Reactive changes of retinal microglia during fatal murine cerebral malaria- Effects of dexamethasone and experimental permeabilization of the blood-brain barrier

Microglial activation and redistribution toward blood vessels are some of t he earliest observable events occurring within the central nervous system ( CNS) during fatal murine cerebral malaria (FMCM), To investigate stimuli th at might modulate microglial reactivity during FMCM we have performed two e xperimental manipulations and observed microglial responses in retinal whol e mounts. First, to determine whether increased blood-brain barrier (BBB) p ermeability in the absence of the malaria parasite initiates the microglial changes, BBB function was compromised experimentally by intracarotid injec tion of arabinose and retinae were examined 12, 24, or 36 hours later. Seco nd, to determine whether the immune response against the malaria parasite m odulates microglial, reactivity, infected mice were treated with dexamethas one before day 4 postinoculation. This treatment regime ameliorates cerebra l complications without affecting parasite growth. We observed that increas ed BBB permeability was sufficient to elicit thickening of microglial proce sses and redistribution of microglia toward the vasculature, characteristic of the early stages of FMCM, However, despite the presence of plasma const ituents in the CNS for up to 36 hours, microglia with amoeboid and vacuolat ed morphology were not observed. Dexamethasone treatment inhibited the up-r egulation of alpha-D-galactose expression and reactive morphological change s in microglia during FMCM. These results suggest that disruption of the CN S milieu by entry of plasma constituents, or circulating malaria parasites in the absence of an immune response, by themselves are insufficient to ind uce the reactive microglial changes that are characteristic of FMCM. In add ition, dexamethasone-sensitive event(s), presumably associated with immune system activation, occurring within the first few days of malaria infection are essential for the development of reactive microglia and subsequent fat al neurological complications.