Title: The protective effect of VEGF-B and its receptor FLT1 in peripheral neuropathy.
Other Titles: Het beschermend effect van VEGF-B en zijn receptor FLT1 in perifere neuropathie.
Authors: Dhondt, Joke; M0318682
Issue Date: 9-Nov-2011
Abstract: Paclitaxel is a microtubule stabilizing agent that is used for the treatment of breast, lung and ovarian cancer. Severe chemotherapy-induced sensory neuropathy occurs in 33% of cancer patients treated with paclitaxel. It compromises the quality of life and is a major dose-limiting factor. Different compounds have been tested for their preventive or therapeutic potential on chemotherapy-induced peripheral neuropathy. Even though in vitro and preclinical studies have led to promising results, so far no clinical trial has identified a drug with effective neuroprotective activity in cancer patients without causing substantial toxicity. VEGF-B is a growth factor that binds to FLT1, a tyrosine kinase receptor. It is the odd one out in the VEGF family, a family of growth factors with mainly angiogenic and lymphangiogenic activities. Indeed, VEGF-Bs angiogenic effects are restricted to the heart. In contrast, it exerts protective effects on cardiomyocytes and on neurons of the central nervous system. Since VEGF-B has protective effects on retinal ganglion cells, dopaminergic and motoneurons in the central nervous system in vitro and in vivo without causing obvious vascular effects, we were interested in examining the therapeutic potential of this growth factor in the sensory nervous system.We studied the role of VEGF-B in the sensory nervous system and tested its therapeutic potential in paclitaxel-induced sensory neuropathy. Administration of low doses of paclitaxel to DRG neurons in vitro led to an increase in the expression of ATF3, a marker of neuronal stress and injury, while higher concentrations of paclitaxel caused loss of mitochondrial membrane potential and cell death. Administration of VEGF-B protein protected the sensory neurons of the DRG against paclitaxel-induced neuronal stress and cell death in vitro through its FLT1 receptor. It also preserved the mitochondrial membrane potential after exposure to paclitaxel.In our in vivo model of paclitaxel-induced peripheral neuropathy, paclitaxel was injected via the subplantar route into the skin of the hind limb for four consecutive days. This caused hypoalgesia, retrograde degeneration of the sensory axons and reduced vascular perfusion in the hind foot. Neuronal overexpression of VEGF-B or FLT1 prevented paclitaxel-induced neuropathy. Local delivery of VEGF-B gene or protein also exerted protective effects. Moreover, the protective effect of recombinant VEGF-B protein was a direct effect on the neurons. VEGF-B did not affect the blood vesselsUnlike VEGF, that has widespread effects on endothelial cells, VEGF-B does not affect the blood vessels in the nervous system. The lack of general toxicity after administration of VEGF-B makes it a suitable candidate for the treatment of paclitaxel-induced neuropathy and other neuronal diseases.
Publication status: published
KU Leuven publication type: TH
Appears in Collections:Vesalius Research Centre (-)
Laboratory of Translational Genetics (VIB-KU Leuven Center for Cancer Biology)

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