The PARF Antagonist AChE Inhibitor PMS777 Attenuates LPS-Induced Acute Neuroinflammation

Abstract

When injected into the fourth ventricle, the proinflammagen lipopolysaccharide (LPS) induces acute neuroinflammation in the whole brain of rats. The new compound PMS777 is a novel platelet-activating factor receptor (PAFR) antagonist and acetylcholinesterase (AChE) inhibitor. The current study determined whether PMS777 could provide neuroprotection from the cytotoxic effects associated with LPS-induced neuroinflammation. Acute LPS infusions impaired recognition in rats as measured by the Morris water maze. In addition, LPS infusions decreased the number of AChE positive cells, and increased the number of OX-42 immunoreactive microglia and GFAP immunoreactive astrocytes in the hippocampus, the cortex and the basal nuclei. Furthermore, acute infusions of LPS also impaired organelles associated with protein synthesis. Peripheral administration of PMS777 (i.e., intraperitoneal injection) protected against the impairment in recognition, and attenuated the cytotoxic effects of the acute inflammatory processes upon cholinergic cells, microglia, astrocytes and ultrastructure of hippocampal cells. Here, we propose that the cytotoxic effects of acute neuroinflammation may involve the release of PAF and loss of cholinergic neurons, and this mechanism leads to neuronal dysfunction and spatial memory impairment. The PAFR antagonist inhibitor and AChE inhibitor PMS777 could provide neuroprotection from the cytotoxic effects induced by LPS.