Dual Effect of Doxazosin: Anticancer Activity on SH-SY5Y Neuroblastoma Cells and Neuroprotection on an In Vitro Model of Alzheimer's Disease

Coelho, Bárbara Paranhos; Gaelzer, Mariana Maier; Petry, F.; Hoppe, Juliana Bender; Trindade, Vera Maria Treis; Salbego, Christianne Gazzana; Guma, Fátima Theresinha Costa Rodrigues

doi:10.1016/j.neuroscience.2019.02.005

Cited by 22 publications

(18 citation statements)

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“…In this study, we found that terazosin inhibited GSK3β pathway in vitro, as re ected by increased pGSK3β expression after terazosin treatment. This nding is consistent with a previous study which found that doxazosin, another α1-ARs antagonist, also increased the levels of pGSK3β (30). It is well-recognized that activation of GSK-3β could increase the expression and activity of BACE1, thus promoting the amyloidogenic pathway (31,32).…”

Section: Discussionsupporting

confidence: 93%

Inhibiting α1-adrenergic Receptor Signaling Pathway Ameliorates Alzheimer’s Disease Type Pathologies and Behavioral Deficits in an AD Mouse Model

Wang

et al. 2021

Preprint

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Background The role of α1 adrenergic receptors (α1-ARs) signaling pathway in the pathogenesis of Alzheimer’s disease (AD) has rarely been investigated. Clarifying pathophysiological functions of α1-ARs in the AD brain is helpful for better understanding the pathogenesis and screening novel therapeutic target of AD. Methods This study included 2 arms of in vivo investigations: 1) 6-month-old female APPswe/PS1 mice were intravenously treated with AAV-PHP.eB-shRNA (ARs)-GFP or AAV-PHP.eB-GFP for 3 months. 2) 3-month-old female APPswe/PS1 mice were daily treated with 0.5 mg/kg terazosin or equal saline for 6 months. SH-SY5Y cell lines bearing human Amyloid precurssor protein were treated with terazosin or saline for investigating possible mechanisms. Results α1-ARs knockdown mice exhibited improved behavioral performances than control mice. α1-ARs knockdown mice had significantly lower brain amyloid burden, as reflected by soluble Aβ species, compact and total plaques, than control mice. The α1-ARs inhibitor terazosin substantially reduced Aβ deposition, attenuated downstream pathologies including Tau hyperphosphorylation, glial activation, neuronal loss, synaptic dysfunction, and rescued behavioral deficits of APPswe/PS1 mice. In vitro investigation demonstrated that α1-ARs inhibition down-regulated BACE1 expression, and promoted ser9 phosphorylation of GSK-3β, thus reduced Aβ production. Conclusions This study indicates that inhibition of α1-ARs signaling pathway might represent a promising therapeutic strategy for AD.

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Section: Discussionsupporting

confidence: 93%

Inhibiting α1-adrenergic Receptor Signaling Pathway Ameliorates Alzheimer’s Disease Type Pathologies and Behavioral Deficits in an AD Mouse Model

Wang

et al. 2021

Preprint

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“…Some previous animal studies [ 23 - 25 , 27 , 28 ] have observed low drug binding in the rat cerebral cortex, suggesting that the drug is unlikely to penetrate the BBB. In addition, doxazosin had a neuroprotective effect in an in vitro model of Alzheimer disease [ 32 ]. However, terazosin was shown to cause cognitive impairment by decreasing of serotonin level [ 23 ].…”

