Effects of phenothiazine-structured compounds on APP processing in Alzheimer's disease cellular model

Yuksel, Melike; Biberoglu, Kevser; Onder, Seda; Akbulut, K. Gonca; Tacal, Özden

doi:10.1016/j.biochi.2017.04.012

Cited by 17 publications

(18 citation statements)

References 53 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…It is completely different from the amyloidogenic pathway, and the production of non-amyloidogenic pathway, sAPPα, has neurotropic and neuroprotective properties ( Meineck et al, 2016 ). There is wide consensus that activation of α-secretase could increase production of neuroprotective sAPPα ( Zhang et al, 2012 ; Corrigan et al, 2012a , b ; Jeong, 2017 ; Yuksel et al, 2017 ). In productive process of Aβ, BACE1 is responsible for the chief function of β-secretase ( Maloney and Lahiri, 2011 ).…”

Section: Discussionmentioning

confidence: 99%

Gastrodin Attenuates Bilateral Common Carotid Artery Occlusion-Induced Cognitive Deficits via Regulating Aβ-Related Proteins and Reducing Autophagy and Apoptosis in Rats

Liu

Gao

et al. 2018

Front. Pharmacol.

View full text Add to dashboard Cite

Gastrodin (GAS), an active constituent extracted from Gastrodia elata Blume, is used to treat ischemic stroke, epilepsy, dizziness, and dementia for centuries in China. This study examined its effects on vascular dementia (VD) and the underlying molecular mechanisms. VD was established by ligation of bilateral common carotid artery occlusion (BCCAO). A total of 7 days after BCCAO surgery, GAS (15, 30, and 60 mg/kg) was orally administered for 28 consecutive days to evaluate therapeutic effects. Cognitive function was tested by the Morris water maze. The neuronal morphological changes were examined via Hematoxylin–Eosin staining. Flow cytometry was used for evaluating apoptosis in the hippocampi. The target protein expression was examined by Western blot. The results showed that BCCAO induced cognitive impairment, hippocampus CA1 and CA3 pyramidal neuron damage, beta-amyloid (Aβ) deposition, excessive autophagy, and apoptosis. GAS treatment significantly improved BCCAO-induced cognitive deficits and hippocampus neuron damage. Molecular analysis revealed that GAS exerted the protective effect via reducing the levels of Aβ1–40/42, APP, and β-site APP-cleaving enzyme 1 expression, and increasing Aβ-related protein, a disintegrin and metalloprotease 10, and insulin degrading enzyme expression. Meanwhile, GAS inhibited excessive autophagy via decreasing Beclin-1, LC3-II, and p62 levels. Furthermore, GAS inhibited apoptosis through the downregulation of Bax and upregulation of Bcl-2. Moreover, P38 MAPK signaling pathway was involved in the process. Our findings demonstrate that GAS was effective in the treatment of BCCAO-induced VD via targeting Aβ-related protein formation and inhibiting autophagy and apoptosis of hippocampus neurons.

show abstract

Section: Discussionmentioning

confidence: 99%

Gastrodin Attenuates Bilateral Common Carotid Artery Occlusion-Induced Cognitive Deficits via Regulating Aβ-Related Proteins and Reducing Autophagy and Apoptosis in Rats

Liu

Gao

et al. 2018

Front. Pharmacol.

View full text Add to dashboard Cite

show abstract

“…The drug therapies for AD are based on the cholinergic hypothesis that AD begins as a deficiency in the production of the neurotransmitter acetylcholine. Cholinesterase inhibition might impact the processing of amyloid in AD [ 51 ] and cholinesterase inhibitors have been suggested as the standard drugs for the treatment of AD. The inhibitors of acetylcholinesterase (AChE) and butyrylcholinesterase (BChE) show potential in the treatment process of AD.…”

