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The Journal of Neuroscience, January 24, 2007, 27(4):901-908; doi:10.1523/JNEUROSCI.4289-06.2007

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Neurobiology of Disease
Endoplasmic Reticulum Stress Inhibition Protects against Excitotoxic Neuronal Injury in the Rat Brain

Anna-Leena Sokka,^1 * Noora Putkonen,^1 * Giuseppa Mudo,² Evgeny Pryazhnikov,³ Sami Reijonen,¹ Leonard Khiroug,³ Natale Belluardo,² Dan Lindholm,^1,4,5  and Laura Korhonen^1,5 

¹Minerva Medical Research Institute, Biomedicum Helsinki, FIN-00290 Helsinki, Finland, ²Department of Experimental Medicine, Division of Human Physiology, University of Palermo, I-90134 Palermo, Italy, ³Neuroscience Center and ⁴Faculty of Biosciences, University of Helsinki, FIN-00014 Helsinki, Finland, and ⁵Department of Neuroscience, Neurobiology, Biomedical Centre, S-75123 Uppsala, Sweden

Correspondence should be addressed to Dr. Laura Korhonen, Minerva Medical Research Institute, Biomedicum Helsinki, Haartmaninkatu 8, FIN-00290 Helsinki, Finland. Email: Laura.T.Korhonen{at}helsinki.fi

Elevated brain glutamate with activation of neuronal glutamate receptors accompanies neurological disorders, such as epilepsy and brain trauma. However, the mechanisms by which excitotoxicity triggers neuronal injury are not fully understood. We have studied the glutamate receptor agonist kainic acid (KA) inducing seizures and excitotoxic cell death. KA caused the disintegration of the endoplasmic reticulum (ER) membrane in hippocampal neurons and ER stress with the activation of the ER proteins Bip, Chop, and caspase-12. Salubrinal, inhibiting eIF2 (eukaryotic translation initiation factor 2 subunit ) dephosphorylation, significantly reduced KA-induced ER stress and neuronal death in vivo and in vitro. KA-induced rise in intracellular calcium was not affected by Salubrinal. The results show that ER responses are essential parts of excitotoxicity mediated by glutamate receptor activation and that Salubrinal decreases neuronal death in vivo. Inhibition of ER stress by small molecular compounds may be beneficial for treatment of various neuronal injuries and brain disorders.

Key words: kainic acid; hippocampus; salubrinal; PERK; eIF2; caspase-12

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Received Oct. 2, 2006; revised Nov. 27, 2006; accepted Dec. 15, 2006.

Correspondence should be addressed to Dr. Laura Korhonen, Minerva Medical Research Institute, Biomedicum Helsinki, Haartmaninkatu 8, FIN-00290 Helsinki, Finland. Email: Laura.T.Korhonen{at}helsinki.fi

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