Ameboid microglia are activated macrophages in the developing brain. With a
ge, these cells undergo gradual transformation into the adult form, known a
s ramified or resting microglia. In response to neuronal insults, microglia
change their morphology and immunophenotype and proliferate to become full
-blown brain macrophages. Microglia release a battery of neurotoxic substan
ces. Responses to neuronal damage occur at various intervals after the insu
lt, suggesting that microglia may be an attractive target for pharmacologic
intervention. The cerebrospinal fluid (CSF) of Alzheimer disease (AD) pati
ents contains antibodies that recognize activated microglia in the developi
ng rat and in the ischemic gerbil brain. These results suggest that AD shar
es common mechanisms related to the activation of microglia with both these
experimental models. In vitro, the xanthine derivative propentofylline (PP
F) depresses the production of reactive oxygen intermediates produced by ma
crophages. To appreciate in vivo interactions of PPF, two models were emplo
yed: developing rats and adult gerbils exposed to ischemia. Newborn rats we
re administered PPF (10 mg/kg) for 7 days. Gerbils were exposed to 5 min of
transient forebrain ischemia and received PPF (10 mg/kg) 24 h later until
the day before sacrifice. Animals were sacrificed at 7 or 14 days after rep
erfusion. Brains were processed for immunocytochemistry. Reactive microglia
were visualized with monoclonal antibodies OX18 and OX42 or AD-CSF microgl
ia antibodies. In the case of ischemia, an antibody against the amyloid pre
cursor protein (APP) (residues 676-695) was included. Newborn rats receivin
g PPF for 7 days displayed a dramatic reduction in the number of activated
microglia compared with untreated littermates. Ischemic control in gerbils
showed complete nerve death, accumulations of APP, and enhanced microglial
reactivity. In gerbils receiving PPF, APP accumulation was absent or very s
light, and activated microglia were downregulated. The ability of PPF to in
terfere with activated microglia suggests that this agent may be useful for
slowing progressive nerve cell death associated with AD, which is consider
ed to be largely influenced by pathologic glial reactions.