Pluronic-modified superoxide dismutase 1 attenuates angiotensin II-induced increase in intracellular superoxide in neurons.

Abstract

Overexpressing superoxide dismutase 1 (SOD1; also called Cu/ZnSOD), an intracellular superoxide (O(2)(*-))-scavenging enzyme, in central neurons inhibits angiotensin II (AngII) intraneuronal signaling and normalizes cardiovascular dysfunction in diseases associated with enhanced AngII signaling in the brain, including hypertension and heart failure. However, the blood-brain barrier and neuronal cell membranes impose a tremendous impediment for the delivery of SOD1 to central neurons, which hinders the potential therapeutic impact of SOD1 treatment on these diseases. To address this, we developed conjugates of SOD1 with poly(ethylene oxide)-poly(propylene oxide)-poly(ethylene oxide) block copolymer (Pluronic) (SOD1-P85 and SOD1-L81), which retained significant SOD1 enzymatic activity. The modified SOD1 effectively scavenged xanthine oxidase/hypoxanthine-derived O(2)(*-), as determined by HPLC and the measurement of 2-hydroxyethidium. Using catecholaminergic neurons, we observed an increase in neuronal uptake of SOD1-Pluronic after 1, 6, or 24h, compared to neurons treated with pure SOD1 or PEG-SOD1. Importantly, without inducing neuronal toxicity, SOD1-Pluronic conjugates significantly inhibited AngII-induced increases in intraneuronal O(2)(*-) levels. These data indicate that SOD1-Pluronic conjugates penetrate neuronal cell membranes, which results in elevated intracellular levels of functional SOD1. Pluronic conjugation may be a new delivery system for SOD1 into central neurons and therapeutically beneficial for AngII-related cardiovascular diseases.

• Authors: Xiang Yi, Matthew C Zimmerman, Ruifang Yang, Jing Tong, Serguei Vinogradov, Alexander V Kabanov
• Journal: Free radical biology & medicine (Free Radic Biol Med) Vol. 49 Issue 4 Pg. 548-58 (Aug 15 2010) ISSN: 1873-4596 [Electronic] United States
• PMID: 20493251 (Publication Type: Journal Article, Research Support, N.I.H., Extramural, Research Support, Non-U.S. Gov't)
• Copyright: Published by Elsevier Inc.

Chemical References

• pluronic block copolymer p85
• Poloxamer
• Superoxides
• Angiotensin II
• Poloxalene
• Superoxide Dismutase
• Superoxide Dismutase-1

Topics

• Angiotensin II (antagonists & inhibitors, pharmacology)
• Animals
• Cattle
• Cells, Cultured
• Neurons (cytology, drug effects, metabolism)
• Poloxalene (chemistry, pharmacology)
• Poloxamer (chemistry, pharmacology)
• Superoxide Dismutase (chemistry, metabolism)
• Superoxide Dismutase-1
• Superoxides (metabolism)