EFFECTS OF CHRONIC INTRAHIPPOCAMPAL INFUSION OF LIPOPOLYSACCHARIDE INTHE RAT

Astrogliosis and microglial activation are associated with many neurod egenerative disorders including multiple sclerosis, its animal model e xperimental allergic encephalomyelitis, and Alzheimer's disease. To ad dress the hypothesis that chronic astroglial or microglial activation could be contributing factors to neuronal death or injury, the immunos timulant lipopolysaccharide was infused into the hippocampus for 16 da ys using Alzet mini-osmotic pumps attached to a cannula. Placement of the cannula and infusion of vehicle for 16 days caused a hippocampal l esion with a volume of 0.5 +/- 0.1 mm(3). Infusion of lipopolysacchari de at the dose of 2.0 mu g/day produced a lesion of 4.9 +/- 1.3 mm(3) (P < 0.01, Newman-Keuls), whereas, a lower dose of 0.2 mu g/day caused a lesion of 1.3 +/- 0.3 mm(3) (P < 0.05). The lesion was defined as a focal necrotic reaction with fibrin deposits outlining an area at an early stage of encapsulation. No apparent neuronal loss was observed b y Cresyl Violet staining outside the encapsulated necrotic area. There was a pronounced astrogliosis and an increase in activated macrophage s throughout the lipopolysaccharide-infused hippocampus as determined by glial fibrillary acidic protein and ED-1 immunohistochemistry, resp ectively. Choline acetyltransferase and glutamic acid decarboxylase en zyme activities, used as functional measures of neuronal viability for cholinergic and GABAergic neurons, respectively, were unaffected in t he hippocampus following a 16 day infusion of lipopolysaccharide at th e doses of 0.2, 0.6 and 2.0 mu g/day. In addition, unilateral infusion of lipopolysaccharide into the hippocampus did not affect 24 h locomo tion when tested on day 13, body temperature or weight gain. Under the experimental conditions employed in the present study, chronic infusi on of lipopolysaccharide into the hippocampus resulted in a dose-depen dent focal necrotic lesion at the site of infusion. In tissue surround ing the encapsulated lesion, neurons were present among the reactive a strocytes and increased number of macrophages suggesting that astrocyt es and macrophages can be activated without causing neuronal loss.