Anti-Neuroinflammatory Effects of the Calcium Channel Blocker Nicardipine on Microglial Cells: Implications for Neuroprotection

Huang, Bor-Ren; Chang, Pei-Chun; Yeh, Wei-Lan; Lee, Chih‐Hao; Tsai, Cheng-Fang; Lin, Chi‐Tsai; Lin, Hsiao‐Yun; Liu, Yushu; Wu, Caren Yu-Ju; Ko, Pei-Ying; Huang, Shiang-Suo; Hsu, Horng‐Chaung; Lu, Dah‐Yuu

doi:10.1371/journal.pone.0091167

Cited by 59 publications

(40 citation statements)

References 72 publications

Supporting

Mentioning

Contrasting

Unclassified

Order By: Relevance

“…An in vitro migration assay was performed using Costar Transwell inserts (Costar, Brooklyn, NY, USA; pore size 8 mm) as described in our previous reports (Chuang et al 2013, Huang et al 2014a. Before performing the transmigration assay, cells were pretreated for 30 min with different concentrations of inhibitors or transfected with various DN mutants for 24 h. On the basis of the results of a cell viability assay, the various concentrations of inhibitors used did not affect colon cancer cell death (data not shown).…”

Section: Transmigration Assaymentioning

confidence: 99%

Brain-derived neurotrophic factor regulates cell motility in human colon cancer

Huang¹,

Lin²,

Lin³

et al. 2015

Endocrine-Related Cancer

Self Cite

View full text Add to dashboard Cite

Brain-derived neurotrophic factor (BDNF) is a potent neurotrophic factor that has been shown to affect cancer cell metastasis and migration. In the present study, we investigated the mechanisms of BDNF-induced cell migration in colon cancer cells. The migratory activities of two colon cancer cell lines, HCT116 and SW480, were found to be increased in the presence of human BDNF. Heme oxygenase-1 (HO)-1 is known to be involved in the development and progression of tumors. However, the molecular mechanisms that underlie HO-1 in the regulation of colon cancer cell migration remain unclear. Expression of HO-1 protein and mRNA increased in response to BDNF stimulation. The BDNF-induced increase in cell migration was antagonized by a HO-1 inhibitor and HO-1 siRNA. Furthermore, the expression of vascular endothelial growth factor (VEGF) also increased in response to BDNF stimulation, as did VEGF mRNA expression and transcriptional activity. The increase in BDNF-induced cancer cell migration was antagonized by a VEGF-neutralizing antibody. Moreover, transfection with HO-1 siRNA effectively reduced the increased VEGF expression induced by BDNF. The BDNF-induced cell migration was regulated by the ERK, p38, and Akt signaling pathways. Furthermore, BDNF-increased HO-1 and VEGF promoter transcriptional activity were inhibited by ERK, p38, and AKT pharmacological inhibitors and dominantnegative mutants in colon cancer cells. These results indicate that BDNF increases the migration of colon cancer cells by regulating VEGF/HO-1 activation through the ERK, p38, and PI3K/Akt signaling pathways. The results of this study may provide a relevant contribution to our understanding of the molecular mechanisms by which BDNF promotes colon cancer cell motility.

show abstract

Section: Transmigration Assaymentioning

confidence: 99%

Brain-derived neurotrophic factor regulates cell motility in human colon cancer

Huang¹,

Lin²,

Lin³

et al. 2015

Endocrine-Related Cancer

Self Cite

View full text Add to dashboard Cite

show abstract

“…Nicardipine, another anti-hypertensive agent, consistently had one of the highest levels of activity in suppressing the abnormal accumulation of GFP-LC3 vesicles in CbCln3 ∆ex7/8/∆ex7/8 cells ( Table 1 and Table S2, this study, and in [13]), and it was reported to potentially have a preventative effect in Alzheimer's disease through its effects on the cerebral vasculature [51]. Nicardipine has been demonstrated to have potential as a neuroprotective and anti-inflammatory agent in other neurodegenerative diseases [51,52]. Representative micrograph images of the effects of fluspirilene, nicardipine, and verapamil, and dose-response activity in the GFP-LC3 assay are shown in Figure 2a,b.…”

Section: Validation Of Autophagy-lysosomal Phenotype Correction In Cbmentioning

confidence: 81%

An Autophagy Modifier Screen Identifies Small Molecules Capable of Reducing Autophagosome Accumulation in a Model of CLN3-Mediated Neurodegeneration

