4,4'-Diisothiocyanostilbene-2,2'-disulfonic Acid (DIDS) Ameliorates Ischemia-Hypoxia-Induced White Matter  Damage in Neonatal Rats through Inhibition of the  Voltage-Gated Chloride Channel ClC-2

Zhao, Baixiong; Quan, Hongyu; Ma, Teng; Tian, Yanping; Cai, Qian; Liu, Hongli

doi:10.3390/ijms160510457

Cited by 11 publications

(12 citation statements)

References 24 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…This process usually occurs in the third trimester of pregnancy and even last after birth 9 . Numerous studies have shown that during the period when OPCs differentiate into early OLs, immature OLs were vulnerable to injury factors, such as hypoxia-ischemia 10 , toxicity 11 , oxidative stress 12 etc. which led to OPCs/Pre-OLs injury and myelination disturbance 13 .…”

Section: Introductionmentioning

confidence: 99%

Activated ClC-2 Inhibits p-Akt to Repress Myelination in GDM Newborn Rats

He¹,

Peng²,

Yang³

et al. 2017

Int. J. Biol. Sci.

Self Cite

View full text Add to dashboard Cite

This study aims to investigate the effect and mechanism of type 2 voltage-gated chloride channel (ClC-2) on myelin development of newborn rats' cerebral white matter with gestational diabetes mellitus (GDM). In this study, GDM model was induced in late pregnant rat model. The alteration of ClC-2 expression in various developmental stages of cerebral white matter with/without being exposed to high glucose was analyzed using RT-PCR, active oxygen detection, TUNEL staining, Western Blot as well as immuno-histochemical staining. Our results showed that ClC-2 mRNA and protein expressions in GDM group were significantly increased in white matter of fetal rats after E18 stage, and elevated the level of TNF-α and iNOS in white matter at P0 and P3 stage of newborn rats. Meanwhile, In GDM group, reactive oxygen species (ROS) levels of the white matter at E18, P0, and P3 stage were significantly higher than control group. Furthermore, the expression level of myelin transcription factor Olig2 at P0 stage and CNPase at P3 stage were strikingly lower than that of the control group. In GDM group, ClC-2 expression in the corpus callosum (CC) and cingulate gyrus (CG) regains, and TUNEL positive cell number were increased at P0 and P3 stage. However, PDGFα positive cell number at P0 stage and CNPase expression at P3 stage were significantly decreased. Caspase-3 was also increased in those white matter regions in GDM group, but p-Akt expression was inhibited. While DIDS (a chloride channel blocker) can reverse these changes. In conclusion, ClC-2 and caspase-3 were induced by GDM, which resulted in apoptosis and myelination inhibition. The effect was caused by repressing PI3K-Akt signaling pathway. Application of ClC-2 inhibitor DIDS showed protective effects on cerebral white matter damage stimulated by high glucose concentration.

show abstract

Section: Introductionmentioning

confidence: 99%

Activated ClC-2 Inhibits p-Akt to Repress Myelination in GDM Newborn Rats

He¹,

Peng²,

Yang³

et al. 2017

Int. J. Biol. Sci.

Self Cite

View full text Add to dashboard Cite

show abstract

“…2) A criti-cal reduction of blood flow to a region of the brain such as an acute obstruction of an artery causes ischemia, which elevates levels of free radicals, extracellular glutamate and intracellular calcium, resulting in inflammation, neurologic malfunctions and neuronal cell death. 30) DIDS significantly downgraded the level of reactive oxygen species in chronic cerebral ischemiahypoxia rat models. 31) Even if DIDS itself upregulates neuronal cell death locally, it is likely to inhibit the expansion of death signals between cells in the ischemic penumbra broadly, leading to the putative benefit.…”

Section: Discussionmentioning

confidence: 96%

“…Recently, we have reported that 15d-PGJ 2 inhibited the phosphoinositide 3-kinase (PI3K)-Akt pathway, resulting in the neuronal apoptosis. 32,33) 15d-PGJ 2 is not only one of neurodegenerative mediators 30) but also one of endogenous anticancer agents. 34) The cytotoxicity of 15d-PGJ 2 was potentiated by the combination with other pharmaceutical agents in renal cell carcinoma.…”

Section: Discussionmentioning

confidence: 99%

4,4-Diisothiocyanatostilbene Disulfonic Acid Enhanced 15-Deoxy-Δ<sup>12,14</sup>-prostaglandin J<sub>2</sub>-Induced Neuronal Apoptosis

