title: Pretreatment with the ciclosporin derivative NIM811 reduces delayed neuronal death in the hippocampus after transient forebrain ischaemia.
abstract: OBJECTIVE
  There have been several previous studies showing that ciclosporin, a ligand for cyclophilin D (CypD), reduces mitochondrial permeability transition (mPT) and ameliorates delayed neuronal death. NIM811 is a non-immunosuppressive ciclosporin derivative that also inhibits mPT, but has significantly less cytotoxicity than ciclosporin. Actually, in animal experiments, several investigators have reported that NIM811 ameliorates central nervous system disorders, such as traumatic brain injury, transient focal cerebral ischaemia and spinal cord injury. Therefore, we evaluated whether the ciclosporin derivative, NIM811 reduces mPT and ameliorates delayed neuronal death in the hippocampal CA1 sectors in mice when subjected to transient forebrain ischaemia.
  
  
  METHODS
  Male C57BL/6 mice were treated with 50 mg/kg ciclosporin, 10, 50 or 100 mg/kg NIM811 or phosphate-buffered saline. At 30 min post-injection, all mice were subjected to 20 min bilateral common carotid artery occlusion (BCCAO). To estimate delayed neuronal death, the sections were prepared for HE staining and terminal deoxynucleotidyl transferase-mediated dUTP end-labelling (TUNEL) staining at 72 h after 20 min BCCAO. Furthermore, using 5,5',6,6'-tetrachloro-1,1',3,3'-tetraethylbenzimidazolocarbocyanine iodide (JC-1) staining technique, we evaluated whether NIM811 (1, 10, 100 or 1000 microm) inhibited mPT in the neurons exposed to 100 microm glutamate.
  
  
  RESULTS
  Both delayed neuronal injury and apoptosis in the hippocampal CA1 sectors were significantly ameliorated at 72 h after transient forebrain ischaemia in the mice treated with 100 mg/kg NIM811 or 50 mg/kg ciclosporin. The treatments with 100 microm and 1,000 microm NIM811 significantly inhibited the reduction of mitochondrial membrane potential in the neurons exposed to 100 microm glutamate.
  
  
  CONCLUSIONS
  These findings strongly suggest that NIM811 inhibits mPT and ameliorates delayed neuronal death in mice subjected to transient forebrain ischaemia.
authors.affiliation: Department of Neurosurgery, Hokkaido University Graduate School of Medicine, Sapporo, Japan. karimasa@med.hokudai.ac.jp
authors.forename: Masaaki
authors.initials: M
authors.lastname: Hokari
authors.forename: Satoshi
authors.initials: S
authors.lastname: Kuroda
authors.forename: Yoshinobu
authors.initials: Y
authors.lastname: Iwasaki
mesh_terms: D000818:Animals; D017209:Apoptosis / Q000187:drug effects*; D001562:Benzimidazoles; D002232:Carbocyanines; D016572:Cyclosporine / Q000008:administration & dosage / Q000494:pharmacology* / Q000627:therapeutic use; D018698:Glutamic Acid / Q000633:toxicity; D006624:Hippocampus / Q000187:drug effects*; D020287:In Situ Nick-End Labeling; D002546:Ischemic Attack, Transient / Q000188:drug therapy* / Q000473:pathology; D008297:Male; D053078:Membrane Potential, Mitochondrial / Q000187:drug effects; D051379:Mice; D008810:Mice, Inbred C57BL; D008928:Mitochondria / Q000187:drug effects*; D009474:Neurons / Q000187:drug effects*; D018696:Neuroprotective Agents / Q000008:administration & dosage / Q000494:pharmacology* / Q000627:therapeutic use; D010539:Permeability; D016548:Prosencephalon / Q000187:drug effects
chemical_list: D001562:Benzimidazoles; D002232:Carbocyanines; D018696:Neuroprotective Agents; C068624:5,5',6,6'-tetrachloro-1,1',3,3'-tetraethylbenzimidazolocarbocyanine; D018698:Glutamic Acid; D016572:Cyclosporine