Isradipine prevents rotenone-induced intracellular calcium rise that accelerates senescence in human neuroblastoma SH-SY5Y cells

Yu, Xiaorui; Li, X.; Jiang, Genling; Wang, X.; Chang, Hebron C.; Hsu, Walter H.; Li, Qinglin

doi:10.1016/j.neuroscience.2013.04.062

Cited by 33 publications

(16 citation statements)

References 43 publications

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“…Our results showing that the L-type Ca 2+ channel blocker isradipine reduces basal OCR and is protective against MPP + fill this gap and provide support for this hypothesis. However, we found no such protective effect of isradipine on toxicity to rotenone, a finding that is at odds with a previous report [47]. Further experiments will be required to test the possibility that this lack of neuroprotection is due to the broader nature of the action of this toxin.…”

Section: Discussioncontrasting

confidence: 98%

Elevated Mitochondrial Bioenergetics and Axonal Arborization Size Are Key Contributors to the Vulnerability of Dopamine Neurons

et al. 2015

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Although the mechanisms underlying the loss of neurons in Parkinson's disease are not well understood, impaired mitochondrial function and pathological protein aggregation are suspected as playing a major role. Why DA (dopamine) neurons and a select small subset of brain nuclei are particularly vulnerable to such ubiquitous cellular dysfunctions is presently one of the key unanswered questions in Parkinson's disease research. One intriguing hypothesis is that their heightened vulnerability is a consequence of their elevated bioenergetic requirements. Here, we show for the first time that vulnerable nigral DA neurons differ from less vulnerable DA neurons such as those of the VTA (ventral tegmental area) by having a higher basal rate of mitochondrial OXPHOS (oxidative phosphorylation), a smaller reserve capacity, a higher density of axonal mitochondria, an elevated level of basal oxidative stress, and a considerably more complex axonal arborization. Furthermore, we demonstrate that reducing axonal arborization by acting on axon guidance pathways with Semaphorin 7A reduces in parallel the basal rate of mitochondrial OXPHOS and the vulnerability of nigral DA neurons to the neurotoxic agents MPP(+) (1-methyl-4-phenylpyridinium) and rotenone. Blocking L-type calcium channels with isradipine was protective against MPP(+) but not rotenone. Our data provide the most direct demonstration to date in favor of the hypothesis that the heightened vulnerability of nigral DA neurons in Parkinson's disease is directly due to their particular bioenergetic and morphological characteristics.

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Section: Discussioncontrasting

confidence: 98%

Elevated Mitochondrial Bioenergetics and Axonal Arborization Size Are Key Contributors to the Vulnerability of Dopamine Neurons

et al. 2015

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“…We investigated the effect of retinoic acid, an agonist of RXRA, and observed an upregulation of ITPR2 expression (Supporting Information Figure S14). In line with these data, an increase in ITPR2 expression was observed in several transcriptomic analyses upon treatment of cells with retinoic acid (Yu, Li, et al, 2013; Yu, Zhang, et al, 2013; Zheng et al, 2005). However, in our experimental conditions, we did not observe any effect of retinoic acid on cell proliferation (Supporting Information Figure S14), suggesting that removing the repressive RXRA transcriptional activity (knockdown) and activating RXRA transcriptional activity (retinoic acid treatment) are not functionally equivalent even if both result in ITPR2 gene expression.…”

Section: Discussionsupporting

confidence: 63%

“…Intracellular calcium levels have been shown to increase in various cell types in response to senescence‐inducing stresses (Borodkina et al, 2016; Wiel et al, 2014; Yu, Li, et al, 2013; Yu, Zhang, Zhou, Yao, & Li, 2013) and activation of the calcium‐dependent transcription factor nuclear factor of activated T cells (NFAT) by the calcium/calmodulin/calcineurin pathway is known to regulate senescence (Manda et al, 2016; Wu et al, 2010). However, how calcium signaling is controlled is still only partially understood.…”

Section: Introductionmentioning

confidence: 99%

The nuclear receptor RXRA controls cellular senescence by regulating calcium signaling

