The cytotoxicity of chronic neuroinflammation upon basal forebrain cholinergic neurons of rats can be attenuated by glutamatergic antagonism or cyclooxygenase-2 inhibition

• Published in: Experimental brain research Vol. 134; no. 1; pp. 58 - 65
• Main Authors: WILLARD, L. B, HAUSS-WEGRZYNIAK, B, DANYSZ, W, WENK, G. L
• Format: Journal Article
• Language: English
• Published: Berlin Springer 01.09.2000
• Subjects: Acetylcholine - metabolism; Animals; Anti-Inflammatory Agents, Non-Steroidal - pharmacology; Biological and medical sciences; Cholinergic Fibers - chemistry; Cholinergic Fibers - drug effects; Cholinergic Fibers - enzymology; Chronic Disease; cyclooxygenase 1; Cyclooxygenase 2; Encephalitis - drug therapy; Encephalitis - enzymology; Encephalitis - physiopathology; Excitatory Amino Acid Antagonists - pharmacology; Glutamic Acid - metabolism; Image Cytometry - methods; Isoenzymes - antagonists & inhibitors; Isoenzymes - metabolism; Male; Medical sciences; Memantine - pharmacology; Nerve Tissue Proteins - analysis; Neuropharmacology; Neuroprotective agent; Pharmacology. Drug treatments; Phenols - pharmacology; Prosencephalon - cytology; Prosencephalon - enzymology; Prosencephalon - immunology; Prostaglandin-Endoperoxide Synthases - metabolism; Radioimmunoassay; Rats; Rats, Inbred F344; Receptors, N-Methyl-D-Aspartate - antagonists & inhibitors; Thiazoles - pharmacology; Cholinergic neuron; Prostaglandin-endoperoxide synthase; Neuroprotection; Rat; Enzyme; Rodentia; Central nervous system; Cytotoxicity; Inflammation; Prosencephalon; Vertebrata; Mammalia; Cell death; Animal; Neurotoxin; Prostanoid; Excitatory aminoacid; Lipopolysaccharide; Oxidoreductases; Antagonist; NMDA receptor; Protection
• ISSN: 0014-4819; 1432-1106
• DOI: 10.1007/s002210000446

The proinflammagen lipopolysaccharide (LPS) was infused chronically (37 days) into the basal forebrain of rats. The current study determined whether the chronic administration of either a non-competitive N-methyl-D-aspartate- (NMDA-) sensitive receptor antagonist, memantine, or a selective cyclooxygenase-2 (COX2)/lipoxygenase inhibitor, CI987, could provide significant neuroprotection from the cytotoxic effects of LPS-induced neuroinflammation. Chronic LPS infusions decreased cortical choline acetyltransferase activity, which paralleled a decline in the number of choline-acetyltransferase-immunoreactive-cells within the basal forebrain as well as the number of activated resident microglia. The infusions appeared to be selective for cholinergic neurons. Peripheral administration of memantine (i.p.) or CI987 (s.c.) significantly attenuated the cytotoxic effects of the chronic inflammatory processes upon cholinergic cells within the basal forebrain. However, only CI987 attenuated the neuroinflammation produced by LPS and the subsequent changes in microglial activation. These results indicate that the cytotoxic effects of chronic neuroinflammation may involve prostanoid synthesis and may operate through NMDA receptors, and that the effects of prostaglandins occur upstream to NMDA-receptor activation.