Estrogen and P2 Purinergic Receptor Systems in Microglia: Therapeutic Targets for Neuroprotection

Microglia, the primary resident immune cell population in the CNS, react to signals of injury or infection and produce inflammatory cytokines, chemokines, and reactive oxygen species, many of which can be neurotoxic in large quantities. Indeed microglial hyperactivation is thought to contribute to the pathology of many neurodegenerative disorders as well as ischemic and traumatic brain injuries, suggesting that agents with the capacity to target microglial activities may be beneficial for treating neuronal injury. In this review, we discuss two seemingly unrelated microglial receptor signaling systems that potently modulate many microglial properties; purinergic P2 and estrogen receptors. Purinergic receptors regulate key microglial functions, including their production of pro-inflammatory cytokines, neurotrophic factors, migration, phagocytosis and chemotaxis. Many of these same endpoints are also altered by estrogen receptor signaling in microglia. Here we summarize the current microglial research in both receptor areas, particularly as it relates to ischemic and traumatic CNS injuries. We provide evidence from our own laboratory of potential cross-talk between these receptor systems and discuss evidence indicating that both purinergic and estrogen receptors may represent useful therapeutic targets for the treatment of CNS disorders.