6533b837fe1ef96bd12a2a49

RESEARCH PRODUCT

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

Dan LindholmGiuseppa MudòAnna-leena SokkaSami ReijonenNoora PutkonenNatale BelluardoEvgeny PryazhnikovLeonard KhirougLaura Korhonen

subject

PERKMaleKainic acidProgrammed cell deathcaspase-12ExcitotoxicityBiologymedicine.disease_causeEndoplasmic ReticulumHippocampusCalcium in biologyeIF2 alphaSalubrinalchemistry.chemical_compoundsalubrinalmedicineExcitatory Amino Acid AgonistsAnimalsRats WistarNeuronsKainic AcidhippocampuGeneral NeuroscienceEndoplasmic reticulumGlutamate receptorBrainNeural InhibitionArticlesCell biologyRatsOxidative StresschemistryUnfolded protein responseNeuroscience

description

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 eIF2α (eukaryotic translation initiation factor 2 subunit α) dephosphorylation, significantly reduced KA-induced ER stress and neuronal deathin vivoandin 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 deathin vivo. Inhibition of ER stress by small molecular compounds may be beneficial for treatment of various neuronal injuries and brain disorders.

10.1523/jneurosci.4289-06.2007https://europepmc.org/articles/PMC6672923/