This review provides useful findings for future expansion of indications as research leading to drug repurposing of epalrestat.

Topics: Aldehyde Reductase; Antioxidants; Cadmium; Chelating Agents; Diabetes Mellitus; Diabetic Neuropathies; Endothelial Cells; Environmental Pollutants; Glutathione; Humans; Ligases; Metallothionein; NF-E2-Related Factor 2; Reactive Oxygen Species; Rhodanine; Thiazolidines

We investigated the effect of zinc supplementation on the expression of metallothionein, lipid peroxidation (malondialdehyde, MDA), and poly(ADP-ribose) polymerase-1 (PARP-1) in the sciatic nerve, motor nerve conduction velocity of the left sciatic posterior tibial nerve in streptozotocin (STZ)-induced diabetic rats. Twenty-four male rats were equally divided into four groups. The first group served as untreated controls although the second group received 5 mg/kg/day zinc chloride. The third group was treated with STZ to induce diabetes, and the fourth group was treated with STZ and supplemented with zinc. A gradual but insignificant decline in motor nerve conduction velocity was observed at 2 weeks of induction of diabetes. Zinc supplementation markedly attenuated the decrease in motor nerve conduction velocity at week 8 post-induction of diabetes. Furthermore, the tactile response threshold of diabetic rats receiving normal saline was lower than that of diabetic rats receiving zinc supplementation. Additionally, zinc supplementation accentuated the increase in the mRNA transcript levels of metallothionein but attenuated the increase in the mRNA transcript levels of PARP-1. At week 8 post-induction of diabetes, diabetic rats receiving normal saline had markedly higher MDA contents than diabetic rats receiving zinc supplementation. In conclusion, the present study shows that zinc has a protective effect against diabetes-induced peripheral nerve damage by stimulating metallothionein synthesis and downregulating oxidative stress.

Topics: Animals; Diabetes Mellitus, Experimental; Diabetic Neuropathies; Dietary Supplements; Dose-Response Relationship, Drug; Male; Metallothionein; Oxidative Stress; Peripheral Nerves; Rats; Rats, Sprague-Dawley; Streptozocin; Up-Regulation; Zinc

Because diabetic neuropathy (DN) appears to result from oxidative stress in neuronal tissues, antioxidant treatment should counteract the condition. Metallothionein (MT) and superoxide dismutase (SOD) are free-radical scavengers, but their ability to cross biological membranes is limited. Applying cell penetrating peptide technologies, we made Tat-MT and Tat-SOD constructs and tested their ability to protect PC12 cells, as surrogates of peripheral nerve cells, from various forms of oxidative damage. Tat-MT and Tat-SOD were successfully delivered to PC12 cells, and the intracellular activities of MT and SOD increased in line with the amount of protein delivered. These agents inhibited cellular damage and apoptotic signaling caused by three different types of injuries (high glucose, hypoxia, and advanced glycation end product injury). We also examined transduction of Tat-MT and Tat-SOD into Otsuka Long-Evans Tokushima fatty rats. A single ip injection of Tat-MT and Tat-SOD resulted in increased radical scavenging activity and decreased apoptosis, by inhibiting nuclear factor κB and MAPK signaling. Continuous treatment resulted in improved myelination of sciatic nerves and delayed the clinical development of DN. We conclude that effective delivery of a combination antioxidant treatment may facilitate the repair of damage in patients with DN.

Topics: Animals; Antioxidants; Apoptosis Regulatory Proteins; Cell Death; Cell Hypoxia; Diabetic Neuropathies; Drug Delivery Systems; Electrophysiological Phenomena; Glucose; Male; Metallothionein; Neurons; PC12 Cells; Rats; Rats, Inbred OLETF; Rats, Long-Evans; Reactive Oxygen Species; Recombinant Fusion Proteins; Superoxide Dismutase; tat Gene Products, Human Immunodeficiency Virus; Transduction, Genetic