Section: Alpha Blockersmentioning

confidence: 99%

Cognitive Function and Urologic Medications for Lower Urinary Tract Symptoms

2020

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Special considerations should be made when selecting medications for the treatment of lower urinary tract symptoms (LUTS) in older patients especially those over 65 years old. This review summarizes the relationship between current treatments for LUTS and cognitive impairment. Although the recently reported association between dementia and tamsulosin is debatable, the effects of α-blockers and pharmacokinetics are not reported in this context. Five-alpha reductase inhibitors appear to affect mood. However, the association between the development of dementia and cognitive impairment is unlikely. Anticholinergic agents, other than trospium, fesoterodine, and imdafenacin have a relatively high distribution in the central nervous system. In particular, oxybutynin is reported to cause cognitive impairment. Several animal studies on the blood-brain barrier permeability of oxybutynin support this. Therefore, care must be taken when they are used in older patients (65 years and older). Beta-3 agonists are an alternative to, or may be used in combination with, anticholinergic drugs for patients with an overactive bladder (OAB). Several phase 2 and 3 clinical studies report high tolerability and efficacy, making them relatively safe for OAB treatment. However, there is a possibility that cognitive function may be affected; thus, long-term study data are required. We have reviewed studies investigating the correlation of urologic medications with cognitive dysfunction and have provided an overview of drug selection, as well as other considerations in older patients (65 years and older) with LUTS. This narrative review has focused primarily on articles indexed in PubMed, Google Scholar, Scopus, and Embase databases. No formal search strategy was used, and no meta-analysis of data was performed.

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“…Genome-wide association studies on AD patient brains have demonstrated significant expression changes in genes that regulate vesicular trafficking, cytoskeleton, energy metabolism, inflammation, ubiquitin-proteosome system, and autophagy (Liang et al, 2007). Besides these, it has been reported that the phosphoinositide 3-kinase (PI3K)/AKT-mTOR signaling pathway, nuclear factor kappa B (NF-κB), and mitogen-activated protein kinase (MAPK) pathways are activated in neurons in several neuropathological conditions (Zheng et al, 2017;Coelho et al, 2019;Saha et al, 2020).…”

Section: Introductionmentioning

confidence: 99%

“…Previous studies proved that Aβ 1−42 has neurotoxic potential, interfering with synaptic plasticity and affecting several cellular signaling pathways (Selkoe, 2001). Thus, neurons exposed to appropriate Aβ 1−42 (less than 10 µM) are routinely used to obtain the in vitro AD models (Arbo et al, 2017;Coelho et al, 2019).…”

Section: Introductionmentioning

confidence: 99%

Protect Effects of Seafood-Derived Plasmalogens Against Amyloid-Beta (1–42) Induced Toxicity via Modulating the Transcripts Related to Endocytosis, Autophagy, Apoptosis, Neurotransmitter Release and Synaptic Transmission in SH-SY5Y Cells

Feng

Song

Shen

et al. 2021

Front. Aging Neurosci.

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To investigate the underlying mechanisms of decreased plasmalogens (Pls) levels in neurodegenerative diseases, here the effects of seafood-derived Pls on undifferentiated and differentiated human SH-SY5Y neuroblastoma cells exposed to amyloid-β1–42 was analyzed. Transcriptional profiles indicated that a total of 6,581 differentially expressed genes (DEGs) were significantly identified among different experimental groups, and KEGG analysis indicated that these DEGs were related to AD, endocytosis, synaptic vesicle cycle, autophagy and cellular apoptosis. After Pls treatment, the striking expression changes of ADORA2A, ATP6V1C2, CELF6, and SLC18A2 mRNA strongly suggest that Pls exerts a beneficial role in alleviating AD pathology partly by modulating the neurotransmitter release and synaptic transmission at the transcriptional level. Besides these, GPCRs are also broadly involved in Pls-signaling in neuronal cells. These results provide evidence for supporting the potential use of Pls as an effective therapeutic approach for AD.

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Dual Effect of Doxazosin: Anticancer Activity on SH-SY5Y Neuroblastoma Cells and Neuroprotection on an In Vitro Model of Alzheimer's Disease

Cited by 22 publications

References 50 publications

Inhibiting α1-adrenergic Receptor Signaling Pathway Ameliorates Alzheimer’s Disease Type Pathologies and Behavioral Deficits in an AD Mouse Model

Inhibiting α1-adrenergic Receptor Signaling Pathway Ameliorates Alzheimer’s Disease Type Pathologies and Behavioral Deficits in an AD Mouse Model

Cognitive Function and Urologic Medications for Lower Urinary Tract Symptoms

Protect Effects of Seafood-Derived Plasmalogens Against Amyloid-Beta (1–42) Induced Toxicity via Modulating the Transcripts Related to Endocytosis, Autophagy, Apoptosis, Neurotransmitter Release and Synaptic Transmission in SH-SY5Y Cells

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