Pharmacological antagonism of the ionotropic purinergic receptor- P2X7R has been studied for effects on inflammatory reactivity and neuronal viability in amyloid-beta1-42-injected rat hippocampus. Amyloid-beta1-42-injected brains (7-day postinjection) demonstrated marked increases in P2X7R expression, gliosis, leakiness of blood-brain barrier and loss of hippocampal neurons. The P2X7R antagonist, Brilliant Blue G reduced levels of purinergic receptor expression, attenuated gliosis, diminished leakiness of blood-brain barrier and was neuroprotective in peptide-injected brain. Brilliant Blue G also demonstrated neuroprotection and antagonism against inflammatory responses induced by the P2X7R agonist, 2',3'-(benzoyl-4-benzoyl)-ATP. This study has shown intrahippocampal injection of Ab1–42  or the P2X7R ligand BzATP is associated with increased inflammatory reactivity, BBB leakiness and neurodegeneration.  Antagonism of P2X7R is suggested as a novel maneuver to reduce the consequences of inflammatory reactivity in AD brain.The findings constitute the first report that pharmacological inhibition of P2X7R, possibly by acting to inhibit inflammatory reactivity, confers neuroprotection in an animal model of Alzheimer's disease brain.