Neuroprotective response after photodynamic therapy

Role of vascular endothelial growth factor

Misa Suzuki, Yoko Ozawa, Shunsuke Kubota, Manabu Hirasawa, Seiji Miyake, Kousuke Noda, Kazuo Tsubota, Kazuaki Kadonosono, Susumu Ishida

Research output: Contribution to journalArticle

10 Citations (Scopus)

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.Conclusion: 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.

Original languageEnglish
Article number176
JournalJournal of Neuroinflammation
Volume8
DOIs
Publication statusPublished - 2011 Dec 16

Fingerprint

Photochemotherapy
Vascular Endothelial Growth Factor A
Photoreceptor Cells
Phosphatidylinositol 3-Kinases
Apoptosis Regulatory Proteins
Intravitreal Injections
2-(4-morpholinyl)-8-phenyl-4H-1-benzopyran-4-one
Macular Degeneration
Blood Vessels
Lasers
Immunohistochemistry
Apoptosis

Keywords

  • Akt
  • Bax
  • Neuroprotection
  • Pdt
  • Retina
  • Vegf

ASJC Scopus subject areas

  • Cellular and Molecular Neuroscience
  • Neurology
  • Immunology
  • Neuroscience(all)

Cite this

Neuroprotective response after photodynamic therapy : Role of vascular endothelial growth factor. / Suzuki, Misa; Ozawa, Yoko; Kubota, Shunsuke; Hirasawa, Manabu; Miyake, Seiji; Noda, Kousuke; Tsubota, Kazuo; Kadonosono, Kazuaki; Ishida, Susumu.

In: Journal of Neuroinflammation, Vol. 8, 176, 16.12.2011.

Research output: Contribution to journalArticle

Suzuki, Misa ; Ozawa, Yoko ; Kubota, Shunsuke ; Hirasawa, Manabu ; Miyake, Seiji ; Noda, Kousuke ; Tsubota, Kazuo ; Kadonosono, Kazuaki ; Ishida, Susumu. / Neuroprotective response after photodynamic therapy : Role of vascular endothelial growth factor. In: Journal of Neuroinflammation. 2011 ; Vol. 8.
@article{b50034bffa4e47e6bbeb7de89d83059a,
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.Conclusion: 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.",
keywords = "Akt, Bax, Neuroprotection, Pdt, Retina, Vegf",
author = "Misa Suzuki and Yoko Ozawa and Shunsuke Kubota and Manabu Hirasawa and Seiji Miyake and Kousuke Noda and Kazuo Tsubota and Kazuaki Kadonosono and Susumu Ishida",
year = "2011",
month = "12",
day = "16",
doi = "10.1186/1742-2094-8-176",
language = "English",
volume = "8",
journal = "Journal of Neuroinflammation",
issn = "1742-2094",
publisher = "BioMed Central",

}

TY - JOUR

T1 - Neuroprotective response after photodynamic therapy

T2 - Role of vascular endothelial growth factor

AU - Suzuki, Misa

AU - Ozawa, Yoko

AU - Kubota, Shunsuke

AU - Hirasawa, Manabu

AU - Miyake, Seiji

AU - Noda, Kousuke

AU - Tsubota, Kazuo

AU - Kadonosono, Kazuaki

AU - Ishida, Susumu

PY - 2011/12/16

Y1 - 2011/12/16

N2 - 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.Conclusion: 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.

AB - 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.Conclusion: 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.

KW - Akt

KW - Bax

KW - Neuroprotection

KW - Pdt

KW - Retina

KW - Vegf

UR - http://www.scopus.com/inward/record.url?scp=83455203275&partnerID=8YFLogxK

UR - http://www.scopus.com/inward/citedby.url?scp=83455203275&partnerID=8YFLogxK

U2 - 10.1186/1742-2094-8-176

DO - 10.1186/1742-2094-8-176

M3 - Article

VL - 8

JO - Journal of Neuroinflammation

JF - Journal of Neuroinflammation

SN - 1742-2094

M1 - 176

ER -