Properties of activated microglia and pharmacologic interference by propentofylline

Abstract

Ameboid microglia are activated macrophages in the developing brain. With age, these cells undergo gradual transformation into the adult form, known as 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 substances. Responses to neuronal damage occur at various intervals after the insult, suggesting that microglia may be an attractive target for pharmacologic intervention. The cerebrospinal fluid (CSF) of Alzheimer disease (AD) patients contains antibodies that recognize activated microglia in the developing rat and in the ischemic gerbil brain. These results suggest that AD shares common mechanisms related to the activation of microglia with both these experimental models. In vitro, the xanthine derivative propentofylline (PPF) depresses the production of reactive oxygen intermediates produced by macrophages. To appreciate in vivo interactions of PPF, two models were employed: developing rats and adult gerbils exposed to ischemia. Newborn rats were 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 reperfusion. Brains were processed for immunocytochemistry. Reactive microglia were visualized with monoclonal antibodies OX18 and OX42 or AD-CSF microglia antibodies. In the case of ischemia, an antibody against the amyloid precursor protein (APP) (residues 676-695) was included. Newborn rats receiving 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 slight, and activated microglia were downregulated. The ability of PPF to interfere with activated microglia suggests that this agent may be useful for slowing progressive nerve cell death associated with AD, which is considered to be largely influenced by pathologic glial reactions.