title: The specific PKR inhibitor C16 prevents apoptosis and IL-1β production in an acute excitotoxic rat model with a neuroinflammatory component.
abstract: The double-stranded RNA-dependent protein kinase (PKR), an apoptotic inducer, regulates much pro-inflammatory cytokine production. The purpose of this study was to evaluate in vivo the effects of the specific PKR inhibitor C16 in the striatum in an acute excitotoxic rat model with an important neuroinflammatory component. Inflammation was induced by unilateral striatal injection of quinolinic acid (QA) in 10-week-old normotensive rats. Animals were separated into groups receiving either vehicle or C16 for both sham and QA rats. The effects were assessed in ipsi- and contralateral striata by immunoblotting for PKR activation, by Luminex assay for cytokine levels and by immunofluorescent staining for cleaved caspase-3 to detect neuronal apoptosis. The highest dose of C16 (600μg/kg; C16-2) in QA rats reduced expression of the active catalytic domain of the PKR vs. that in vehicle-injected QA rats. A robust increase of IL-1β levels on the contralateral side of QA rats was prevented by C16-2 (97% inhibition). Macroscopic and microscopic observation of cerebral tissue (Hematoxylin & Eosin staining) revealed that tissue integrity was more preserved with C16-2 treatment than its vehicle in QA rats. Furthermore, C16-2 treatment decreased by 47% the neuronal loss and by 37% the number of positive cleaved caspase-3 neurons induced by QA injection. In conclusion, C16 prevented not only the PKR-induced neuronal loss but also the inflammatory response in this acute excitotoxic in vivo model, highlighting its promising neuroprotective properties to rescue acute brain lesions.
authors.affiliation: INSERM U930, Tours, France; Université François Rabelais de Tours, UMR U930, Tours, France. Electronic address: claire.tronel-2@etu.univ-tours.fr.
authors.forename: C
authors.initials: C
authors.lastname: Tronel
authors.affiliation: EA 3808, University of Poitiers, "Molecular Targets and Therapeutics of Alzheimer's Disease (CiMoTheMA)", 6 rue de la Milétrie, BP 199, 86034 Poitiers, France.
authors.forename: G
authors.initials: G
authors.lastname: Page
authors.affiliation: INSERM U930, Tours, France; Université François Rabelais de Tours, UMR U930, Tours, France.
authors.forename: S
authors.initials: S
authors.lastname: Bodard
authors.affiliation: INSERM U930, Tours, France; Université François Rabelais de Tours, UMR U930, Tours, France.
authors.forename: S
authors.initials: S
authors.lastname: Chalon
authors.affiliation: INSERM U930, Tours, France; Université François Rabelais de Tours, UMR U930, Tours, France.
authors.forename: D
authors.initials: D
authors.lastname: Antier
mesh_terms: D000208:Acute Disease; D000818:Animals; D017209:Apoptosis / Q000187:drug effects* / Q000502:physiology; D053148:Caspase 3 / Q000378:metabolism; D003342:Corpus Striatum / Q000187:drug effects / Q000378:metabolism / Q000473:pathology; D004195:Disease Models, Animal; D007093:Imidazoles / Q000494:pharmacology*; D007211:Indoles / Q000494:pharmacology*; D007249:Inflammation / Q000188:drug therapy / Q000378:metabolism; D053583:Interleukin-1beta / Q000096:biosynthesis*; D008297:Male; D009474:Neurons / Q000187:drug effects / Q000378:metabolism; D047428:Protein Kinase Inhibitors / Q000494:pharmacology*; D051381:Rats; D017208:Rats, Wistar; D019892:eIF-2 Kinase / Q000037:antagonists & inhibitors* / Q000378:metabolism
chemical_list: D007093:Imidazoles; D007211:Indoles; D053583:Interleukin-1beta; D047428:Protein Kinase Inhibitors; D019892:eIF-2 Kinase; D053148:Caspase 3
keywords: Caspase-3; Cytokines; Neuroinflammation; Neuroprotection; Oxindole/imidazole C16; PKR