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Endoplasmic Reticulum Stress Plays Critical Role in Brain Damage After Cerebral Ischemia/Reperfusion in Rats

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Abstract

The endoplasmic reticulum(ER) stress plays a vital role in mediating ischemic neuronal cell death. However, very little is known about the role of ER stress in mediating pathophysiological reactions to acute brain injuries. An attempt was therefore made to assess the role of cerebral ischemia/reperfusion (I/R) induced ER stress and its modulation on outcome of ischemic insult. Focal cerebral ischemia was induced in rats by middle cerebral artery occlusion (MCAO) for 2 h followed by varying time points of reperfusion. The brain loci specific and time-dependent alterations were seen in the expression pattern of molecular markers, i.e., heat-shock protein 70 (HSP70) for cytoplasmic dysfunction, glucose-regulated protein 78 (GRP78), Caspase-12, C/EBP homologous protein/growth arrest and DNA damage-inducible gene 153 (CHOP/GADD153), activating transcription factor 4 (ATF-4), and Processed X-box protein 1 (xbp1) mRNA for ER dysfunction. Further, histological examinations indicated pronounced brain damage, massive neuronal loss, and DNA fragmentation predominantly in the striatum and cortex. The enhanced expression of GRP78, Caspase-12, CHOP/GADD153, ATF4 and processing of xbp1 mRNA in the affected brain regions clearly indicate the critical involvement of ER-mediated cell death/survival mechanisms and also collectively demonstrated the activation of unfolded protein response (UPR). Moreover, Salubrinal, a selective inhibitor of eIF2α dephosphorylation was used to counteract ER stress, which significantly increased the phosphorylation of eukaryotic translation initiation factor 2 subunit α (eIF2α), leading to reduced brain damage after I/R injury. Therefore, inhibition of ER stress following I/R injury may be used as key therapeutic target for neuroprotection.

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Acknowledgment

Mr. Venkata Prasuja Nakka and Ms. Anchal Gusain received Senior Research Fellowship from the Council of Scientific and Industrial Research, New Delhi, India.

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Authors and Affiliations

  1. Division of Pharmacology, Central Drug Research Institute, Lucknow, 226001, India

    Venkata Prasuja Nakka, Anchal Gusain & Ram Raghubir

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  1. Venkata Prasuja Nakka
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  2. Anchal Gusain
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  3. Ram Raghubir
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Correspondence to Ram Raghubir.

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+CDRI Communication No. 7749.

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Supplementary Figure

Coronal brain sections of TTC staining showing the ipsilateral brain damage after 2 h ischemia followed by different time intervals of reperfusion (TIFF 536 kb)

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Nakka, V.P., Gusain, A. & Raghubir, R. Endoplasmic Reticulum Stress Plays Critical Role in Brain Damage After Cerebral Ischemia/Reperfusion in Rats. Neurotox Res 17, 189–202 (2010). https://doi.org/10.1007/s12640-009-9110-5

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  • DOI: https://doi.org/10.1007/s12640-009-9110-5

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