Petcherski

Chandrachud

Butz

et al. 2019

Cells

View full text Add to dashboard Cite

Alterations in the autophagosomal–lysosomal pathway are a major pathophysiological feature of CLN3 disease, which is the most common form of childhood-onset neurodegeneration. Accumulating autofluorescent lysosomal storage material in CLN3 disease, consisting of dolichols, lipids, biometals, and a protein that normally resides in the mitochondria, subunit c of the mitochondrial ATPase, provides evidence that autophagosomal–lysosomal turnover of cellular components is disrupted upon loss of CLN3 protein function. Using a murine neuronal cell model of the disease, which accurately mimics the major gene defect and the hallmark features of CLN3 disease, we conducted an unbiased search for modifiers of autophagy, extending previous work by further optimizing a GFP-LC3 based assay and performing a high-content screen on a library of ~2000 bioactive compounds. Here we corroborate our earlier screening results and identify expanded, independent sets of autophagy modifiers that increase or decrease the accumulation of autophagosomes in the CLN3 disease cells, highlighting several pathways of interest, including the regulation of calcium signaling, microtubule dynamics, and the mevalonate pathway. Follow-up analysis on fluspirilene, nicardipine, and verapamil, in particular, confirmed activity in reducing GFP-LC3 vesicle burden, while also demonstrating activity in normalizing lysosomal positioning and, for verapamil, in promoting storage material clearance in CLN3 disease neuronal cells. This study demonstrates the potential for cell-based screening studies to identify candidate molecules and pathways for further work to understand CLN3 disease pathogenesis and in drug development efforts.

show abstract

“…Moreover, GABA A receptor‐mediated [Cl − ] i accumulation could induce cell swelling and alterations of [Ca 2+ ] i . Lastly, VGCC blockers may modulate neuroinflammation by means of reducing oxidative stress (Surmeier et al ., ) and production of proinflammatory cytokines (Huang et al ., ). These possibilities and the mechanisms of disruption in proinflammatory environments should be investigated further in future studies.…”

Section: Discussionmentioning

confidence: 99%

Inflammation alters AMPA‐stimulated calcium responses in dorsal striatal D2 but not D1 spiny projection neurons

Winland

Welsh

Sepulveda-Rodriguez

et al. 2017

Eur J of Neuroscience

View full text Add to dashboard Cite

Neuroinflammation precedes neuronal loss in striatal neurodegenerative diseases and can be exacerbated by the release of proinflammatory molecules by microglia. These molecules can affect trafficking of AMPARs. The preferential trafficking of calcium-permeable versus impermeable AMPARs can result in disruptions of [Ca2+]i and alter cellular functions. In striatal neurodegenerative diseases, changes in [Ca2+]i and L-type voltage-gated calcium channels (VGCCs) have been reported. Therefore, the present study sought to determine whether a proinflammatory environment alters AMPA-stimulated [Ca2+]i through calcium-permeable AMPARs and/or L-type VGCCs in dopamine-2 and dopamine-1 expressing striatal spiny projection neurons (D2 and D1 SPNs) in the dorsal striatum. Mice expressing the calcium indicator protein, GCaMP in D2 or D1 SPNs, were utilized for calcium imaging. Microglial activation was assessed by morphology analyses. To induce inflammation, acute mouse striatal slices were incubated with lipopolysaccharide (LPS). Here we report that LPS treatment potentiated AMPA responses only in D2 SPNs. When a nonspecific VGCC blocker was included, we observed a decrease of AMPA-stimulated calcium fluorescence in D2 but not D1 SPNs. The remaining agonist induced [Ca2+]i was mediated by calcium-permeable AMPARs because the responses were completely blocked by a selective calcium-permeable AMPAR antagonist. We used isradipine, the highly selective L-type VGCC antagonist to determine the role of L-type VGCCs in SPNs treated with LPS. Isradipine decreased AMPA-stimulated responses selectively in D2 SPNs after LPS treatment. Our findings suggest that dorsal striatal D2 SPNs are specifically targeted in proinflammatory conditions and that L-type VGCCs and calcium-permeable AMPARs are important mediators of this effect.

show abstract

Anti-Neuroinflammatory Effects of the Calcium Channel Blocker Nicardipine on Microglial Cells: Implications for Neuroprotection

Cited by 59 publications

References 72 publications

Brain-derived neurotrophic factor regulates cell motility in human colon cancer

Brain-derived neurotrophic factor regulates cell motility in human colon cancer

An Autophagy Modifier Screen Identifies Small Molecules Capable of Reducing Autophagosome Accumulation in a Model of CLN3-Mediated Neurodegeneration

Inflammation alters AMPA‐stimulated calcium responses in dorsal striatal D2 but not D1 spiny projection neurons

Contact Info

Product

Resources

About