title: Endoplasmic reticulum stress inhibition protects against excitotoxic neuronal injury in the rat brain.
abstract: 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 eIF2alpha (eukaryotic translation initiation factor 2 subunit alpha) 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.
authors.affiliation: Minerva Medical Research Institute, Biomedicum Helsinki, FIN-00290 Helsinki, Finland.
authors.forename: Anna-Leena
authors.initials: AL
authors.lastname: Sokka
authors.forename: Noora
authors.initials: N
authors.lastname: Putkonen
authors.forename: Giuseppa
authors.initials: G
authors.lastname: Mudo
authors.forename: Evgeny
authors.initials: E
authors.lastname: Pryazhnikov
authors.forename: Sami
authors.initials: S
authors.lastname: Reijonen
authors.forename: Leonard
authors.initials: L
authors.lastname: Khiroug
authors.forename: Natale
authors.initials: N
authors.lastname: Belluardo
authors.forename: Dan
authors.initials: D
authors.lastname: Lindholm
authors.forename: Laura
authors.initials: L
authors.lastname: Korhonen
mesh_terms: D000818:Animals; D001921:Brain / Q000187:drug effects / Q000378:metabolism* / Q000473:pathology; D004721:Endoplasmic Reticulum / Q000187:drug effects / Q000378:metabolism* / Q000473:pathology; D018690:Excitatory Amino Acid Agonists / Q000633:toxicity*; D006624:Hippocampus / Q000187:drug effects / Q000378:metabolism / Q000473:pathology; D007608:Kainic Acid / Q000633:toxicity; D008297:Male; D009433:Neural Inhibition / Q000502:physiology*; D009474:Neurons / Q000187:drug effects / Q000378:metabolism* / Q000473:pathology; D018384:Oxidative Stress / Q000187:drug effects / Q000502:physiology*; D051381:Rats; D017208:Rats, Wistar
chemical_list: D018690:Excitatory Amino Acid Agonists; D007608:Kainic Acid