[Mechanisms of neuroprotective effects of therapeutic acetylcholinesterase inhibitors used in treatment of Alzheimer's disease].
Donepezil, galanthamine, and tacrine are therapeutic acetylcholinesterase (AChE) inhibitors used for the treatment of Alzheimer's disease. The aim of this paper is to review recent findings on their neuroprotective properties and the mechanisms of neuroprotection against glutamate neurotoxicity in rat cortical neurons. First, the hallmark of neurotoxicity induced by two different glutamate treatment conditions was examined, revealing that acute glutamate treatment (1 mM, 10 min) induces necrotic neuronal death and that moderate glutamate treatment (100 microM, 24 hr) induces apoptotic neuronal death. Next, we showed that therapeutic AChE inhibitors protect cortical neurons from glutamate neurotoxicity in a time- and concentration-dependent manner. We examined the mechanism of this neuroprotective effect and found that the neuroprotective effects against both acute and moderate glutamate treatments are mediated through nicotinic acetylcholine receptors (nAChRs), or more specifically, the effects of donepezil and galanthamine are mediated through alpha4- and alpha7-nAChR. We also showed that donepezil and galanthamine protect cortical neurons against acute glutamate treatment-induced neurotoxicity at steps before, and that tacrine protects at steps after, nitric oxide radical formation. On the other hand, the neuroprotective effects of donepezil and galanthamine, but not of tacrine, against neurotoxicity induced by moderate glutamate treatment were mediated through the phosphatidylinositol 3-kinase-Akt pathway. These findings unveiled the hitherto unknown neuroprotective effects of therapeutic AChE inhibitors and provided valuable insights into its neuroprotective mechanisms. They may very likely form the basis for a novel treatment strategy against Alzheimer's disease.
Takatori
Yuki
Y
Department of Pharmacology, Graduate School of Pharmaceutical Sciences, Kyoto University, Japan. ytakator@dwc.doshisha.ac.jp
D000544:Alzheimer Disease / Q000188:drug therapy*; D000818:Animals; D016923:Cell Death / Q000187:drug effects; D002478:Cells, Cultured; D002540:Cerebral Cortex / Q000166:cytology / Q000187:drug effects; D002800:Cholinesterase Inhibitors / Q000494:pharmacology / Q000627:therapeutic use*; D000077265:Donepezil; D005702:Galantamine / Q000494:pharmacology / Q000627:therapeutic use; D005971:Glutamates / Q000633:toxicity; D006801:Humans; D007189:Indans / Q000494:pharmacology / Q000627:therapeutic use; D009474:Neurons / Q000187:drug effects; D018696:Neuroprotective Agents / Q000494:pharmacology / Q000627:therapeutic use*; D019869:Phosphatidylinositol 3-Kinases / Q000502:physiology; D010880:Piperidines / Q000494:pharmacology / Q000627:therapeutic use; D051381:Rats; D011978:Receptors, Nicotinic / Q000502:physiology; D013619:Tacrine / Q000494:pharmacology / Q000627:therapeutic use
D002800:Cholinesterase Inhibitors; D005971:Glutamates; D007189:Indans; D018696:Neuroprotective Agents; D010880:Piperidines; D011978:Receptors, Nicotinic; D005702:Galantamine; D013619:Tacrine; D000077265:Donepezil; D019869:Phosphatidylinositol 3-Kinases