Methylmercury exposure downregulates the expression of Racl and leads to neuritic degeneration and ultimately apoptosis in cerebrocortical neurons

Fujimura, Masatake; Usuki, Fusako; Sawada, Masumi; Rostène, William; Godefroy, David; Takashima, Akihiko

doi:10.1016/j.neuro.2008.10.002

Cited by 59 publications

(34 citation statements)

References 38 publications

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“…Rho GTPases activation has been investigated for their involvement in neurological disorders such as spinal cord injury, traumatic brain injury, stroke and Alzheimer's disease [18,[51][52][53]. Although many studies show Rho GTPases activation promotes cell survival, impairing of Rho GTPases inhibits growth of tumors by inducing apoptosis [54,55], there are still opposite conclusions supporting that activation of Rho GTPase elicits cell apoptosis, consistent with our present study [56,57]. In the present study, NaAsO 2 induced Cdc42 or Rac1 activation.…”

Section: Liu Et Al: Protective Role Of Neuroglobin In Rat Cerebellarsupporting

confidence: 87%

Neuroglobin Plays a Protective Role in Arsenite-Induced Cytotoxicity by Inhibition of Cdc42 and Rac1GTPases in Rat Cerebellar Granule Neurons

Liu

Gao

An³

et al. 2015

Cell Physiol Biochem

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Background and Aims: We have previously shown that neuroglobin (Ngb) expression can be regulated by sodium arsenite (NaAsO₂) exposure in rat cerebellar granule neurons (CGNs). However, the precise molecular mechanisms of Ngb action are largely unknown. Ras homolog (Rho) guanosine triphosphatases (Rho GTPases) are involved in the regulation of a number of cellular processes, including cell cytotoxicity. It has been reported that Ngb can act as a guanine nucleotide dissociation inhibitior (GDI) role to inactivate Rho GTPases. Therefore, we investigated Rho GTPases activation induced by NaAsO₂ exposure in rat CGNs and effects of Rho GTPases activation on the cells. We also investigated the role of Ngb in this process. Methods: Primary cultures of CGNs were prepared from 7-day-old Wistar rat pups. The cytotoxic effects of NaAsO₂ on CGNs were evaluated using the Cell Counting Kit-8 assay and TUNEL staining. RNA interference technology was used to silence Ngb, and the subsequent effects were evaluated by quantitative RT-PCR and Western blot. Cdc42 and Rac1 activation were measured by pull-down assay and Western blot. Results: NaAsO₂ induced cytotoxicity in rat CGNs, increased GTP-bound form of Cdc42 and Rac1 GTPases in the cells. Furthermore, inhibition of Cdc42 or Rac1 activity using the inhibitor ZCL278 or NSC23766 decreased apoptosis and increased cell viability in the cells exposed to NaAsO₂. Using siRNA-mediated knockdown, we show that NaAsO₂-induced cytotoxicity was exacerbated, activation of Cdc42 (GTP-Cdc42) and Rac1 (GTP-Rac1) was increased in Ngb RNA silencing cells. Conclusions: cytotoxic effects of NaAsO₂ on rat CGNs is induced at least partly by Cdc42 and Rac1 activation, and Ngb can inhibit Cdc42 and Rac1 activation to play protective role in rat CGNs exposed to NaAsO₂.

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Section: Liu Et Al: Protective Role Of Neuroglobin In Rat Cerebellarsupporting

confidence: 87%

Neuroglobin Plays a Protective Role in Arsenite-Induced Cytotoxicity by Inhibition of Cdc42 and Rac1GTPases in Rat Cerebellar Granule Neurons

Liu

Gao

An³

et al. 2015

Cell Physiol Biochem

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“…Furthermore, inhibition of Cdc42 or Rac1 increased the viability of the cells exposed to 30 μM NaAsO 2 . There are conclusions supporting that activation of Rho GTPases elicits cell apoptosis [49][50][51], consistent with our present study. Results of the present study disclosed that activation of Rac1 GTPases was related to apoptosis induced by arsenite exposure.…”

Section: Discussionsupporting

confidence: 93%

Rac1 and Cdc42 Play Important Roles in Arsenic Neurotoxicity in Primary Cultured Rat Cerebellar Astrocytes

Liu

et al. 2015

Biol Trace Elem Res

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This study aimed to explore whether Rac1 and Cdc42, representative members of Ras homologue guanosine triphosphatases (Rho GTPases), are involved in neurotoxicity induced by arsenic exposure in rat nervous system. Expressions of Rac1 and Cdc42 in rat cerebellum and cerebrum exposed to different doses of NaAsO2 (Wistar rats drank 0, 2, 10, and 50 mg/L NaAsO2 water for 3 months) were examined. Both Rac1 and Cdc42 expressions increased significantly in a dose-dependent manner in cerebellum (P < 0.01) by Western blot and immunohistochemistry assay, but in cerebrum, Rac1 and Cdc42 expressions only in 2 mg/L exposure groups were significantly higher than those in control groups (P < 0.01). Five to 50 μM NaAsO2 decreased cell viability in a dose-dependent manner in primary cultured rat astrocytes, whereas 1 μM NaAsO2 increased the cell viability in these cells. Rac1 inhibitor, NSC23766, decreased NaAsO2-induced apoptosis and increased the cell viability in primary cultured rat cerebellar astrocytes exposed to 30 μM NaAsO2. Cdc42 inhibitor, ZCL278, increased cell viability in the cells exposed to 30 μM NaAsO2. Taken together, our current studies in vivo and in vitro indicate that activations of Rac1 and Cdc42 play a very important role in arsenic neurotoxicity in rat cerebellum, providing a new insight into arsenic neurotoxicity.

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“…In order to identify the cellular origin of our primary culture system, we performed immunocytochemical analyses using antibodies for neuronal-and glial-specific markers, including nestin (1/20 diluent, R&D Systems, Minneapolis, MN, USA), neuronal nuclei (NeuN) (1/500, Chemicon, Temecula, USA), glial fibrillary acidic protein (GFAP) (1/5 diluent, Dako, Tokyo, Japan) and ionized calcium binding adaptor molecule 1 (Iba1) (1/500 diluent, Wako Pure Chemical). For apoptosis analysis, deoxynucleotidyl transferase-mediated dUTP nick-end labeling (TUNEL) was performed as described previously (Fujimura et al, 2009a(Fujimura et al, , 2011.…”

Section: Methodsmentioning

confidence: 99%

Low concentrations of methylmercury inhibit neural progenitor cell proliferation associated with up-regulation of glycogen synthase kinase 3β and subsequent degradation of cyclin E in rats

Fujimura

Usuki

2015

Toxicology and Applied Pharmacology

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Methylmercury exposure downregulates the expression of Racl and leads to neuritic degeneration and ultimately apoptosis in cerebrocortical neurons

Cited by 59 publications

References 38 publications

Neuroglobin Plays a Protective Role in Arsenite-Induced Cytotoxicity by Inhibition of Cdc42 and Rac1GTPases in Rat Cerebellar Granule Neurons

Neuroglobin Plays a Protective Role in Arsenite-Induced Cytotoxicity by Inhibition of Cdc42 and Rac1GTPases in Rat Cerebellar Granule Neurons

Rac1 and Cdc42 Play Important Roles in Arsenic Neurotoxicity in Primary Cultured Rat Cerebellar Astrocytes

Low concentrations of methylmercury inhibit neural progenitor cell proliferation associated with up-regulation of glycogen synthase kinase 3β and subsequent degradation of cyclin E in rats

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