Acetylcholinesterase inhibitors used in treatment of Alzheimer's disease prevent glutamate neurotoxicity via nicotinic acetylcholine receptors and phosphatidylinositol 3-kinase cascade

  title={Acetylcholinesterase inhibitors used in treatment of Alzheimer's disease prevent glutamate neurotoxicity via nicotinic acetylcholine receptors and phosphatidylinositol 3-kinase cascade},
  author={Yuki Takada-Takatori and Toshiaki Kume and Mitsuhiro Sugimoto and Hiroshi Katsuki and Hachiro Sugimoto and Akinori Akaike},

Roles of nicotinic receptors in acetylcholinesterase inhibitor-induced neuroprotection and nicotinic receptor up-regulation.

It is shown that acetylcholinesterase inhibitors protect neurons from glutamate-induced neurotoxicity in the primary culture of rat cortical neurons and that nicotinic receptor expression levels are regulated, a property which may have some bearing on their therapeutic effects.

Mechanisms of Neuroprotective Effects of Nicotine and Acetylcholinesterase Inhibitors: Role of α4 and α7 Receptors in Neuroprotection

Results suggest that nicotine as well as AChE inhibitors, donepezil and galantamine, prevent glutamate neurotoxicity through α4 and α7 nAChRs and the PI3K-Akt pathway.

Acetylcholinesterase inhibitors rapidly activate Trk neurotrophin receptors in the mouse hippocampus

Nicotinic Acetylcholine Receptor Signaling: Roles in Neuroprotection

Results suggest that nAChR stimulation suppresses the inflammatory response induced by bradykinin via the PI3K-Akt pathway in astrocytes, and suggests that nicotine as well as donepezil prevents glutamate neurotoxicity through Α4- and α7-nAChRs and the phosphatidylinositol 3-kinase (PI3K)/Akt pathways.

Donepezil, a potent acetylcholinesterase inhibitor, induces caspase-dependent apoptosis in human promyelocytic leukemia HL-60 cells.

It is demonstrated for the first time that donepezil displayed an induction of apoptosis in HL-60 cells via a mitochondria-mediated caspase-dependent pathway.



Nicotinic Acetylcholine Receptor-Mediated Neuroprotection by Donepezil Against Glutamate Neurotoxicity in Rat Cortical Neurons

The results suggest that donepezil not only protects cortical neurons against glutamate neurotoxicity via α4β2- and α7-nAChRs but also prevents apoptotic neuronal death.

Janus Kinase 2, an Early Target of α7 Nicotinic Acetylcholine Receptor-mediated Neuroprotection against Aβ-(1–42) Amyloid*

Evidence is provided that nicotine stimulation of α7 nAChR transduces signals to phosphatidylinositol 3-kinase and Akt via Janus kinase 2 (JAK2) in a cascade, which results in neuroprotection, suggesting a pivotal role for JAK2.

Protective effect of dopamine D2 agonists in cortical neurons via the phosphatidylinositol 3 kinase cascade

It is suggested that D2 dopaminergic receptor activation plays an important role in neuroprotection against glutamate cytotoxicity and that the up‐regulation of Bcl‐2 expression via the PI3K cascade is, at least partially, involved in this effect.

α7 Nicotinic Receptor Transduces Signals to Phosphatidylinositol 3-Kinase to Block A β-Amyloid-induced Neurotoxicity*

Findings indicate that the α7 nicotinic receptor transduces signals to PI3K in a cascade, which ultimately contributes to a neuroprotective effect, which might form the basis of a new treatment for AD.

Unequal Neuroprotection Afforded by the Acetylcholinesterase Inhibitors Galantamine, Donepezil, and Rivastigmine in SH-SY5Y Neuroblastoma Cells: Role of Nicotinic Receptors

The results show that galantamine, donepezil, and rivastigmine afford neuroprotection through a mechanism that is likely unrelated to AChE inhibition, and seemed to be linked to α7 nicotinic receptors and the PI3K-Akt pathway.

β-Amyloid Activates the Mitogen-Activated Protein Kinase Cascade via Hippocampal α7 Nicotinic Acetylcholine Receptors:In Vitro and In Vivo Mechanisms Related to Alzheimer's Disease

These findings support the model that derangement of hippocampus signal transduction cascades in AD arises as a consequence of increased Aβ burden and chronic activation of the ERK MAPK cascade in an α7 nAChR-dependent manner that eventually leads to the downregulation of ERK2 MAPK and decreased phosphorylation of CREB protein.

Donepezil modulates nicotinic receptors of substantia nigra dopaminergic neurones

Donepezil depressed even maximal responses to nicotine, revealing a noncompetitive mechanism of action; moreover, the inhibition of nAChRs was voltage and time independent, and Pretreatment with vesamicol or methamidophos did not prevent the reduction of nicotine‐induced currents.

Nicotinic receptor stimulation protects neurons against β‐amyloid toxicity

It is suggested that nicotinic receptor stimulation, especially α‐receptor activation, may be able to protect neurons from degeneration induced by Aβ and may have effects that counter the progress of AD.