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Role of Endoplasmic Reticulum (ER) Stress in Cocaine-Induced Microglial Cell Death

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Abstract

While it has been well-documented that drugs of abuse such as cocaine can enhance progression of human immunodeficiency virus (HIV)-associated neuropathological disorders, the underlying mechanisms mediating these effects remain poorly understood. The present study was undertaken to examine the effects of cocaine on microglial viability. Herein we demonstrate that exposure of microglial cell line-BV2 or rat primary microglia to exogenous cocaine resulted in decreased cell viability as determined by MTS and TUNEL assays. Microglial toxicity of cocaine was accompanied by an increase in the expression of cleaved caspase-3 as demonstrated by western blot assays. Furthermore, increased microglial toxicity was also associated with a concomitant increase in the production of intracellular reactive oxygen species, an effect that was ameliorated in cells pretreated with NADPH oxidase inhibitor apocynin, thus emphasizing the role of oxidative stress in this process. A novel finding of this study was the involvement of endoplasmic reticulum (ER) signaling mediators such as PERK, Elf2α, and CHOP, which were up regulated in cells exposed to cocaine. Reciprocally, blocking CHOP expression using siRNA ameliorated cocaine-mediated cell death. In conclusion these findings underscore the importance of ER stress in modulating cocaine induced microglial toxicity. Understanding the link between ER stress, oxidative stress and apoptosis could lead to the development of therapeutic strategies targeting cocaine-mediated microglial death/dysfunction.

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Acknowledgment

Funding

This work was supported by grants DA020392, DA023397 and DA024442 (SB) and DA030285 (HY) from the National Institutes of Health.

Conflict of interest statement

Authors claim no actual or potential conflicts of interest

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Authors and Affiliations

  1. Department of Pharmacology and Experimental Neuroscience, University of Nebraska Medical Center, Omaha, NE, 68198-5880, USA

    Blaise Mathias Costa, Honghong Yao, Lu Yang & Shilpa Buch

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  1. Blaise Mathias Costa
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  2. Honghong Yao
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  3. Lu Yang
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  4. Shilpa Buch
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Correspondence to Shilpa Buch.

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Costa, B.M., Yao, H., Yang, L. et al. Role of Endoplasmic Reticulum (ER) Stress in Cocaine-Induced Microglial Cell Death. J Neuroimmune Pharmacol 8, 705–714 (2013). https://doi.org/10.1007/s11481-013-9438-8

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  • DOI: https://doi.org/10.1007/s11481-013-9438-8

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