Roles of microglial purinergic receptors in inflammatory conditions of the brain

Hyun Beom Choi
2006
Microglia, the resident immune cells of brain, mediate inflammatory responses leading to progressive neuronal damage in neurodegenerative diseases. Binding of ATP to purinergic receptors activates microglia thereby inducing cellular responses in inflamed brain cells. The two families of purinergic receptors, labelled P2XR (ionotropic) and P2YR (metabotropic) contribute to inflammatory responses in microglia. The first two parts of my study focused on the involvement and role of the ionotropic
more » ... of the ionotropic purinergic receptor, P2X₇R in mediating inflammatory responses such as secretion of pro-inflammatory factors in vitro and in vivo. The final part of my study concentrated on purinergic receptor-dependent intracellular Ca²⁺([Ca²⁺]i) mobilization and functional responses in human fetal microglia [i.e. foetal microglia]. A detailed in vivo study was carried out on the involvement of P2X₇R in mediating lipopolysaccharide (LPS)-induced inflammatory responses and neuronal damage in rat striatum. LPS-injected striatum exhibited a marked increase in the expression and production of P2X₇R compared with control (saline)-injected animals. Additionally, LPS injection upregulated a host of pro-inflammatory mediators and reduced neuronal viability. The P2X₇R antagonist, oxidized ATP (oxATP) was effective in attenuating expressions of all inflammatory mediators; most importantly oxATP was protective for striatal neurons. In vitro, I found LPS stimulation of cultured human microglia enhanced cellular expressions of inflammatory mediators and increased [Ca²⁺]i mobilization which were blocked with oxATP treatment. Overall, the results from this work indicate that P2X₇R plays a critical role in LPS-induced inflammatory responses including induction of neuronal damage. Subsequently a series of studies was designed to examine putative roles of P2X₇R in mediating inflammatory responses with relevance to the pathology typical of Alzheimer's disease (AD). First, I found microglia isolated from AD brains expressed enhanced P2X₇R compared with microg [...]
doi:10.14288/1.0092895 fatcat:q7volew7mnf47n25ash64hin7q