title: Amelioration of diabetic neuropathy by TAT-mediated enhanced delivery of metallothionein and SOD.
abstract: 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.
authors: Department of Internal Medicine and Bioengineering, Hanyang University College of Medicine and Engineering, Seongdong-gu, Seoul 471-020, Korea.
authors: Dongsoo
authors: D
authors: Min
authors: Hyunok
authors: H
authors: Kim
authors: Leejin
authors: L
authors: Park
authors: Tae Hwa
authors: TH
authors: Kim
authors: Sejin
authors: S
authors: Hwang
authors: Mi Jung
authors: MJ
authors: Kim
authors: Seongho
authors: S
authors: Jang
authors: Yongsoo
authors: Y
authors: Park
mesh_terms: D000818:Animals; D000975:Antioxidants / Q000008:administration & dosage; D051017:Apoptosis Regulatory Proteins / Q000378:metabolism; D016923:Cell Death / Q000187:drug effects; D015687:Cell Hypoxia / Q000187:drug effects; D003929:Diabetic Neuropathies / Q000188:drug therapy* / Q000378:metabolism / Q000473:pathology; D016503:Drug Delivery Systems; D055724:Electrophysiological Phenomena; D005947:Glucose / Q000633:toxicity; D008297:Male; D008668:Metallothionein / Q000008:administration & dosage* / Q000235:genetics; D009474:Neurons / Q000187:drug effects / Q000378:metabolism / Q000473:pathology; D016716:PC12 Cells; D051381:Rats; D020334:Rats, Inbred OLETF; D020318:Rats, Long-Evans; D017382:Reactive Oxygen Species / Q000633:toxicity; D011993:Recombinant Fusion Proteins / Q000008:administration & dosage / Q000235:genetics; D013482:Superoxide Dismutase / Q000008:administration & dosage* / Q000235:genetics; D014161:Transduction, Genetic; D054322:tat Gene Products, Human Immunodeficiency Virus / Q000008:administration & dosage / Q000235:genetics
chemical_list: D000975:Antioxidants; D051017:Apoptosis Regulatory Proteins; D017382:Reactive Oxygen Species; D011993:Recombinant Fusion Proteins; D054322:tat Gene Products, Human Immunodeficiency Virus; D008668:Metallothionein; D013482:Superoxide Dismutase; D005947:Glucose