title: In vitro evidence for mycophenolic acid dose-related cytotoxicity in human retinal cells.
abstract: OBJECTIVE
  Mycophenolic acid (MPA) is an immunosuppressive agent that controls noninfectious uveitis. Intravitreal MPA delivery may be a potential adjuvant therapy in patients who have to discontinue steroid or immunosuppressive systemic therapy because of side effects. The aims of this study are to evaluate the in vitro effects of MPA over human retinal pigment epithelium (ARPE-19) and human Muller cells (MIO M-1).
  
  
  METHODS
  ARPE-19 cells and MIO M-1 cells were exposed to 25, 50, and 100 µg/mL of MPA (Roche Bioscience, Palo Alto, CA) for 24 hours. Toxicity was evaluated by trypan blue dye-exclusion cell viability assay, caspase-3/7 apoptosis-related assay, and JC-1 mitochondrial membrane potential assay.
  
  
  RESULTS
  The MPA (25 µg/mL and 50 µg/mL) did not cause reduction in cell viability or significant change in caspase-3/7 activity in both cell lines tested. Mycophenolic acid (100 µg/mL) caused a significant decrease in cell viability (P < 0.01) and higher caspase-3/7 activity (P < 0.05) in both cell lines compared with untreated cells. The JC-1 mitochondrial membrane potential did not show statistically significant differences for both cell lines and all concentration tested when compared with untreated controls (P > 0.05).
  
  
  CONCLUSIONS
  Intraocular delivery may be a potential alternative for the treatment of noninfectious uveitis, either by intravitreal injection or sustained-release drug-delivery systems, in doses of 50 µg/mL or lower.
authors.affiliation: *Department of Ophthalmology, University of São Paulo Medical School, São Paulo, Brazil; †Department of Ophthalmology, School of Medicine, University of California, Irvine, California; ‡Department of Psychology, Psychology Institute, University of São Paulo, São Paulo, Brazil.
authors.forename: Leandro C
authors.initials: LC
authors.lastname: Zacharias
authors.forename: Francisco Max
authors.initials: FM
authors.lastname: Damico
authors.forename: Maria C
authors.initials: MC
authors.lastname: Kenney
authors.forename: Fabio
authors.initials: F
authors.lastname: Gasparin
authors.forename: Felipe B
authors.initials: FB
authors.lastname: Acquesta
authors.forename: Dora F
authors.initials: DF
authors.lastname: Ventura
authors.forename: Walter Y
authors.initials: WY
authors.lastname: Takahashi
authors.forename: Baruch D
authors.initials: BD
authors.lastname: Kuppermann
mesh_terms: D001562:Benzimidazoles / Q000494:pharmacology; D002232:Carbocyanines / Q000494:pharmacology; D053148:Caspase 3 / Q000378:metabolism; D053179:Caspase 7 / Q000378:metabolism; D002460:Cell Line; D002470:Cell Survival / Q000187:drug effects; D004305:Dose-Response Relationship, Drug; D004791:Enzyme Inhibitors / Q000633:toxicity*; D063928:Ependymoglial Cells / Q000187:drug effects* / Q000201:enzymology / Q000473:pathology; D006801:Humans; D053078:Membrane Potential, Mitochondrial / Q000187:drug effects; D009173:Mycophenolic Acid / Q000633:toxicity*; D055213:Retinal Pigment Epithelium / Q000187:drug effects* / Q000201:enzymology / Q000473:pathology; D014343:Trypan Blue / Q000378:metabolism
chemical_list: D001562:Benzimidazoles; D002232:Carbocyanines; D004791:Enzyme Inhibitors; C068624:5,5',6,6'-tetrachloro-1,1',3,3'-tetraethylbenzimidazolocarbocyanine; D053148:Caspase 3; D053179:Caspase 7; D009173:Mycophenolic Acid; D014343:Trypan Blue