(+/-)-huprine Y, (-)-huperzine A and tacrine do not show neuroprotective properties in an apoptotic model of neuronal cytoskeletal alteration.
Acetylcholinesterase inhibitors (AChEI) are among the drugs most widely used in the treatment of Alzheimer's disease. They increase the levels of acetylcholine and thus improve the cognitive symptoms that are impaired. We tested whether specific AChEI show additional neuroprotective properties against colchicine-induced apoptosis in cerebellar granule neurons (CGNs), a well established apoptotic model mediated by neuronal cytoskeleton alteration. Colchicine-induced apoptosis is due to an increase in the activity of GSK-3beta and CDK5, two enzymes involved in cytoskeletal alteration. Furthermore, the intrinsic apoptotic pathway is activated by colchicines, as revealed by cytochrome c release and Bax translocation. Tacrine, (-)-huperzine A and (+/-)-huprine Y, the AChEI tested in the study, did not reverse the loss of neuronal viability induced by colchicine. Moreover, the increase in apoptotic features induced by colchicine treatment, as measured by flow cytometry and nuclear chromatin condensation, was not prevented by these AChEI. Although some of these drugs are of interest to treat Alzheimer's disease, their lack of efficacy in the prevention of colchicine-induced apoptosis in CGNs suggests that they cannot prevent neuronal loss due to cytoskeleton alteration.
Jordá
E G
EG
Unitat de Farmacologia i Farmacognòsia, Barcelona, Spain.
Verdaguer
E
E
Jiménez
A
A
Canudas
A M
AM
Rimbau
V
V
Camps
P
P
Muñoz-Torrero
D
D
Camins
A
A
Pallàs
M
M
D000470:Alkaloids; D000544:Alzheimer Disease / Q000188:drug therapy / Q000378:metabolism / Q000473:pathology; D000634:Aminoquinolines / Q000008:administration & dosage / Q000494:pharmacology*; D000818:Animals; D000831:Animals, Newborn; D017209:Apoptosis / Q000187:drug effects*; D002531:Cerebellum / Q000187:drug effects / Q000378:metabolism / Q000473:pathology; D002800:Cholinesterase Inhibitors / Q000008:administration & dosage / Q000494:pharmacology*; D003078:Colchicine / Q000009:adverse effects / Q000037:antagonists & inhibitors; D003599:Cytoskeleton / Q000187:drug effects* / Q000473:pathology; D004195:Disease Models, Animal; D005434:Flow Cytometry; D038362:Glycogen Synthase Kinase 3 / Q000187:drug effects / Q000378:metabolism; D006576:Heterocyclic Compounds, 4 or More Rings / Q000008:administration & dosage / Q000494:pharmacology*; D009474:Neurons / Q000187:drug effects / Q000378:metabolism / Q000473:pathology; D018696:Neuroprotective Agents / Q000008:administration & dosage / Q000494:pharmacology*; D051381:Rats; D017207:Rats, Sprague-Dawley; D012717:Sesquiterpenes / Q000008:administration & dosage / Q000494:pharmacology*; D013619:Tacrine / Q000008:administration & dosage / Q000494:pharmacology*
D000470:Alkaloids; D000634:Aminoquinolines; D002800:Cholinesterase Inhibitors; D006576:Heterocyclic Compounds, 4 or More Rings; D018696:Neuroprotective Agents; D012717:Sesquiterpenes; C404519:huprine Y; C050426:huperzine A; D013619:Tacrine; D038362:Glycogen Synthase Kinase 3; D003078:Colchicine