Amyloid peptide toxicity and microtubule-stabilizing drugs.
Based on microtubule (MT) disruption observed in primary neurons exposed to fibrillar amyloid peptides (A beta), we tested the potential protective effect of MT-stabilizing drugs such as Taxol against A beta-induced disruption of the cytoskeleton. Although Taxol was strongly protective, the fact that it does not cross the blood brain barrier (BBB) led us to synthesize and test other agents with MT-stabilizing properties and possible penetration into the brain. Our studies have thus far demonstrated that several MT-stabilizing agents, including some with structures quite different from that of Taxol, showed significant protective effects. However, not all agents that promoted MT-assembly were protective, suggesting additional mechanisms are involved in the actions of the drugs. A small number of neuroprotective compounds appear to have potential to enter the brain and thus might be tested to see if they slow progression of neurodegeneration in an appropriate animal model of Alzheimer's disease.
Michaelis
Mary L
ML
Department of Pharmacology and Toxicology, University of Kansas, Lawrence 66045, USA. mlm@ukans.edu
Chen
Yingxue
Y
Hill
Sarah
S
Reiff
Emily
E
Georg
Gunda
G
Rice
Antonie
A
Audus
Kenneth
K
D000544:Alzheimer Disease / Q000188:drug therapy; D016229:Amyloid beta-Peptides / Q000633:toxicity*; D000818:Animals; D001812:Blood-Brain Barrier; D016923:Cell Death / Q000187:drug effects; D002478:Cells, Cultured; D003599:Cytoskeleton / Q000187:drug effects; D008870:Microtubules / Q000187:drug effects* / Q000473:pathology; D009474:Neurons / Q000187:drug effects* / Q000473:pathology; D018696:Neuroprotective Agents / Q000138:chemical synthesis / Q000494:pharmacology* / Q000627:therapeutic use; D017239:Paclitaxel / Q000494:pharmacology*; D051381:Rats
D016229:Amyloid beta-Peptides; D018696:Neuroprotective Agents; D017239:Paclitaxel