Back to Search
Start Over
Neuroprotective Effects of DTIO, A Novel Analog of Nec-1, in Acute and Chronic Stages After Ischemic Stroke
- Source :
- Neuroscience. 390
- Publication Year :
- 2018
-
Abstract
- Receptor-interacting protein 1 kinase (RIP1K) plays a key role in necroptosis. Necrostatin-1 (Nec-1), a specific inhibitor of RIP1K, provides neuroprotection against ischemic brain injury, associating with inhibition of inflammation. Recently, our group synthesized a novel analog of Nec-1, 5-(3',5'-dimethoxybenzal)-2-thio-imidazole-4-ketone (DTIO). The present study investigated the effect of DTIO on ischemic stroke-induced brain injury in both acute and chronic phase and its underlying mechanism. In vivo, DTIO treatment reduced infarct volume and improved neurological deficits in the acute phase after permanent middle cerebral artery occlusion (pMCAO) and it also attenuated brain atrophy and promoted brain functional recovery in the chronic phase post-cerebral ischemia/reperfusion (I/R). In vitro, DTIO treatment decreased lactate dehydrogenase (LDH) leakage and necrotic cell death in the oxygen and glucose deprivation (OGD) or oxygen and glucose deprivation and reoxygenation (OGD/R)-induced neuronal or astrocytic cell injury. Simultaneously, DTIO suppressed the production and release of inflammatory cytokines, and reduced the formation of glial scar. Homology modeling analysis illustrated that DTIO had an ability of binding to RIP1K. Furthermore, immunoprecipitation analysis showed that DTIO inhibited the phosphorylation of RIP1K and decreased the interaction between the RIP1K and RIP3K. In addition, knockdown of RIP1K had neuroprotective effects and inhibited the release of proinflammatory cytokines, but didn't have a significant effect on DTIO-mediated neuroprotection. In conclusion, DTIO has protective effects on acute ischemic stroke and promotes functional recovery during chronic phase, associating with protecting ischemic neurons and astrocytes, inhibiting inflammation, and lessening the glial scar formation via inhibiting of the RIP1K.
- Subjects :
- 0301 basic medicine
Male
Indoles
Necroptosis
Ischemia
Inflammation
Pharmacology
Neuroprotection
Glial scar
Proinflammatory cytokine
Brain Ischemia
Rats, Sprague-Dawley
03 medical and health sciences
0302 clinical medicine
In vivo
medicine
Animals
Neurons
Mice, Inbred ICR
business.industry
General Neuroscience
Imidazoles
Recovery of Function
medicine.disease
Protein Structure, Tertiary
Stroke
030104 developmental biology
medicine.anatomical_structure
Neuroprotective Agents
Astrocytes
Receptor-Interacting Protein Serine-Threonine Kinases
Chronic Disease
medicine.symptom
Inflammation Mediators
business
030217 neurology & neurosurgery
Astrocyte
Signal Transduction
Subjects
Details
- ISSN :
- 18737544
- Volume :
- 390
- Database :
- OpenAIRE
- Journal :
- Neuroscience
- Accession number :
- edsair.doi.dedup.....dc4affb9b7a95217a4ff61ee20e38ef8