A translocator protein 18 kDa agonist protects against cerebral ischemia/reperfusion injury.

Abstract

BACKGROUND:

Cerebral ischemia is a leading cause of death and disability with limited treatment options. Although inflammatory and immune responses participate in ischemic brain injury, the molecular regulators of neuroinflammation after ischemia remain to be defined. Translocator protein 18 kDa (TSPO) mainly localized to the mitochondrial outer membrane is predominantly expressed in glia within the central nervous system during inflammatory conditions. This study investigated the effect of a TSPO agonist, etifoxine, on neuroinflammation and brain injury after ischemia/reperfusion.

METHODS:

We used a mouse model of middle cerebral artery occlusion (MCAO) to examine the therapeutic potential and mechanisms of neuroprotection by etifoxine.

RESULTS:

TSPO was upregulated in Iba1+ or CD11b+CD45int cells from mice subjected to MCAO and reperfusion. Etifoxine significantly attenuated neurodeficits and infarct volume after MCAO and reperfusion. The attenuation was pronounced in mice subjected to 30, 60, or 90 min MCAO. Etifoxine reduced production of pro-inflammatory factors in the ischemic brain. In addition, etifoxine treatment led to decreased expression of interleukin-1β, interleukin-6, tumor necrosis factor-α, and inducible nitric oxide synthase by microglia. Notably, the benefit of etifoxine against brain infarction was ablated in mice depleted of microglia using a colony-stimulating factor 1 receptor inhibitor.

CONCLUSIONS:

These findings indicate that the TSPO agonist, etifoxine, reduces neuroinflammation and brain injury after ischemia/reperfusion. The therapeutic potential of targeting TSPO requires further investigations in ischemic stroke.

• Authors: Han-Dong Li, Minshu Li, Elaine Shi, Wei-Na Jin, Kristofer Wood, Rayna Gonzales, Qiang Liu
• Journal: Journal of neuroinflammation (J Neuroinflammation) Vol. 14 Issue 1 Pg. 151 (07 28 2017) ISSN: 1742-2094 [Electronic] England
• PMID: 28754131 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)

Chemical References

• Bzrp protein, mouse
• Cytokines
• Neuroprotective Agents
• Oxazines
• RNA, Messenger
• Receptors, GABA
• Tumor Necrosis Factor-alpha
• etifoxine

Topics

• Animals
• Brain Edema (drug therapy, etiology)
• Brain Infarction (drug therapy, etiology)
• Cytokines (metabolism)
• Disease Models, Animal
• Drug Administration Schedule
• Flow Cytometry
• Gene Expression Regulation (drug effects)
• Infarction, Middle Cerebral Artery (drug therapy)
• Mice
• Microglia (drug effects, metabolism, pathology)
• Neurologic Examination
• Neuroprotective Agents (therapeutic use)
• Oxazines (therapeutic use)
• RNA, Messenger
• Receptors, GABA (metabolism)
• Reperfusion Injury (drug therapy, pathology)
• Time Factors
• Tumor Necrosis Factor-alpha (metabolism)