Redistribution and degeneration of retinal astrocytes in experimental murine cerebral malaria: relationship to disruption of the blood-retinal barrier.
To determine whether astrocytes play a critical role in the pathogenesis 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 die showing cerebral symptoms; a "resolving" model, in which mice exhibit mild cerebral symptoms, but then recover; and a non-CM model, in which cerebral symptoms are not seen. In the fatal model, retinal astrocytes lost their even distribution from day 3 post-inoculation (p.i.) with malaria parasites, progressing to gliosis (day 5 p.i.), well before the onset of cerebral symptoms on day 6-7 p.i. At the terminal stage of the disease there was a loss of astrocyte processes contacting retinal vessels, often along vessel segments containing adherent monocytes. These features occurred in a mild form in the resolving model and were absent in the non-CM models. To investigate the mechanisms underlying these astrocytic changes, we carried out two experimental manipulations. Firstly, since dexamethasone ameliorates cerebral complications in the fatal CM model, the astrocytic response was monitored after dexamethasone treatment on days 0 and 1 p.i., or days 3 and 4 p.i. Second, to determine whether increased blood-retinal barrier (BRB) permeability initiates the astrocyte changes, breakdown of the BRB was induced experimentally by intra-carotid injection of arabinose and astrocyte morphology and distribution were examined 12, 24, and 48 h later. Retinal astrocytes in both the dexamethasone- and the arabinose-treated groups showed loss of even astrocyte distribution but no loss of astrocyte ensheathment of vessels. It is concluded that: i) astrocytes are involved in the pathogenesis of EMCM, since these changes are only prominent in the fatal model and occur substantially before the onset of cerebral symptoms; ii) the initial changes in astrocyte distribution may be a consequence of the increase in BRB permeability; and iii) the immune response triggered by the malaria parasite may be responsible for the loss of astrocyte ensheathment of vessel segments.
Medana
I M
IM
Department of Pathology, University of Sydney, Australia.
Chan-Ling
T
T
Hunt
N H
NH
D000818:Animals; D001089:Arabinose / Q000494:pharmacology; D001253:Astrocytes / Q000502:physiology* / Q000648:ultrastructure; D001813:Blood-Retinal Barrier / Q000187:drug effects; D001973:Bromodeoxyuridine / Q000378:metabolism; D003907:Dexamethasone / Q000494:pharmacology; D005904:Glial Fibrillary Acidic Protein / Q000378:metabolism / Q000494:pharmacology; D005938:Glucocorticoids / Q000494:pharmacology; D007150:Immunohistochemistry; D016779:Malaria, Cerebral / Q000188:drug therapy / Q000473:pathology / Q000503:physiopathology*; D051379:Mice; D008808:Mice, Inbred CBA; D008811:Mice, Inbred DBA; D009000:Monocytes / Q000187:drug effects; D051381:Rats; D012160:Retina / Q000502:physiology* / Q000648:ultrastructure; D012162:Retinal Degeneration / Q000473:pathology / Q000503:physiopathology*
D005904:Glial Fibrillary Acidic Protein; D005938:Glucocorticoids; D003907:Dexamethasone; D001089:Arabinose; D001973:Bromodeoxyuridine