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Protective effect of Hsp70i against chronic social isolation stress in the rat hippocampus

  • Translational Neurosciences - Original Article
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Abstract

Stress-related glucocorticoids and glutamate release has been implicated in depression. Glutamate neurotoxicity is mediated, in part, by the production of nitric oxide via nitric oxide synthase (NOS) isoforms and mitochondrial damage. We previously reported that chronic social isolation stress triggers proapoptotic signaling in the rat prefrontal cortex, but not in the hippocampus. Given that the hippocampus is highly sensitive to stress, we examined signaling cascades underlying the hippocampal cellular protection through the NOS pathway, antioxidant capacity and heat shock protein (Hsp) expression. We investigated neuronal (nNOS) and inducible (iNOS) protein levels, subcellular protein distributions of nuclear factor-κB (NF-κB), CuZnSOD and MnSOD activity, reduced glutathione (GSH), stress-inducible Hsp70 (Hsp70i) protein expression and serum corticosterone (CORT) levels of rats exposed to 21 days of chronic social isolation, an animal model of depression, alone or in combination with 2 h of acute immobilization or cold stress (combined stress). Both acute stressors elevated CORT, with lesser magnitude increase in chronically isolated rats exposed to novel acute stress as compared to acute stressors alone, indicating compromised HPA axis activity. Acute cold decreased nuclear CuZnSOD activity and stimulated NF-κB nuclear translocation. Chronic social isolation resulted in no activation of NF-κB, but led to decreased GSH, iNOS and increased nNOS and Hsp70i levels, alterations that remained following combined stressors. Decreased mitochondrial MnSOD activity after combined stressors suggests compromised detoxifying capacity. These data indicate that Hsp70i upregulation may provide hippocampal cellular protection against chronic social isolation stress mediated by downregulation of iNOS protein expression through suppression of NF-κB activation.

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Acknowledgments

This work was supported by the Ministry of Education and Science of the Republic of Serbia, Grant 173044.

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The authors declare that they have no conflict of interest.

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Authors and Affiliations

  1. Laboratory of Molecular Biology and Endocrinology, Institute of Nuclear Sciences “Vinča”, University of Belgrade, P. O. Box 522-090, 11001, Belgrade, Serbia

    Jelena Zlatković & Dragana Filipović

  2. Central Institute of Mental Health, Institute of Psychopharmacology, Mannheim, Germany

    Rick E. Bernardi

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  1. Jelena Zlatković
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  2. Rick E. Bernardi
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  3. Dragana Filipović
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Correspondence to Dragana Filipović.

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Zlatković, J., Bernardi, R.E. & Filipović, D. Protective effect of Hsp70i against chronic social isolation stress in the rat hippocampus. J Neural Transm 121, 3–14 (2014). https://doi.org/10.1007/s00702-013-1066-1

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