salubrinal and Seizures

Endoplasmic reticulum (ER) stress has been indicated to be involved in the pathogenesis of epilepsy. Sodium valproate (VPA), one of the most commonly used antiepileptic drugs, is reported to regulate ER stress in many neurological diseases. However, the effect of VPA on ER stress in epilepsy remains unclear. The current study was performed to investigate the role of ER stress in the neuroprotection of VPA against seizure induced by pentylenetetrzole (PTZ). Our results showed that VPA treatment could inhibit the increased expressions of ER stress proteins (GRP78 and CHOP), and significantly reduce neuronal apoptosis in the PTZ-induced experimental seizure model. In addition, Salubrinal, an ER stress inhibitor, was used as a positive control, and exhibited neuroprotective effects via inhibiting excessive ER stress in the seizure model, which further supported that the inhibition in ER stress by VPA treatment could exert neuroprotection in seizures. In summary, our work demonstrated for the first time that ER stress was involved in the neuroprotective potential of VPA for seizures.

Topics: Animals; Anticonvulsants; Apoptosis; Cinnamates; Endoplasmic Reticulum Chaperone BiP; Endoplasmic Reticulum Stress; Heat-Shock Proteins; Hippocampus; Male; Mice, Inbred C57BL; Neuroprotective Agents; Pentylenetetrazole; Seizures; Thiourea; Transcription Factor CHOP; Valproic Acid

Kainic acid (KA)-induced neuronal death is closely linked to endoplasmic reticulum (ER) and mitochondrial dysfunction. Parkin is an ubiquitin E3 ligase that mediates the ubiquitination of the Bcl-2 family of proteins and its mutations are associated with neuronal apoptosis in neurodegenerative diseases. We investigated the effect of salubrinal, an ER stress inhibitor, on the regulation of ER stress and mitochondrial apoptosis induced by KA, in particular, by controlling parkin expression. We showed that salubrinal significantly reduced seizure activity and increased survival rates of mice with KA-induced seizures. We found that salubrinal protected neurons against apoptotic death by reducing expression of mitochondrial apoptotic factors and elF2α-ATF4-CHOP signaling proteins. Interestingly, we showed that salubrinal decreased the KA-induced parkin expression and inhibited parkin translocation to mitochondria, which suggests that parkin may regulate a cross-talk between ER and mitochondria. Collectively, inhibition of ER stress attenuates mitochondrial apoptotic and ER stress pathways and controls parkin-mediated neuronal death following KA-induced seizures.

Topics: Animals; Anticonvulsants; Apoptosis; Cinnamates; Endoplasmic Reticulum; Endoplasmic Reticulum Stress; Hippocampus; Kainic Acid; Male; Mice, Inbred ICR; Mitochondria; Neurons; Neuroprotective Agents; Nitric Oxide Synthase Type II; Random Allocation; Seizures; Survival Analysis; Thiourea; Ubiquitin-Protein Ligases