A TSPO ligand attenuates brain injury after intracerebral hemorrhage

Abstract

Intracerebral hemorrhage (ICH) is a devastating disease without effective treatment. After ICH, the immediate infiltration of leukocytes and activation of microglia are accompanied by a rapid up-regulation of the 18-kDa translocator protein (TSPO). TSPO ligands have shown anti-inflammatory and neuroprotective properties in models of CNS injury. In this study, we determined the impact of a TSPO ligand, etifoxine, on brain injury and inflammation in 2 mouse models of ICH. TSPO was up-regulated in Iba1+ cells from brains of patients with ICH and in CD11b+CD45int cells from mice subjected to collagenase-induced ICH. Etifoxine significantly reduced neurodeficits and perihematomal brain edema after ICH induction by injection of either autologous blood or collagenase. In collagenase-induced ICH mice, the protection of etifoxine was associated with reduced leukocyte infiltration into the brain and microglial production of IL-6 and TNF-α. Etifoxine improved blood–brain barrier integrity and diminished cell death. Notably, the protective effect of etifoxine was abolished in mice depleted of microglia by using a colony-stimulating factor 1 receptor inhibitor. These results indicate that the TSPO ligand etifoxine attenuates brain injury and inflammation after ICH. TSPO may be a viable therapeutic target that requires further investigations in ICH.—Li, M., Ren, H., Sheth, K. N., Shi, F.-D., Liu, Q. A TSPO ligand attenuates brain injury after intracerebral hemorrhage.

Diagnostic and Therapeutic Potential of TSPO Studies Regarding Neurodegenerative Diseases, Psychiatric Disorders, Alcohol Use Disorders, Traumatic Brain Injury, and Stroke: An Update

“…In addition, Etifoxine treatment led to decreased expression of IL-1β, IL-6, TNF-α, and iNOS 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 [194]. These findings indicate that the TSPO ligand Etifoxine reduces neuroinflammation and brain injury after ischemia/reperfusion [194].…”

“…Notably, the benefit of Etifoxine against brain infarction was ablated in mice depleted of microglia using a colony-stimulating factor 1 receptor inhibitor [194]. These findings indicate that the TSPO ligand Etifoxine reduces neuroinflammation and brain injury after ischemia/reperfusion [194]. This presents one reason why the therapeutic potential of targeting TSPO warrants further investigation in ischemic stroke.…”

“…Etifoxine significantly attenuated neurodeficits and infarct volume after middle cerebral artery occlusion (MCAO) and reperfusion. The attenuation was pronounced in mice subjected to 30, 60, or 90 min of MCAO [194]. Etifoxine reduced the production of proinflammatory factors in the ischemic brain.…”

“…As the mitochondrial TSPO is obviously a protein that is involved in various aspects of stroke, it was recognized that it can be targeted for treatment of this condition. Li et al investigated the effect of the TSPO ligand Etifoxine on neuroinflammation and brain injury after ischemia/reperfusion [194]. Etifoxine significantly attenuated neurodeficits and infarct volume after middle cerebral artery occlusion (MCAO) and reperfusion.…”

Inhibition of activator protein 1 attenuates neuroinflammation and brain injury after experimental intracerebral hemorrhage

“…An autologous blood injection model was induced in mice as described previously. [19][20][21] Briefly, after mice were anesthetized with an intraperitoneal injection of 5% chloral hydrate at a dose of 8 mL/ kg body weight, 30 μL nonheparinized autologous blood was withdrawn from the angular vein and infused into a 50 μL microliter syringe with a 26 G needle (Hamilton). For autologous blood injection, we drilled a 1 mm diameter hole (2.3 mm right lateral to midline and 0.5 mm anterior to bregma) in the skull of the mice.…”