Abstract Details

Title Clioquinol Elicits Cytotoxic Effects on Cultured Astrocytes Through the Impairment of the Autophagy-Lysosome Pathway

Topic General Neurology

Presentation(s) S51 - General Neurology: Models of Clinical Care and Disease (2:36 PM-2:48 PM)

Poster/Presentation
Number 009

Background CQ is a causative agent for subacute myeloopticoneuropathy (SMON), although the pathogenesis of SMON remains unclear. In contrast to its potential toxic effects, CQ has recently gained attention as a new therapy for neurodegenerative diseases. To utilize CQ as a possible new therapy, clarifying the mechanism of CQ-induced neurotoxicity is essential to avoid its potential adverse effects as seen in SMON.

Objective We evaluated a possible cytotoxicity of clioqinol (CQ) on glial cells.

Design/Methods We examined whether CQ induces cell death of astrocytes and if so, we will explore the molecular mechanisms for CQ-induced cell death of astrocytes (KT5 cells). We also examine lysosomal acid hydrolase activities in cells treated with CQ. Moreover, we investigate the effect of CQ for accumulation of autophagic vacuoles, lysosomal acidity, cellular ATP levels, reactive oxygen species (ROS) production, and mitochondrial membrane potential.

Results CQ caused up-regulation of microtubule-associated protein light chain-3 (LC3-II) and p62 in a dose- and time-dependent manner, suggesting autophagy flux and impairment of autophagic degradation. Consistent with these findings, CQ induced the accumulation of cellular autophagic vacuoles. In addition, CQ inhibited lysosomal enzyme activities without altering lysosomal pH. CQ also induced enhanced ROS production, a decline of cellular ATP levels, the change of mitochondrial membrane potential, and eventual cell death. This cell death did not appear to occur via apoptosis, because no obvious upregulation of activated caspase-3 activities or Annexin V expression was observed. Intriguingly, the addition of 3-methyladenine blocked the autophagic flux and augmented cytotoxicity.

Conclusions These results strongly suggest that CQ impairs autophagy-lysosomal system and therefore exerts cytotoxicity against cultured astrocytes. Furthermore, we demonstrated the inhibition of autophagy triggered by CQ augmented cytotoxicity, indicating that the autophagy flux initiated by CQ exerts cytoprotective effects on the cells.

Authors/Disclosures
PRESENTER	No disclosure on file
Tatsuro M. Mutoh, MD, PhD, FAAN (Fujita Health University Hospital)	Dr. Mutoh has nothing to disclose.

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