Neuroprotective response after photodynamic therapy: Role of vascular endothelial growth factor

Abstract

BackgroundAnti-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.MethodsWe 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.ResultsAt 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.ConclusionCytotoxic 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.

Resveratrol prevents the development of choroidal neovascularization by modulating AMP-activated protein kinase in macrophages and other cell types

“…However, the continuous inhibition of VEGF to suppress CNV may be harmful for the surrounding tissues, as VEGF has important physiological roles in maintaining the choroidal vessels that feed the retina [58] and in supporting the survival of retinal neural cells under pathogenic conditions [59,60]. Moreover, once CNV has developed, the neural retina may be permanently damaged.…”

Predicting recurrences of macular edema due to branch retinal vein occlusion during anti-vascular endothelial growth factor therapy

“…However, retinal neurons may have been more severely affected by changes in the microenvironment, such as cytokine and ionic changes, related to repeated macular edema over a prolonged period. Although VEGF plays a neuroprotective role [28,29], the extracellular fluid that causes edema may contain various neurotoxic cytokines that can damage the retinal neurons; previous reports have shown that levels of various inflammatory cytokines (e.g., interleukin-6 and monocyte chemotactic protein-1) were increased in the vitreous fluid of BRVO patients [30].…”

Fenofibrate Inhibits Cytochrome P450 Epoxygenase 2C Activity to Suppress Pathological Ocular Angiogenesis

“…Neovascularization can be suppressed with anti-angiogenic agents, such as anti-vascular endothelial growth factor (VEGF) molecules (Cheung et al, 2012, Liu et al, 2015). However, anti-VEGF therapy can also suppress normal vessel growth and neuronal survival (Suzuki et al, 2011, Sato et al, 2012). Therefore, therapeutic agents inhibiting ocular neovascularization with fewer adverse effects are desirable.…”