title: Neuroprotective response after photodynamic therapy: role of vascular endothelial growth factor.
abstract: BACKGROUND
  Anti-vascular endothelial growth factor (VEGF) drugs and/or photodynamic therapy (PDT) constitute current treatments targeting pathological vascular tissues in tumors and age-related macular degeneration. Concern that PDT might induce VEGF and exacerbate the disease has led us to current practice of using anti-VEGF drugs with PDT simultaneously. However, the underlying molecular mechanisms of these therapies are not well understood.
  
  
  METHODS
  We assessed VEGF levels after PDT of normal mouse retinal tissue, using a laser duration that did not cause obvious tissue damage. To determine the role of PDT-induced VEGF and its downstream signaling, we intravitreally injected a VEGF inhibitor, VEGFR1 Fc, or a PI3K/Akt inhibitor, LY294002, immediately after PDT. Then, histological and biochemical changes of the retinal tissue were analyzed by immunohistochemistry and immunoblot analyses, respectively.
  
  
  RESULTS
  At both the mRNA and protein levels, VEGF was upregulated immediately and transiently after PDT. VEGF suppression after PDT resulted in apoptotic destruction of the photoreceptor cell layer in only the irradiated area during PDT. Under these conditions, activation of the anti-apoptotic molecule Akt was suppressed in the irradiated area, and levels of the pro-apoptotic protein BAX were increased. Intravitreal injection of a PI3K/Akt inhibitor immediately after PDT increased BAX levels and photoreceptor cell apoptosis.
  
  
  CONCLUSIONS
  Cytotoxic stress caused by PDT, at levels that do not cause overt tissue damage, induces VEGF and activates Akt to rescue the neural tissue, suppressing BAX. Thus, the immediate and transient induction of VEGF after PDT is neuroprotective.
authors.affiliation: Laboratory of Retinal Cell Biology, Keio University School of Medicine, Shinanomachi, Shinjuku-ku, Tokyo, Japan.
authors.forename: Misa
authors.initials: M
authors.lastname: Suzuki
authors.forename: Yoko
authors.initials: Y
authors.lastname: Ozawa
authors.forename: Shunsuke
authors.initials: S
authors.lastname: Kubota
authors.forename: Manabu
authors.initials: M
authors.lastname: Hirasawa
authors.forename: Seiji
authors.initials: S
authors.lastname: Miyake
authors.forename: Kousuke
authors.initials: K
authors.lastname: Noda
authors.forename: Kazuo
authors.initials: K
authors.lastname: Tsubota
authors.forename: Kazuaki
authors.initials: K
authors.lastname: Kadonosono
authors.forename: Susumu
authors.initials: S
authors.lastname: Ishida
mesh_terms: D000818:Animals; D017209:Apoptosis / Q000502:physiology; D007834:Lasers; D051379:Mice; D008810:Mice, Inbred C57BL; D018696:Neuroprotective Agents / Q000378:metabolism*; D019869:Phosphatidylinositol 3-Kinases / Q000378:metabolism; D000081082:Phosphoinositide-3 Kinase Inhibitors; D010778:Photochemotherapy / Q000379:methods*; D051057:Proto-Oncogene Proteins c-akt / Q000037:antagonists & inhibitors / Q000378:metabolism; D012160:Retina / Q000166:cytology / Q000378:metabolism / Q000473:pathology / Q000528:radiation effects; D015398:Signal Transduction / Q000502:physiology; D042461:Vascular Endothelial Growth Factor A / Q000235:genetics / Q000378:metabolism*; D040281:Vascular Endothelial Growth Factor Receptor-1 / Q000037:antagonists & inhibitors / Q000378:metabolism; D051028:bcl-2-Associated X Protein / Q000235:genetics / Q000378:metabolism
chemical_list: D018696:Neuroprotective Agents; D019869:Phosphatidylinositol 3-Kinases; D000081082:Phosphoinositide-3 Kinase Inhibitors; D051057:Proto-Oncogene Proteins c-akt; D042461:Vascular Endothelial Growth Factor A; D040281:Vascular Endothelial Growth Factor Receptor-1; D051028:bcl-2-Associated X Protein