Im. Medana et al., REDISTRIBUTION AND DEGENERATION OF RETINAL ASTROCYTES IN EXPERIMENTALMURINE CEREBRAL MALARIA - RELATIONSHIP TO DISRUPTION OF THE BLOOD-RETINAL BARRIER, Glia, 16(1), 1996, pp. 51-64
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.