title: Cyclosporine A Treatment Abrogates Ischemia-Induced Neuronal Cell Death by Preserving Mitochondrial Integrity through Upregulation of the Parkinson's Disease-Associated Protein DJ-1.
abstract: Hypoxic-ischemia alters mitochondrial membrane potential (Δψm), respiratory-related enzymes, and mitochondrial DNA (mtDNA). Drugs acting on mitochondria, such as cyclosporine A (CsA), may reveal novel mitochondria-based cell death signaling targets for stroke. Our previous studies showed that Parkinson's disease-associated protein DJ-1 participates in the acute endogenous neuroprotection after stroke via mitochondrial pathway. DJ-1 was detected immediately after stroke and efficiently translocated into the mitochondria offering a new venue for developing treatment strategies against stroke. Here, we examined a molecular interaction between CsA and mitochondrial integrity in the in vitro acute stroke model of oxygen glucose deprivation/reperfusion (OGD/R) injury with emphasis on DJ-1.
  
  
  
  Primary rat neuronal cells (PRNCs) were exposed to OGD/R injury and processed for immunocytochemistry, ELISA, and mitochondria-based molecular assays to reveal the role of DJ-1 in CsA modulation of mitochondrial integrity.
  
  
  
  Administration of CsA before stroke onset (24 h pre-OGD/R) afforded significantly much more robust neuroprotective effects than when CsA was initiated after stroke (2 h post-OGD/R), revealing that CsA exerted neuroprotection in the early phase of ischemic stroke. CsA prevented the mitochondria-dependent cell death signaling pathway involved in cytochrome c (Cyt c)-induced intrinsic apoptotic process. CsA preserved cellular ATP content, but not hexokinase activity under hypoxic conditions. CsA prevented both mtDNA decrement and Δψm degradation after reperfusion, and enhanced secretion of DJ-1 in the mitochondria, coupled with reduced oxidative stress.
  
  
  
  These observations provided evidence that CsA maintained mitochondrial integrity likely via DJ-1 upregulation, supporting the concept that mitochondria-based treatments targeting the early phase of disease progression may prove beneficial in stroke.
authors.affiliation: Center of Excellence for Aging & Brain Repair, Department of Neurosurgery and Brain Repair, University of South Florida Morsani College of Medicine, Tampa, FL, USA.|School of Physical Therapy & Rehabilitation Sciences, University of South Florida Morsani College of Medicine, Tampa, FL, USA.
authors.forename: Naoki
authors.initials: N
authors.lastname: Tajiri
authors.affiliation: Center of Excellence for Aging & Brain Repair, Department of Neurosurgery and Brain Repair, University of South Florida Morsani College of Medicine, Tampa, FL, USA.
authors.forename: Cesar V
authors.initials: CV
authors.lastname: Borlongan
authors.affiliation: Center of Excellence for Aging & Brain Repair, Department of Neurosurgery and Brain Repair, University of South Florida Morsani College of Medicine, Tampa, FL, USA.
authors.forename: Yuji
authors.initials: Y
authors.lastname: Kaneko
mesh_terms: D000255:Adenosine Triphosphate / Q000378:metabolism; D000704:Analysis of Variance; D000818:Animals; D002470:Cell Survival / Q000187:drug effects; D002540:Cerebral Cortex / Q000166:cytology; D016572:Cyclosporine / Q000494:pharmacology*; D045304:Cytochromes c / Q000633:toxicity; D004272:DNA, Mitochondrial / Q000378:metabolism; D004334:Drug Administration Schedule; D004622:Embryo, Mammalian; D005452:Fluoresceins / Q000493:pharmacokinetics; D005947:Glucose / Q000172:deficiency; D019298:Glucose-6-Phosphate / Q000378:metabolism; D005978:Glutathione / Q000378:metabolism; D000860:Hypoxia / Q000188:drug therapy* / Q000378:metabolism; D053078:Membrane Potential, Mitochondrial / Q000187:drug effects; D009474:Neurons / Q000187:drug effects* / Q000502:physiology*; D000071617:Protein Deglycase DJ-1 / Q000235:genetics / Q000378:metabolism*; D051381:Rats; D015854:Up-Regulation / Q000187:drug effects* / Q000235:genetics
chemical_list: D004272:DNA, Mitochondrial; D005452:Fluoresceins; C085925:calcein AM; D019298:Glucose-6-Phosphate; D016572:Cyclosporine; D000255:Adenosine Triphosphate; D045304:Cytochromes c; C404267:PARK7 protein, rat; D000071617:Protein Deglycase DJ-1; D005978:Glutathione; D005947:Glucose
keywords: Cytochrome c; Mitochondrial DNA; Mitochondrial membrane potential (Δψm); Mitochondrial permeability transition pore; Oxygen glucose deprivation/reperfusion injury