Warnier

Raynard

et al. 2018

Aging Cell

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Calcium signaling is emerging as a key pathway controlling cellular senescence, a stable cell proliferation arrest playing a fundamental role in pathophysiological conditions, such as embryonic development, wound healing, cancer, and aging. However, how calcium signaling is regulated is still only partially understood. The inositol 1, 4, 5‐trisphosphate receptor type 2 (ITPR2), an endoplasmic reticulum calcium release channel, was recently shown to critically contribute to the implementation of senescence, but how ITPR2 expression is controlled is unclear. To gain insights into the regulation of ITPR2 expression, we performed an siRNA screen targeting 160 transcription factors and epigenetic regulators. Interestingly, we discovered that the retinoid X receptor alpha (RXRA), which belongs to the nuclear receptor family, represses ITPR2 expression and regulates calcium signaling though ITPR2 and the mitochondrial calcium uniporter (MCU). Knockdown of RXRA induces the production of reactive oxygen species (ROS) and DNA damage via the ITPR2‐MCU calcium signaling axis and consequently triggers cellular senescence by activating p53, whereas RXRA overexpression decreases DNA damage accumulation and then delays replicative senescence. Altogether, our work sheds light on a novel mechanism controlling calcium signaling and cellular senescence and provides new insights into the role of nuclear receptors.

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“…We further evaluated potential down-stream targets of VEGF-B with western analysis in a commonly used cell line model that displays hallmark characteristics of DA neurons, the SH-SY5Y neuroblastoma cell line treated with rotenone (for example, Wang et al, 2002; Ruan et al, 2010; Yu et al, 2013). We first established that the VEGF-B receptor VEGFR-1 indeed is expressed in the cells with immunocytochemistry (Figure 8).…”

Section: Resultsmentioning

confidence: 99%

Comparative study of the neurotrophic effects elicited by VEGF-B and GDNF in preclinical in vivo models of Parkinson’s disease

et al. 2014

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Vascular endothelial growth factor B (VEGF-B) has recently been shown to be a promising novel neuroprotective agent for several neurodegenerative conditions. In the current study we extended previous work on neuroprotective potential for Parkinson’s disease (PD) by testing an expanded dose range of VEGF-B (1 μg and 10 μg) and directly comparing both neuroprotective and neurorestorative effects of VEGF-B in progressive unilateral 6-hydroxydopamine (6-OHDA) PD models to a single dose of glial cell line-derived neurotrophic factor (GDNF, 10 μg), that has been established by several groups as a standard in both preclinical PD models. In the amphetamine-induced rotational tests the treatment with 1 and 10 μg VEGF-B resulted in significantly improved motor function of 6-OHDA-lesioned rats compared to vehicle-treated 6-OHDA-lesioned rats in the neuroprotection paradigm. Both doses of VEGF-B caused an increase in tyrosine hydroxylase (TH)-positive cell and fiber count in the substantia nigra (SN) and striatum in the neuroprotective experiment. The effect size was comparable to the effects seen with GDNF. In the neurorestoration paradigm, VEGF-B injection had no significant effect in either the behavioral or the immunohistochemical analyses, whereas GDNF injection significantly improved the amphetamine-induced rotational behavior and reduced TH-positive neuronal cell loss in the SN. We also present a strong positive correlation (p = 1.9 e-50) of the expression of VEGF-B with nuclear-encoded mitochondrial genes involved in fatty acid metabolism in rat midbrain, pointing to the mitochondria as a site of action of VEGF-B. GDNF showed a positive correlation with nuclear-encoded mitochondrial genes that was not nearly as strong (p = 0.018). VEGF-B counteracted rotenone-induced reduction of (a) fatty acid transport protein 1 and 4 levels and (b) both Akt protein and phosphorylation levels in SH-SY5Y cells. We further verified VEGF-B expression in the human SN pars compacta of healthy controls and Parkinson’s disease patients, in neuronal cells that show co-expression with neuromelanin. These results have demonstrated that VEGF-B has potential as a neuroprotective agent for PD therapy and should be further investigated.

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Isradipine prevents rotenone-induced intracellular calcium rise that accelerates senescence in human neuroblastoma SH-SY5Y cells

Cited by 33 publications

References 43 publications

Elevated Mitochondrial Bioenergetics and Axonal Arborization Size Are Key Contributors to the Vulnerability of Dopamine Neurons

Elevated Mitochondrial Bioenergetics and Axonal Arborization Size Are Key Contributors to the Vulnerability of Dopamine Neurons

The nuclear receptor RXRA controls cellular senescence by regulating calcium signaling

Comparative study of the neurotrophic effects elicited by VEGF-B and GDNF in preclinical in vivo models of Parkinson’s disease

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