ACUTE 3-NITROPROPIONIC ACID INTOXICATION INDUCES STRIATAL ASTROCYTIC CELL-DEATH AND DYSFUNCTION OF THE BLOOD-BRAIN-BARRIER - INVOLVEMENT OFDOPAMINE TOXICITY

Mechanisms underlying the selective vulnerability of the lateral stria tal area to the toxic effects of 3-nitropropionic acid (3-NPA) were in vestigated in rats. A single exposure to 3-NPA (20 mg/kg, s.c.) induce d no deficits in behavior and histology, but subsequent injection prod uced motor symptoms, catalepsy, lip smacking, abnormal gait, paddling, rolling, opisthotonos, tremor, recombence, somnolence and so on, in 3 0% of the animals within a few hours. Diffusion-weighted magnetic reso nance 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 imm unoglobulin G was detected, indicating blood-brain barrier (BBB) dysfu nction. Electron microscopy revealed edema and disorganization of stru ctures inside the astrocytic end-feet around the branches of the later al striatal artery. Neurons were less vulnerable than astrocytes to th e 3-NPA injury. Treatment of the rats with D-2 receptor agonist prior to exposure to 3-NPA attenuated the behavioral abnormalities and histo logical damage whereas pretreatment with D-2 antagonist exacerbated th ese changes. The concentrations of extracellular dopamine (DA) and dih ydroxyphenyl acetic acid (DOPAC) were both increased in rats exposed t o 3-NPA. In vitro imaging of astrocytes revealed a progressive increas e in [Ca2+](i) after superfusion with 3-NPA, and the 'ceiling' level w as maintained even after extensive washing. DA superfusion also increa sed the astrocytic [Ca2+](i) and this increase was reversible. Data in dicate that 3-NPA-induced striatal damage was associated with astrocyt ic cell death and dysfunction of the BBB. Intracellular edema and extr eme Ca2+ overload induced by the toxin were further aggravated by an i ncrease in the level of DA activity. These factors acting either singl y or in combination may trigger astrocyte destruction. (C) 1997 Elsevi er Science Ireland Ltd.