Koma

Yamamoto

Kumagai

et al. 2019

Biological & Pharmaceutical Bulletin

View full text Add to dashboard Cite

4,4-Diisothiocyanatostilbene disulfonic acid (DIDS), an antagonist of anion channel including voltage-dependent anion channel (VDAC), acts as both neurotoxicant and neuroprotectant, resulting in the controversy. VDAC contributes to neuronal apoptosis and is a candidate target protein of 15-deoxy-Δ 12,14-prostaglandin J 2 (15d-PGJ 2). Caspase-3 is activated during neuronal apoptosis caused by 15d-PGJ 2. In the present study, we ascertained whether DIDS was neuroprotective or neurotoxic in the primary culture of rat cortical neurons. Neuronal cell viabilities were primarily evaluated by the 3-(4,5-dimethyl-2-thiazolyl)-2,5-diphenyl-2H tetrazolium bromide (MTT) reduction assay. Plasma membrane integrity and apoptosis were detected by the staining of propidium iodide (PI) and Hoechst33342, respectively. Alternatively, apoptosis was also measured by caspase-3 assay kit. DIDS did not prevent neurons from undergoing the 15d-PGJ 2-induced apoptosis. In contrast, DIDS caused neuronal cell death in a concentration-dependent manner by itself, confirming its neurotoxicity. The sublethal application of DIDS did not decrease MTT-reducing activity, increase caspase-3 activity, condense chromatin, allow PI to enter neuron and degenerate neuronal morphology significantly. Interestingly, DIDS enhanced the 15d-PGJ 2-induced neuronal apoptosis markedly under the sublethal condition. To our knowledge, this is the first report of synergistic effects of DIDS on the neurotoxicity of 15d-PGJ 2. Key words primary cortical neuron; 15-deoxy-Δ 12,14-prostaglandin J 2 ; apoptosis; 4,4-diisothiocyanatostilbene disulfonic acid; voltage-dependent anion channel

show abstract

“…By contrast, the excessive activation of CLC-2 may lead to cell damage. A report concerning the white matter of neonatal rats demonstrated that ischemia-hypoxia elevated the activation of CLC-2 and subsequently initiated apoptosis in OLs ( 23 ). He et al ( 36 ) reported that, in the white matter of newborn rats that presented with gestational diabetes mellitus, activation of CLC-2 resulted in apoptosis and myelination inhibition via repression of the phosphatidylinositol 3-kinase-protein kinase B signaling pathway.…”

Section: Discussionmentioning

confidence: 99%

“…Additionally, Ca 2+ transients are considerably larger in mature OLs compared with OPCs, indicating that Ca 2+ may be a signal for the initiation of myelin formation ( 22 ). The inhibition of voltage-gated chloride channel (CLC)-2, by 4,4′-diisothiocyanostilbene-2,2′-disulfonic acid (DIDS), is able to protect developing OLs in the white matter following ischemia-hypoxia injury in neonatal rats ( 23 ). However, the function of CLC-2 on OPC differentiation and myelination is not fully understood.…”

Section: Introductionmentioning

confidence: 99%

CLC-2 is a positive modulator of oligodendrocyte precursor cell differentiation and myelination

et al. 2018

View full text Add to dashboard Cite

Oligodendrocytes (OLs) are myelin-forming cells that are present within the central nervous system. Impaired oligodendrocyte precursor cell (OPC) differentiation into mature OLs is a major cause of demyelination diseases. Therefore, identifying the underlying molecular mechanisms of OPC differentiation is crucial to understand the processes of myelination and demyelination. It has been acknowledged that various extrinsic and intrinsic factors are involved in the control of OPC differentiation; however, the function of ion channels, particularly the voltage-gated chloride channel (CLC), in OPC differentiation and myelination are not fully understood. The present study demonstrated that CLC-2 may be a positive modulator of OPC differentiation and myelination. Western blotting results revealed that CLC-2 was expressed in both OPCs and OLs. Furthermore, CLC-2 currents (ICLC-2) were recorded in both types of cells. The inhibition of ICLC-2 by GaTx2, a blocker of CLC-2, was demonstrated to be higher in OPCs compared with OLs, indicating that CLC-2 may serve a role in OL differentiation. The results of western blotting and immunofluorescence staining also demonstrated that the expression levels of myelin basic protein were reduced following GaTx2 treatment, indicating that the differentiation of OPCs into OLs was inhibited following CLC-2 inhibition. In addition, following western blot analysis, it was also demonstrated that the protein expression of the myelin proteins yin yang 1, myelin regulatory factor, Smad-interacting protein 1 and sex-determining region Y-box 10 were regulated by CLC-2 inhibition. Taken together, the results of the present study indicate that CLC-2 may be a positive regulator of OPC differentiation and able to contribute to myelin formation and repair in myelin-associated diseases by controlling the number and open state of CLC-2 channels.

show abstract

4,4'-Diisothiocyanostilbene-2,2'-disulfonic Acid (DIDS) Ameliorates Ischemia-Hypoxia-Induced White Matter Damage in Neonatal Rats through Inhibition of the Voltage-Gated Chloride Channel ClC-2

Cited by 11 publications

References 24 publications

Activated ClC-2 Inhibits p-Akt to Repress Myelination in GDM Newborn Rats

Activated ClC-2 Inhibits p-Akt to Repress Myelination in GDM Newborn Rats

4,4-Diisothiocyanatostilbene Disulfonic Acid Enhanced 15-Deoxy-Δ<sup>12,14</sup>-prostaglandin J<sub>2</sub>-Induced Neuronal Apoptosis

CLC-2 is a positive modulator of oligodendrocyte precursor cell differentiation and myelination

Contact Info

Product

Resources

About