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Published on: November 6, 2019
The oxindole/imidazole derivative C16 reduces in vivo brain PKR activation
Sabrina Ingrand1, Laurence Barrier, Claire Lafay-Chebassier
1Research 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
Abstract:
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.
Insights
A novel oxindole/imidazole derivative (C16) effectively inhibits brain double-stranded RNA-dependent protein kinase (PKR) in young rats. This neuroprotective strategy specifically targets apoptotic pathways without promoting cell proliferation or tumorigenesis.
Area of Science:
- Neuroscience
- Molecular Biology
- Pharmacology
Background:
- Double-stranded RNA-dependent protein kinase (PKR) plays a crucial role in apoptosis.
- Inhibiting PKR is a potential neuroprotection strategy.
- Concerns exist regarding PKR inhibition potentially promoting cell proliferation and tumorigenesis.
Purpose of the Study:
- To investigate the effects of a novel PKR inhibitor, C16 (an oxindole/imidazole derivative), in an in vivo model.
- To determine if C16 specifically inhibits PKR without inducing proliferative signaling.
Main Methods:
- Utilized a 7-day-old rat model with high brain PKR activation.
- Administered C16 via acute systemic injection.
- Analyzed the PKR/eIF2alpha apoptotic pathway and the mTOR/p70S6K proliferative pathway.
Main Results:
- C16 specifically inhibited the apoptotic PKR/eIF2alpha signaling pathway.
- C16 did not stimulate the proliferative mTOR/p70S6K signaling mechanism.
- Demonstrated the targeted neuroprotective potential of C16.
Conclusions:
- The novel PKR inhibitor C16 offers a promising neuroprotective strategy.
- C16 selectively targets apoptotic pathways, avoiding adverse proliferative effects.
- This study provides the first evidence of C16's specific mechanism in vivo.