Section: Anti-aβ Effects Of Teamentioning

confidence: 99%

Association of Tea Consumption with Risk of Alzheimer’s Disease and Anti-Beta-Amyloid Effects of Tea

et al. 2018

View full text Add to dashboard Cite

Neurodegenerative disease Alzheimer’s disease (AD) is attracting growing concern because of an increasing patient population among the elderly. Tea consumption is considered a natural complementary therapy for neurodegenerative diseases. In this paper, epidemiological studies on the association between tea consumption and the reduced risk of AD are reviewed and the anti-amyloid effects of related bioactivities in tea are summarized. Future challenges regarding the role of tea in preventing AD are also discussed.

show abstract

“…Due to the reciprocal connections between amyloid pathology and cholinergic function, the development of new ChEIs which reduce the hallmarks of AD has attracted great attention (13). Nowadays, cationic phenothiazine-derived compounds have shown to be prominent drug candidates for the treatment of AD due to their inhibitory effects on cholinesterase activity (14,15), Aβ pathology, and tau aggregation (16)(17)(18). Phenothiazines which are six-membered heterocyclic compounds containing nitrogen and sulfur were discovered during second half of the 19th century.…”

Section: Introductionmentioning

confidence: 99%

“…The findings showed that toluidine blue O (TBO) and thionine (TH) are highly potent inhibitors of both human BChE and human erythrocyte AChE with Ki in the nM-μM range (15). In addition, TBO was also found to affect amyloid precursor protein processing in-vitro and invivo models of AD (16,17). These results encouraged us to test whether a structurally closely related cationic phenothiazine compound, 1,9dimethyl-methylene blue (DMMB) (Figure 1) shows an inhibitory effect on human plasma BChE.…”

Section: Introductionmentioning

confidence: 99%

Kinetics of human butyrylcholinesterase inhibition by 1,9-dimethyl-methylene blue

Biberoglu

2021

Journal of the Turkish Chemical Society Section A: Chemistry

Self Cite

View full text Add to dashboard Cite

Alzheimer's disease (AD) is an irreversible and progressive neurodegenerative disorder, characterized by β-amyloid plaques, neurofibrillary tangles, and loss of cholinergic neurons. Butyrylcholinesterase (BChE) inhibition is a critical strategy for the treatment of AD since BChE causes inactivation of neurotransmitter acetylcholine and has positive effects on promoting the formation of βamyloid fibrils. Our previous studies showed that various phenothiazine-derived compounds such as thionine and toluidine blue O (TBO) cause a potent inhibition of human cholinesterases. TBO was also found to affect amyloid precursor protein processing in-vitro and in-vivo models of AD. In this study, it was aimed to determine the inhibitory effect of 1,9-dimethyl-methylene blue (DMMB), a phenothiazine-derived compound, on human plasma BChE and explore its inhibitory mechanism. The inhibition of human BChE was assessed by the colorimetric method of Ellman using butyrylthiocholine as substrate and 0-0.375 µM of DMMB. The kinetic findings showed that DMMB acts as a linear mixed-type inhibitor of human BChE with Ki value of 23 ± 0.004 nM and α= 3.6 ± 1.6. In conclusion, DMMB, which is a potent inhibitor effective at nM level, may be helpful in designing new cholinesterase inhibitors for the treatment of AD.

show abstract

Effects of phenothiazine-structured compounds on APP processing in Alzheimer's disease cellular model

Cited by 17 publications

References 53 publications

Gastrodin Attenuates Bilateral Common Carotid Artery Occlusion-Induced Cognitive Deficits via Regulating Aβ-Related Proteins and Reducing Autophagy and Apoptosis in Rats

Gastrodin Attenuates Bilateral Common Carotid Artery Occlusion-Induced Cognitive Deficits via Regulating Aβ-Related Proteins and Reducing Autophagy and Apoptosis in Rats

Association of Tea Consumption with Risk of Alzheimer’s Disease and Anti-Beta-Amyloid Effects of Tea

Kinetics of human butyrylcholinesterase inhibition by 1,9-dimethyl-methylene blue

Contact Info

Product

Resources

About