Involvement of sigma-1 receptor in astrocyte activation induced by methamphetamine via up-regulation of its own expression

Journal of Neuroinflammation

Honghong Yao⁵  Ling Chen²  Shilpa Buch⁴  Ming Duan³  Jie Chao¹  Xiaodong Wu⁵  Xinjian Zhu⁵  Ying Bai⁵  Xuan Lv⁵  Yuan Zhang⁵ 

[1] Department of Physiology, Medical School of Southeast University, 87 Dingjiaqiao, Nanjing 210009, China;Department of Physiology, Nanjing Medical University, 140 Hanzhong Road, Nanjing 210029, China;Virosis Laboratory, Key Laboratory of Zoonosis, Ministry of Education, Institute of Zoonosis, Jilin University, 5333 Xi An Road, Changchun 130062, China;Department of Pharmacology and Experimental Neuroscience, University of Nebraska Medical Center, 42nd and Emile, Omaha 68198, NE, USA;Department of Pharmacology, Medical School of Southeast University, 87 Dingjiaqiao, Nanjing 210009, Jiangsu, China

关键词: CREB;    ERK;    Astrocytes;    Methamphetamine;    Sigma-1 receptor;   

Others  :  1137612
DOI  :  10.1186/s12974-015-0250-7

 received in 2014-10-11, accepted in 2015-01-15,  发布年份 2015

【 摘 要 】

Background

Although it has been documented that methamphetamine induces astrocyte activation, the mechanism(s) underlying this effect remain poorly understood. We thus sought to examine the molecular mechanisms involved in methamphetamine-mediated activation of astrocytes with a focus on the role of sigma-1 receptor (σ-1R) in this process.

Methods

The expression of σ-1R and glial fibrillary acidic protein (GFAP) was examined by reverse transcription PCR (RT-PCR), real-time PCR, Western blot, and immunofluorescent staining; phosphorylation of cell signaling pathways was detected by Western blot analysis. Immunoprecipitation was used to determine the interaction between σ-1R and p-Src. Chromatin immunoprecipitation (ChIP) assay was employed to discern the binding of cAMP-response element-binding protein (CREB) with the promoter of σ-1R. The role of σ-1R in astrocyte activation was further validated in σ-1R knockout (KO) mice by Western blot combined with immunofluorescent staining.

Results

Exposure of primary rat astrocytes to methamphetamine increased the expression of σ-1R via the activation of Src, ERK mitogen-activated protein kinase, and downstream CREB pathways. Subsequently, CREB translocated into nucleus and interacted with the promoter of σ-1R resulting in increased expression of σ-1R with a concomitant increase in expression of GFAP. This effect was inhibited in cells treated with the σ-1R antagonist-BD1047, thereby implicating the role of σ-1R in the activation of astrocytes. In vivo relevance of these findings was further corroborated in σ-1R KO mice that were administered methamphetamine. In the methamphetamine administered mice, there was a failure of the drug to induce activation of astrocytes, an effect that was evident in wild-type (WT) mice exposed to methamphetamine.

Conclusions

The study presented herein demonstrates that methamphetamine-mediated activation of astrocytes involved up-regulation of σ-1R through a positive-feedback mechanism. Understanding the regulation of σ-1R expression could provide insights into the development of potential therapeutic strategies for astrocyte activation induced by methamphetamine.

【 授权许可】

   
2015 Zhang et al.; licensee BioMed Central.

【 图 表 】

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