Donepezil‐induced oligodendrocyte differentiation is mediated through estrogen receptors

Abstract

Loss of oligodendrocytes, the myelin-forming cells of the central nervous system, and subsequent failure of myelin development result in serious neurological disorders such as multiple sclerosis. Using primary mouse embryonic neural stem cells (NSCs), we previously demonstrated that donepezil, an acetylcholinesterase inhibitor developed for the treatment of Alzheimer's disease, stimulates the differentiation of NSCs into oligodendrocytes and neurons, albeit at the expense of astrogenesis. However, the precise mechanisms underlying donepezil-induced differentiation remain unclear. In this study, we aimed at elucidating the molecular pathways contributing to donepezil-induced differentiation of mouse-induced pluripotent stem cell-derived neural stem cells (miPSC-NSCs). We used cell-based reporter gene arrays to investigate effects of donepezil on differentiation of miPSC-NSCs. Subsequently, we assessed the molecular pathway underlying donepezil action on differentiation of miPSC-NSCs into mature oligodendrocytes. Donepezil increased the transcriptional activity of estrogen response element under differentiating conditions. Moreover, estrogen receptors α (ERα) and β (ERβ) were highly expressed in MBP-positive mature oligodendrocytes. The ER antagonist ICI 182,780 abrogated the number of MBP-positive oligodendrocytes induced by donepezil, but showed no effect on the differentiation of miPSC-NSCs into Tuj1-positive neurons and GFAP-positive astrocytes. Furthermore, the donepezilinduced generation of mature oligodendrocytes from miPSC-NSC was significantly attenuated by antagonists and siRNA targeting ERα and ERβ. In conclusion, we demonstrated, for the first time, that donepezil-induced oligodendrogenesis is mediated through both ER subtypes, ERα and ERβ.

Myelination Deficits in the Auditory Brainstem of a Mouse Model of Fragile X Syndrome

“…Sox-10 is a mouse monoclonal antibody specific to an epitope mapping between amino acids 2–29 at the N-terminus of the human Sox-10 gene. Sox-10 has been shown to specifically label the oligodendrocyte lineage in the CNS and in mouse brains ( Zuo et al, 2018 ; Barak et al, 2019 ; Imamura et al, 2020 ). Both primary antibodies were visualized using two fluorescent-conjugated secondary antibodies which are listed in Table 2 .…”

Neuroprotective Effects of Cholinesterase Inhibitors: Current Scenario in Therapies for Alzheimer’s Disease and Future Perspectives

“…In the last decade, several reports in the literature have focused on the ability of ChEI to induce neuronal recovery by increasing neurogenesis and neuritogenesis. Several studies demonstrated that donepezil could promote neuronal differentiation and neurite growth in vitro and in vivo [ 80–84 ]. Similar effects were also found for tacrine, galantamine, and rivastigmine [ 85–90 ].…”

Amyloid β, Lipid Metabolism, Basal Cholinergic System, and Therapeutics in Alzheimer’s Disease

“…The efficacy of each of them has been extensively studied in several studies, both in animal models and clinical trials. Its use has shown that it has a beneficial effect in all stages of the disease and could also have a neuroprotective effect by increasing cell viability and reducing neuronal death, as well as the presence of inflammatory mediators [ 225 , 226 ].…”

“…Donepezil is widely prescribed and has been considered a first-line treatment for AD since 1996 with selective activity for AChE. Several studies have indicated that the use of donepezil can reverse the clinical symptoms present in AD and has also been shown to have an anti-neurodegenerative effect, promoting neuronal differentiation and neurite growth [ 225 ]. In animal models, donepezil induced cognitive and behavioral improvements [ 230 ].…”