Nicotine attenuates the β‐amyloid neurotoxicity through regulating metal homeostasis

Zhang, Jie; Liu, Qiang; Chen, Qi; Liu, Nian-Qing; Li, Fuliang; Lu, Zhigang; Qin, Chuan; Zhu, Hua; Hao, Yuying; He, Wei; Zhao, Baolu

doi:10.1096/fj.05-5214fje

Cited by 72 publications

(51 citation statements)

References 47 publications

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“…Immunoblotting for the APP695 protein showed an 86-kDa product in both neo cells (SH-SY5Y transiently transfected with empty vector) and APPsw cells (SH-SY5Y transiently transfected with APP695sw). Consistent with previous studies [21,22], APPsw cells showed significant increases in expression of APP695 compared with neo cells over time (fig. 1).…”

Section: Resultssupporting

confidence: 92%

Effects of Nicorandil in Neuroprotective Activation of PI3K/AKT Pathways in a Cellular Model of Alzheimer's Disease

et al. 2013

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Nicorandil, an ATP-sensitive potassium (K_ATP) channel opener, is known to have protective effects on ischemic injury in heart and brain. One of the most important protective mechanisms is the anti-apoptotic effect on cardiomyocytes and neurons. This study explored the anti-apoptotic effect of nicorandil against neurotoxicity in SH-SY5Y cells overexpressing the Swedish mutant APP (APPsw) and the possible mechanisms involved. We used SH-SY5Y cells transiently transfected with APPsw as a cellular model of Alzheimer's disease. Cells were treated with nicorandil (0.1, 0.5, 1 mM) for 24 h with and without glibenclamide (10 μM), a K_ATP channel inhibitor. The cells were then collected for MTT, apoptosis assay, and Western blot. In addition, we also investigated the potential involvement of the PI3K/Akt pathway in nicorandil-mediated neuroprotection of APPsw cells. Our results showed that nicorandil dose-dependently increased cell viability and reduced the rate of apoptosis as measured by MTT assay and annexin V/PI staining. Western blot showed that nicorandil could upregulate Bcl-2 levels and downregulate Bax and caspase-3 expression. Further studies showed that nicorandil increased the levels of phospho-Akt and upregulated element-binding protein activity by PI3K activation. Applying a PI3K inhibitor, LY294002 blocked the protection. All these findings suggest that nicorandil might be a potential treatment option for Alzheimer's disease.

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Section: Resultssupporting

confidence: 92%

Effects of Nicorandil in Neuroprotective Activation of PI3K/AKT Pathways in a Cellular Model of Alzheimer's Disease

et al. 2013

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“…Furthermore, the nicotinic enhancement of GABA A receptor function could not be prevented by DHβE, though it was supposed that nicotine should produce its modulatory effects via functional α4β2-nAChRs expressed on the neuron. These results echo the findings by Zhang and colleagues that the effect of nicotine against β-amyloid-mediated neurotoxicity could not be blocked by nAChR antagonists [61], suggesting that nicotine may exert its modulatory effects on GABA A receptor-induced currents via a nAChR-independent pathway, or additional mechanisms may exist. For example, SNc DA neurons may express different subtypes of GABA A receptors [62][63][64] and the diversity of GABA A receptors may underlie the complex modulation by nicotine.…”

Section: Discussionsupporting

confidence: 89%

Nicotinic Modulation of GABAA Receptor Function in Single Dopaminergic Neurons Freshly-Dissociated from Rat Substantia Nigra Pars Compacta

