The oxindole/imidazole derivative C16 reduces in vivo brain PKR activation.
Inhibition of double-stranded RNA-dependent protein kinase (PKR) represents an interesting strategy for neuroprotection. However, inhibiting this kinase which triggers the apoptotic process could favour in counterpart cell proliferation and tumorigenesis. Here, we use an in vivo model of 7-day-old rat displaying a high activation of brain PKR to investigate the effects of a new PKR inhibitor identified as an oxindole/imidazole derivative (C16). We show for the first time that acute systemic injection of C16 specifically inhibits the apoptotic PKR/eIF2alpha signaling pathway without stimulating the proliferative mTOR/p70S6K signaling mechanism.
Ingrand
Sabrina
S
Research Group on Brain Aging (EA 3808), University of Poitiers, UFR Médecine-Pharmacie, 6 Rue de la Milétrie, BP 199, 86034 Poitiers Cedex, France. sabrina.ingrand@univ-poitiers.fr
Barrier
Laurence
L
Lafay-Chebassier
Claire
C
Fauconneau
Bernard
B
Page
Guylène
G
Hugon
Jacques
J
D000704:Analysis of Variance; D000818:Animals; D001921:Brain / Q000187:drug effects* / Q000201:enzymology; D004789:Enzyme Activation / Q000187:drug effects; D015852:Eukaryotic Initiation Factor-2 / Q000378:metabolism; D007093:Imidazoles / Q000008:administration & dosage / Q000737:chemistry / Q000494:pharmacology*; D015151:Immunoblotting; D007211:Indoles / Q000008:administration & dosage / Q000737:chemistry / Q000494:pharmacology*; D000078183:Oxindoles; D010766:Phosphorylation / Q000187:drug effects; D011494:Protein Kinases / Q000378:metabolism; D051381:Rats; D017207:Rats, Sprague-Dawley; D015398:Signal Transduction / Q000187:drug effects; D058570:TOR Serine-Threonine Kinases; D019892:eIF-2 Kinase / Q000378:metabolism*
D015852:Eukaryotic Initiation Factor-2; D007093:Imidazoles; D007211:Indoles; D000078183:Oxindoles; C022960:2-oxindole; C029899:imidazole; D011494:Protein Kinases; C546845:mTOR protein, rat; D058570:TOR Serine-Threonine Kinases; D019892:eIF-2 Kinase