title: Methylmercury Causes Blood-Brain Barrier Damage in Rats via Upregulation of Vascular Endothelial Growth Factor Expression.
abstract: Clinical manifestations of methylmercury (MeHg) intoxication include cerebellar ataxia, concentric constriction of visual fields, and sensory and auditory disturbances. The symptoms depend on the site of MeHg damage, such as the cerebellum and occipital lobes. However, the underlying mechanism of MeHg-induced tissue vulnerability remains to be elucidated. In the present study, we used a rat model of subacute MeHg intoxication to investigate possible MeHg-induced blood-brain barrier (BBB) damage. The model was established by exposing the rats to 20-ppm MeHg for up to 4 weeks; the rats exhibited severe cerebellar pathological changes, although there were no significant differences in mercury content among the different brain regions. BBB damage in the cerebellum after MeHg exposure was confirmed based on extravasation of endogenous immunoglobulin G (IgG) and decreased expression of rat endothelial cell antigen-1. Furthermore, expression of vascular endothelial growth factor (VEGF), a potent angiogenic growth factor, increased markedly in the cerebellum and mildly in the occipital lobe following MeHg exposure. VEGF expression was detected mainly in astrocytes of the BBB. Intravenous administration of anti-VEGF neutralizing antibody mildly reduced the rate of hind-limb crossing signs observed in MeHg-exposed rats. In conclusion, we demonstrated for the first time that MeHg induces BBB damage via upregulation of VEGF expression at the BBB in vivo. Further studies are required in order to determine whether treatment targeted at VEGF can ameliorate MeHg-induced toxicity.
authors.affiliation: Department of Neurology, Brain Research Institute, Niigata University, Niigata, Niigata, Japan.
authors.forename: Tetsuya
authors.initials: T
authors.lastname: Takahashi
authors.affiliation: Department of Basic Medical Sciences, National Institute for Minamata Disease, Minamata, Kumamoto, Japan.
authors.forename: Masatake
authors.initials: M
authors.lastname: Fujimura
authors.affiliation: Department of Neurology, Brain Research Institute, Niigata University, Niigata, Niigata, Japan.
authors.forename: Misaki
authors.initials: M
authors.lastname: Koyama
authors.affiliation: Department of Neurology, Brain Research Institute, Niigata University, Niigata, Niigata, Japan.
authors.forename: Masato
authors.initials: M
authors.lastname: Kanazawa
authors.affiliation: Department of Clinical Medicine, National Institute for Minamata Disease, Minamata, Kumamoto, Japan.
authors.forename: Fusako
authors.initials: F
authors.lastname: Usuki
authors.affiliation: Department of Neurology, Brain Research Institute, Niigata University, Niigata, Niigata, Japan.
authors.forename: Masatoyo
authors.initials: M
authors.lastname: Nishizawa
authors.affiliation: Department of Neurology, Brain Research Institute, Niigata University, Niigata, Niigata, Japan.
authors.forename: Takayoshi
authors.initials: T
authors.lastname: Shimohata
mesh_terms: D000818:Animals; D057134:Antibodies, Neutralizing / Q000627:therapeutic use; D001253:Astrocytes / Q000187:drug effects / Q000378:metabolism; D001812:Blood-Brain Barrier / Q000187:drug effects*; D001923:Brain Chemistry; D002199:Capillary Permeability / Q000187:drug effects*; D002524:Cerebellar Ataxia / Q000139:chemically induced* / Q000188:drug therapy / Q000503:physiopathology; D002531:Cerebellum / Q000187:drug effects* / Q000378:metabolism / Q000473:pathology; D008297:Male; D008628:Mercury / Q000032:analysis; D020262:Mercury Poisoning, Nervous System / Q000235:genetics* / Q000378:metabolism / Q000473:pathology; D008767:Methylmercury Compounds / Q000494:pharmacology / Q000633:toxicity*; D009778:Occipital Lobe / Q000187:drug effects / Q000378:metabolism / Q000473:pathology; D051381:Rats; D017208:Rats, Wistar; D013997:Time Factors; D015854:Up-Regulation / Q000187:drug effects; D042461:Vascular Endothelial Growth Factor A / Q000037:antagonists & inhibitors / Q000096:biosynthesis* / Q000235:genetics
chemical_list: D057134:Antibodies, Neutralizing; D008767:Methylmercury Compounds; D042461:Vascular Endothelial Growth Factor A; C467498:vascular endothelial growth factor A, rat; D008628:Mercury