Vascular endothelial growth factor B (VEGF-B) has recently been shown to be a promising novel neuroprotective agent for several neurodegenerative conditions. In the current study we extended previous work on neuroprotective potential for Parkinson's disease (PD) by testing an expanded dose range of VEGF-B (1 and 10 μg) and directly comparing both neuroprotective and neurorestorative effects of VEGF-B in progressive unilateral 6-hydroxydopamine (6-OHDA) PD models to a single dose of glial cell line-derived neurotrophic factor (GDNF, 10 μg), that has been established by several groups as a standard in both preclinical PD models. In the amphetamine-induced rotational tests the treatment with 1 and 10 μg VEGF-B resulted in significantly improved motor function of 6-OHDA-lesioned rats compared to vehicle-treated 6-OHDA-lesioned rats in the neuroprotection paradigm. Both doses of VEGF-B caused an increase in tyrosine hydroxylase (TH)-positive cell and fiber count in the substantia nigra (SN) and striatum in the neuroprotective experiment. The effect size was comparable to the effects seen with GDNF. In the neurorestoration paradigm, VEGF-B injection had no significant effect in either the behavioral or the immunohistochemical analyses, whereas GDNF injection significantly improved the amphetamine-induced rotational behavior and reduced TH-positive neuronal cell loss in the SN. We also present a strong positive correlation (p=1.9e-50) of the expression of VEGF-B with nuclear-encoded mitochondrial genes involved in fatty acid metabolism in rat midbrain, pointing to the mitochondria as a site of action of VEGF-B. GDNF showed a positive correlation with nuclear-encoded mitochondrial genes that was not nearly as strong (p=0.018). VEGF-B counteracted rotenone-induced reduction of (a) fatty acid transport protein 1 and 4 levels and (b) both Akt protein and phosphorylation levels in SH-SY5Y cells. We further verified VEGF-B expression in the human SN pars compacta of healthy controls and PD patients, in neuronal cells that show co-expression with neuromelanin. These results have demonstrated that VEGF-B has potential as a neuroprotective agent for PD therapy and should be further investigated.
Keywords: 2-[4-(2-hydroxyethyl)piperazin-1-yl]ethanesulfonic acid; 6-OHDA; 6-hydroxydopamine; AAV-2; ACSVL; ALS; ANOVA; Acyl-coenzyme A synthetase very long; BSA; CDNF; Chchd10; Chchd3; Coq9; Cs; DA; Etfb; FATP; FATP1; FATP4; Fh1; GDNF; HEPES; Hadhb; Idh3g; MANF; Mcee; OD; Ogdh; PBS; PD; PI; Parkinson’s disease; RT; SN; SNpc; Sdhb; Sdhc; Sdhd; TBST; TH; Tris-Buffered Saline+Tween 20; VEGF-B; adeno-associated virus; amyotrophic lateral sclerosis; analysis of variance; bovine serum albumin; cerebral dopamine neurotrophic factor; citrate synthase; coenzyme Q9 homolog; coiled-coil-helix-coiled-coil-helix domain containing 10; coiled-coil-helix-coiled-coil-helix domain containing 3; dopaminergic; electron-transfer-flavoprotein; fatty acid transport protein; fumarate hydratase 1; glial cell line-derived neurotrophic factor; human substantia nigra pars compacta; hydroxyacyl-CoA dehydrogenase/3-ketoacyl-CoA thiolase/enoyl-CoA hydratase; i.p.; intraperitoneal; isocitrate dehydrogenase [NAD] subunit gamma; mesencephalic astrocyte-derived neurotrophic factor; methylmalonyl CoA epimerase; mitochondria; neuroprotective factors; optical density; oxoglutarate (alpha-ketoglutarate) dehydrogenase lipoamide; phosphate-buffered saline; protease inhibitor; rodent 6-OHDA model; room temperature; substantia nigra; substantia nigra pars compacta; succinate dehydrogenase complex, subunit B, iron sulfur; succinate dehydrogenase complex, subunit C; succinate dehydrogenase complex, subunit D; tyrosine hydroxylase; vascular endothelial growth factor B.
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