Endoplasmic reticulum stress inhibition protects against excitotoxic neuronal injury in the rat brain.
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.
Sokka
Anna-Leena
AL
Minerva Medical Research Institute, Biomedicum Helsinki, FIN-00290 Helsinki, Finland.
Putkonen
Noora
N
Mudo
Giuseppa
G
Pryazhnikov
Evgeny
E
Reijonen
Sami
S
Khiroug
Leonard
L
Belluardo
Natale
N
Lindholm
Dan
D
Korhonen
Laura
L
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
D018690:Excitatory Amino Acid Agonists; D007608:Kainic Acid