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01 November 2005

Morphine modulation of the ubiquitin-proteasome complex is neuroprotective

Suraj Rambhia, Kirk J. Mantione, George B. Stefano, Patrick Cadet

Med Sci Monit 2005; 11(11): BR386-396 :: ID: 430277

Abstract

Background: Over the past several decades, there is a growing need for the development of neuroprotective compounds, e.g, those that can prevent neural death. It was proposed that nitric oxide (NO), when induced
by morphine, would produce neuroprotection in a human neuroblastoma cell line when tested concomitantly with compounds that produce intracellular oxidative stress and neuroinfl ammation.
Material/Methods: NO involvement in intracellular protein degradation controlled by the ubiquitin-proteasome complex was examined. Experiments were performed examining the following: a) neural cell viability and morphology; b) gene specifi c mRNA levels via semi-quantitative RT-PCR; c) protein levels via Western blotting; d) enzymatic activity via fl uorogenic substrate-cleaving assays; and lastly, NO release via the Apollo 4000 real-time amperometric detector.
Results: Morphine induces the production of NO in human neuroblastoma cells, which can be blocked by
naloxone and the cNOS inhibitor L-NAME. Rotenone, which induces oxidative stress and increases the expression of the proteasomal catalytic X subunit, causes the cells to die and morphine inhibits this process via NO. Rotenone also increases the activity of the 20S proteasome, whereas morphine alone or in the presence of rotenone caused a decrease in the activity of the 20S proteasome. Morphine decreases the expression of the immunoproteasome catalytic subunit LMP7 in response to infl ammatory stimulation, demonstrating that morphine’s neuroprotective action does not apply to only oxidative stress. Morphine signifi cantly increases free ubiquitin, suggesting that morphine is inducing neuroprotection by reducing the amount of oxidized proteins targeted for degradation.
Conclusions: Signifi cant neuroprotection on the cellular and molecular levels was demonstrated and serves as a foundation for future work concerning the development of novel ligands for morphine’s mu3
opiate receptor in an effort to prevent cellular death associated with neurodegenerative diseases.

Keywords: NG-Nitroarginine Methyl Ester - pharmacology, Morphine - pharmacology, Enzyme Inhibitors - pharmacology, Naloxone - pharmacology, Neuritis - prevention & control, Neurons - enzymology, Neuroprotective Agents - pharmacology, Nitric Oxide - metabolism, Nitric Oxide Synthase Type I - metabolism, Oxidative Stress - drug effects, Proteasome Endopeptidase Complex - drug effects, Rotenone - pharmacology, Tumor Cells, Cultured, Ubiquitin - metabolism, Ubiquitin-Protein Ligase Complexes - drug effects

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Medical Science Monitor eISSN: 1643-3750