Mechanisms to prevent the toxicity of chronic neuroinflammation on forebrain cholinergic neurons.
Inflammatory processes may play an important role in the degeneration of basal forebrain cholinergic cells Alzheimer's disease. We infused the proinflammagen lipopolysaccharide into the basal forebrain of young rats and determined whether the chronic administration of two novel non-steroidal anti-inflammatory drugs or a pan-caspase synthesis inhibitor, z-Val-Ala-Asp(OMe)-fluoromethyl ketone (zVAD), could provide neuroprotection from the cytotoxic effects of the neuroinflammation. Chronic lipopolysaccharide infusions decreased choline acetyltransferase activity and increased the number of activated microglia within the basal forebrain region. The level of caspases 3, 8 and 9 was increased in ventral caudate/putamen. Non-steroidal anti-inflammatory drug therapy attenuated the toxicity of the inflammation upon cholinergic cells and reduced caspases 3, 8 and 9 activity in the caudate/putamen. zVAD treatment significantly decreased the levels of caspases 3, 8 and 9 but did not provide neuroprotection for the cholinergic neurons. These results suggest that prostaglandins contribute to the degeneration of forebrain cholinergic neurons in Alzheimer's disease.
Arizona Research Laboratories, Division of Neural Systems, Memory and Aging, University of Arizona, 384 Life Sciences North Building, Tucson, AZ 85724, USA. gary@nsma.arizona.edu
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Wenk
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McGann
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Mencarelli
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Hauss-Wegrzyniak
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Del Soldato
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Fiorucci
D000590:Amino Acid Chloromethyl Ketones / Q000494:pharmacology; D000818:Animals; D000894:Anti-Inflammatory Agents, Non-Steroidal / Q000494:pharmacology; D001835:Body Weight / Q000187:drug effects; D061945:Caspase Inhibitors; D002795:Choline O-Acetyltransferase / Q000378:metabolism; D004791:Enzyme Inhibitors / Q000494:pharmacology; D005480:Flurbiprofen / Q000494:pharmacology; D007150:Immunohistochemistry; D007249:Inflammation / Q000139:chemically induced / Q000473:pathology* / Q000517:prevention & control; D008070:Lipopolysaccharides / Q000037:antagonists & inhibitors / Q000633:toxicity; D008297:Male; D009474:Neurons / Q000201:enzymology / Q000473:pathology*; D010275:Parasympathetic Nervous System / Q000473:pathology*; D016548:Prosencephalon / Q000201:enzymology / Q000473:pathology*; D051381:Rats; D011916:Rats, Inbred F344
D000590:Amino Acid Chloromethyl Ketones; D000894:Anti-Inflammatory Agents, Non-Steroidal; D061945:Caspase Inhibitors; D004791:Enzyme Inhibitors; D008070:Lipopolysaccharides; C096713:benzyloxycarbonylvalyl-alanyl-aspartyl fluoromethyl ketone; D005480:Flurbiprofen; D002795:Choline O-Acetyltransferase