REDISTRIBUTION AND DEGENERATION OF RETINAL ASTROCYTES IN EXPERIMENTALMURINE CEREBRAL MALARIA - RELATIONSHIP TO DISRUPTION OF THE BLOOD-RETINAL BARRIER

To determine whether astrocytes play a critical role in the pathogenes is of experimental murine cerebral malaria (EMCM), we examined changes in astrocyte morphology and distribution, using retinal wholemounts, in three models: a fatal cerebral malaria (CM) model, in which mice di e showing cerebral symptoms; a ''resolving'' model, in which mice exhi bit mild cerebral symptoms, but then recover; and a non-CM model, in w hich cerebral symptoms are not seen. In the fatal model, retinal astro cytes lost their even distribution from day 3 post-inoculation (p.i.) with malaria parasites, progressing to gliosis (day 5 p.i.), well befo re the onset of cerebral symptoms on day 6-7 p.i. At the terminal stag e of the disease there was a loss of astrocyte processes contacting re tinal vessels, often along vessel segments containing adherent monocyt es. These features occurred in a mild form in the resolving model and were absent in the non-CM models. To investigate the mechanisms underl ying these astrocytic changes, we carried out two experimental manipul ations. Firstly, since dexamethasone ameliorates cerebral complication s in the fatal CM model, the astrocytic response was monitored after d examethasone treatment on days 0 and 1 p.i., or days 3 and 4 p.i. Seco nd, to determine whether increased blood-retinal barrier (BRB) permeab ility initiates the astrocyte changes, breakdown of the BRB was induce d experimentally by intra-carotid injection of arabinose and astrocyte morphology and distribution were examined 12, 24, and 48 h later. Ret inal astrocytes in both the dexamethasone- and the arabinose-treated g roups showed loss of even astrocyte distribution but no loss of astroc yte ensheathment of vessels. It is concluded that: i) astrocytes are i nvolved in the pathogenesis of EMCM, since these changes are only prom inent in the fatal model and occur substantially before the onset of c erebral symptoms; ii)the initial changes in astrocyte distribution may be a consequence of the increase in BRB permeability; and iii) the im mune response triggered by the malaria parasite may be responsible for the loss of astrocyte ensheathment of vessel segments. (C) 1996 Wiley -Liss, Inc.