Yang¹,

Zhang²,

Wu³

2013

Biochem & Pharmacol

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BackgroundDopaminergic (DAergic) neurons in the substantia nigra pars compacta (SNc) intermingled with gamma-aminobutyric acid-ergic (GABAergic) neurons play a critical role in regulation of voluntary motor coordination, and selective loss of SNc DAergic neurons results in Parkinson's disease (PD) [1,2]. Compared to glutamatergic synaptic inputs, SNc DAergic neurons receive significantly more GABAergic inhibitory inputs [3] from the core of nucleus accumbens, striatum, globus palliuds, dorsolateral ventral pallidum, rostromedial tegmental nucleus, as well as substantia nigra pars reticulate [4][5][6][7][8][9][10][11]. These inhibitory inputs are believed to be key elements of nigral microcircuitry [12][13][14] and represent the key source of inhibitory modulation on DAergic neuron function in the SNc [5,15,16]. Evidence from in vivo single-unit extracellular recordings shows that local pressure application of selective GABA A receptor antagonists, such as bicuculline (Bic) and picrotoxin, results in bust firing of DAergic neurons in rat SNc, suggesting that the activity of SNc DAergic neurons is tonically suppressed by endogenous GABAergic inputs mediated by GABA A receptors [6].Neuronal nicotinic acetylcholine receptors (nAChRs), members of the superfamily of pentameric ligand-gated ion channels [17,18], are widely distributed throughout the brain. Functional alterations in nAChR-mediated cholinergic pathways are found to be involved in a variety of neurodegenerative disorders, such as PD, Alzheimer's diseases [19][20][21], ageing [22,23], and epilepsy [24,25]. A large amount of nAChRs are expressed in mesencephalic DAergic neurons [26][27][28][29][30]. In the SNc, nAChRα2, α4, α5, α6, β2, and β3 subunit mRNAs were detected in most of tested DAergic neurons, α3 and α7 mRNAs were found in about 50% of tested DAergic neurons [31]. Our previous studies, using in situ hybridization, immunohistochemistry, reverse transcriptase polymerase chain reaction (RT-PCR), and electrophysiology, further demonstrated that functional α4β2-and α7-nAChRs are densely expressed on SNc DAergic neurons [32,33]. Bath application of 1 µM nicotine can significantly enhance the inhibitory inputs to the SNc by activating both α7-and non α7-nAChRs at presynaptic terminals in midbrain slices containing the SNc [28]. Moreover, co-localization of α7-nAChRs with GABA A receptors is specifically found at the tips of filopodia extending from dendrites AbstractPrevious studies have shown that nicotine modulates GABAergic transmission onto dopaminergic (DAergic) neurons in the substantia nigra pars compacta (SNc) mainly via presynaptic mechanisms. However, nicotinic modulation of postsynaptic GABA A receptor function in SNc DAergic neurons is unknown. Employing patch-clamp recording technique in single putative DAergic neurons freshly dissociated from rat SNc, we found that functional α4β2-nAChRs were well expressed on majority (77%) of putative SNc DAergic neurons recorded (type ID neurons), while functional α7-nAChRs were only detected in 23% of...

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“…Several reports have confirmed that A␤-Cu complexes are increased in AD brain (11,13,40), and plaques can be dissolved by copper chelators (41). Indeed, drugs that target A␤-Cu interaction show therapeutic efficacy in preclinical AD models and early phase clinical trials (16,(42)(43)(44)(45)(46).…”

Section: Discussionmentioning

confidence: 94%

Sequestration of Copper from β-Amyloid Promotes Selective Lysis by Cyclen-Hybrid Cleavage Agents

Lei

Liu

et al. 2008

Journal of Biological Chemistry

119

110

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Nicotine attenuates the β‐amyloid neurotoxicity through regulating metal homeostasis

Cited by 72 publications

References 47 publications

Effects of Nicorandil in Neuroprotective Activation of PI3K/AKT Pathways in a Cellular Model of Alzheimer's Disease

Effects of Nicorandil in Neuroprotective Activation of PI3K/AKT Pathways in a Cellular Model of Alzheimer's Disease

Nicotinic Modulation of GABAA Receptor Function in Single Dopaminergic Neurons Freshly-Dissociated from Rat Substantia Nigra Pars Compacta

Sequestration of Copper from β-Amyloid Promotes Selective Lysis by Cyclen-Hybrid Cleavage Agents

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