Cholinesterase Inhibitor Donepezil Increases Mitochondrial Biogenesis through AMP-Activated Protein Kinase in the Hippocampus

Abstract

Objective: Donepezil, a widely prescribed drug for Alzheimer's disease (AD), is now considered to have multimodal actions beyond cholinesterase inhibition. We aimed to see whether donepezil enhances mitochondrial biogenesis and relevant signaling pathways since mitochondrial dysfunction is a key feature of the hypometabolic AD brain. Methods: As a metabolic gauge, AMP-activated protein kinase (AMPK) was investigated as a tentative mediator of neurometabolic action of donepezil. Changes in phospho-AMPK levels, mitochondrial biogenesis, and ATP levels were measured upon donepezil treatment using neuroblastoma cells, primary cultured neurons and ex vivo hippocampal tissue of adult mice. Results: Donepezil dose-dependently increased mitochondrial biogenesis and ATP levels as well as expression of PGC-1α and NRF-1 in neuroblastoma cells. Donepezil dose-dependently activated AMPK; however, inhibition of AMPK abolished the observed effects of donepezil, indicating that AMPK is a key mediator of donepezil's action. Notably, mitochondrial biogenesis upon donepezil treatment was mainly observed within dendritic regions of primary cultured hippocampal neurons. Levels of synaptic markers were also increased by donepezil. Finally, AMPK- dependent mitochondrial biogenesis by donepezil was confirmed in organotypic hippocampal tissue. Conclusions: Our findings indicate that AMPK/PGC-1α signaling is involved in beneficial actions of donepezil on neurometabolism. Pharmacological activation of AMPK might be a promising approach to counteract AD pathogenesis associated with brain hypometabolism.

Natural alkaloid bouchardatine ameliorates metabolic disorders in high‐fat diet‐fed mice by stimulating the sirtuin 1/liver kinase B‐1/AMPK axis

“…It has been well known that activation of the AMPK pathway inhibits lipid synthesis but promotes mitochondrial oxidation of fatty acids (Russo et al , ; Kim et al , ,b; Lin et al , ). Consistent with these dual effects on lipid metabolism, Bou were found to reduce lipid accumulation (indicated by the decrease in TG content) in 3T3‐L1 adipocytes, HepG2 cells and the liver of HF mice.…”

“…Therefore, this study aimed to investigate the molecular mechanism of how Bou activates AMPK and to characterize its effects on obesity and associated metabolic disorders in high‐fat diet (HF)‐fed mice, a well‐defined animal model that mimics the pathogenesis of obesity in the general population (Yoneda et al , ; Zeng et al , ; Kim et al , ,b). At the same time, we intend to assess its safety profile by evaluating a wide range of parameters in plasma and key tissues.…”

Early Mitochondrial Adaptations in Skeletal Muscle to Obesity and Obesity Resistance Differentially Regulated by High-Fat Diet

“…Thus, we examined the diverse alterations on mitochondrial biogenesisrelated pathway of DIO and DIO-R mice. In most of the existing studies, AMPK activation also stimulates mitochondrial biogenesis [26][27][28] by increasing the expression of PGC-1α [29,30]. Mice devoid of PGC-1α gene are suggested to exhibit a mild decrease in mitochondrial function associated with an equally modest decrease in mitochondrial mass in most tissues [31,32].…”

Appetite, Metabolism and Hormonal Regulation in Normal Ageing and Dementia

“…Another possibility is concurrent modifications of energy metabolism and muscle tone, because of the presence of atypical parkinsonian symptoms or cases among dementia patients [ 160 ], as well as the administration of acetylcholinesterase inhibitors (ACHEIs) [ 161 ]. Donepezil has been shown to attenuate muscle atrophy and induce neovascularization in vitro and in a murine hind limb ischemia model [ 162 ], and enhance neuronal mitochondrial biogenesis and oxidative phosphorylation in vitro and ex vivo [ 163 ], while it up-regulated adiponectin over leptin synthesis, towards a reduction of total and abdominal fat deposition, in stage 3 to 4 AD patients, within 6 months [ 164 ]. Galantamine-induced adiponectin augmentation and HOMA-IR amelioration have been reported so far in one study in young adults with metabolic syndrome within 4 weeks [ 165 ].…”