title: Acute 3-nitropropionic acid intoxication induces striatal astrocytic cell death and dysfunction of the blood-brain barrier: involvement of dopamine toxicity.
abstract: Mechanisms underlying the selective vulnerability of the lateral striatal area to the toxic effects of 3-nitropropionic acid (3-NPA) were investigated in rats. A single exposure to 3-NPA (20 mg/kg, s.c.) induced no deficits in behavior and histology, but subsequent injection produced motor symptoms, catalepsy, lip smacking, abnormal gait, paddling, rolling, opisthotonos, tremor, recombence, somnolence and so on, in 30% of the animals within a few hours. Diffusion-weighted magnetic resonance imaging of the brains revealed an area of high signal intensity in the bilateral striata. By this stage (within a few hours), striatal astrocytes had become swollen and disintegrated. Extravasation of immunoglobulin G was detected, indicating blood-brain barrier (BBB) dysfunction. Electron microscopy revealed edema and disorganization of structures inside the astrocytic end-feet around the branches of the lateral striatal artery. Neurons were less vulnerable than astrocytes to the 3-NPA injury. Treatment of the rats with D2 receptor agonist prior to exposure to 3-NPA attenuated the behavioral abnormalities and histological damage whereas pretreatment with D2 antagonist exacerbated these changes. The concentrations of extracellular dopamine (DA) and dihydroxyphenyl acetic acid (DOPAC) were both increased in rats exposed to 3-NPA. In vitro imaging of astrocytes revealed a progressive increase in [Ca2+]i after superfusion with 3-NPA, and the 'ceiling' level was maintained even after extensive washing. DA superfusion also increased the astrocytic [Ca2+]i and this increase was reversible. Data indicate that 3-NPA-induced striatal damage was associated with astrocytic cell death and dysfunction of the BBB. Intracellular edema and extreme Ca2+ overload induced by the toxin were further aggravated by an increase in the level of DA activity. These factors acting either singly or in combination may trigger astrocyte destruction.
authors.affiliation: Department of Physiology, Nagoya City University Medical School, Mizuho-ku, Nagoya, Japan. hitoo-n@med.nagoya-cu.ac.jp
authors.forename: H
authors.initials: H
authors.lastname: Nishino
authors.forename: M
authors.initials: M
authors.lastname: Kumazaki
authors.forename: A
authors.initials: A
authors.lastname: Fukuda
authors.forename: I
authors.initials: I
authors.lastname: Fujimoto
authors.forename: Y
authors.initials: Y
authors.lastname: Shimano
authors.forename: H
authors.initials: H
authors.lastname: Hida
authors.forename: T
authors.initials: T
authors.lastname: Sakurai
authors.forename: S B
authors.initials: SB
authors.lastname: Deshpande
authors.forename: H
authors.initials: H
authors.lastname: Shimizu
authors.forename: S
authors.initials: S
authors.lastname: Morikawa
authors.forename: T
authors.initials: T
authors.lastname: Inubushi
mesh_terms: D000818:Animals; D001253:Astrocytes / Q000187:drug effects*; D001522:Behavior, Animal / Q000187:drug effects; D001812:Blood-Brain Barrier / Q000187:drug effects*; D002118:Calcium / Q000378:metabolism; D016923:Cell Death / Q000187:drug effects; D004298:Dopamine / Q000378:metabolism / Q000633:toxicity*; D018492:Dopamine Antagonists / Q000494:pharmacology; D007091:Image Processing, Computer-Assisted; D007150:Immunohistochemistry; D008279:Magnetic Resonance Imaging; D008297:Male; D017551:Microdialysis; D008854:Microscopy, Electron; D017072:Neostriatum / Q000166:cytology* / Q000187:drug effects; D009498:Neurotoxins / Q000633:toxicity*; D009574:Nitro Compounds; D011422:Propionates / Q000633:toxicity*; D051381:Rats; D017208:Rats, Wistar
chemical_list: D018492:Dopamine Antagonists; D009498:Neurotoxins; D009574:Nitro Compounds; D011422:Propionates; C015392:3-nitropropionic acid; D002118:Calcium; D004298:Dopamine