Imidazoline drugs stabilize lysosomes and inhibit oxidative cytotoxicity in astrocytes.
Oxidative stress is a primary pathogenesis in the brain, which is particularly vulnerable to oxidative stress. Maintenance of astrocyte functions under oxidative stress is essential to prevent neuronal injuries and to recover neuronal functions in various pathologic conditions. Imidazoline drugs have affinities for imidazoline receptors, which are highly distributed in the brain, and have been shown to be neuroprotective. This study presented the protective effects of several imidazoline drugs against oxidative cytotoxicity, in primary cultures of astrocytes. Imidazoline drugs, such as idazoxan, guanabenz, guanfacine, BU224, and RS-45041-190, showed protective effects against naphthazarin-induced oxidative cytotoxicity, as evidenced by LDH release and Hoechst 33342/propidium iodide staining. The imidazoline drugs stabilized lysosomes and inhibited naphthazarin-induced lysosomal destabilization, as evidenced by acridine orange relocation. Guanabenz inhibited, the leakage of lysosomal cathepsin D to cytosol, the decreased mitochondrial potential, and the release of mitochondrial cytochrome c, which were induced by naphthazarin. The lysosomal destabilization by oxidative stress and other apoptotic signals and subsequent cathepsin D leakage to the cytosol can induce apoptotic changes of mitochondria and eventually cell death. Therefore, lysosomal stabilization by imidazoline drugs may be ascribed to their protective effects against oxidative cytotoxicity.
Choi
Sang-Hyun
SH
Department of Pharmacology, Korea University College of Medicine, Seoul, South Korea. shchoi@korea.ac.kr
Choi
Dong-Hee
DH
Lee
Jeong-Jin
JJ
Park
Moon-Sung
MS
Chun
Boe-Gwun
BG
D000165:Acridine Orange; D000317:Adrenergic alpha-Antagonists / Q000627:therapeutic use; D000818:Animals; D000831:Animals, Newborn; D000970:Antineoplastic Agents / Q000009:adverse effects / Q000494:pharmacology*; D017209:Apoptosis / Q000187:drug effects*; D001253:Astrocytes / Q000187:drug effects / Q000378:metabolism*; D002402:Cathepsin D / Q000378:metabolism; D002455:Cell Division / Q000187:drug effects*; D002460:Cell Line; D002540:Cerebral Cortex / Q000378:metabolism; D003574:Cytochrome c Group / Q000378:metabolism; D005397:Fish Venoms; D006143:Guanabenz / Q000627:therapeutic use; D016316:Guanfacine / Q000627:therapeutic use; D017320:HIV Protease Inhibitors / Q000494:pharmacology; D019329:Idazoxan / Q000627:therapeutic use; D007093:Imidazoles / Q000627:therapeutic use*; D007211:Indoles / Q000627:therapeutic use; D054833:Isoindoles; D007770:L-Lactate Dehydrogenase / Q000378:metabolism; D008024:Ligands; D008247:Lysosomes / Q000187:drug effects / Q000201:enzymology*; D008564:Membrane Potentials / Q000187:drug effects; D008928:Mitochondria / Q000502:physiology; D009285:Naphthoquinones / Q000009:adverse effects / Q000494:pharmacology*; D009457:Neuroglia / Q000378:metabolism; D010084:Oxidation-Reduction; D010436:Pepstatins / Q000494:pharmacology; D011480:Protease Inhibitors / Q000494:pharmacology; D051381:Rats; D017207:Rats, Sprague-Dawley; D017382:Reactive Oxygen Species / Q000378:metabolism; D011955:Receptors, Drug
D000317:Adrenergic alpha-Antagonists; D000970:Antineoplastic Agents; C105826:BU 224; D003574:Cytochrome c Group; D005397:Fish Venoms; D017320:HIV Protease Inhibitors; D007093:Imidazoles; D007211:Indoles; D054833:Isoindoles; D008024:Ligands; D009285:Naphthoquinones; D010436:Pepstatins; D011480:Protease Inhibitors; D017382:Reactive Oxygen Species; D011955:Receptors, Drug; C097364:4-chloro-2-(imidazolin-2-yl)isoindoline; D016316:Guanfacine; C005503:naphthazarin; D007770:L-Lactate Dehydrogenase; D002402:Cathepsin D; D000165:Acridine Orange; D006143:Guanabenz; C031375:pepstatin; D019329:Idazoxan