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

Abstract

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

Cellular Sources and Regional Variations in the Expression of the Neuroinflammatory Marker Translocator Protein (TSPO) in the Normal Brain

“…However, following injury or during actively progressing tissue pathology, high levels of TSPO can be found in the brain. The inducible TSPO expression that closely follows the distribution pattern of activated microglia rather than astrocytes [ 8 , 10 , 11 , 50 , 51 ] has been the rationale for the use of TSPO ligands for the molecular imaging of active brain pathology irrespective of the primary disease cause [ 2 ].…”

“…The question of constitutive TSPO has recently become more important in the context of new TSPO ligands that show relatively high signals in the normal brain despite the near absence of expressed TSPO in the brain [ 47 , 48 ], as well as recent observations in experimental and clinical studies reporting reduced levels of TSPO [ 18 , 20 ]. While there is broad consensus that the cellular source of induced TSPO expression in the diseased brain is located in activated microglia [ 8 , 10 , 11 , 50 , 51 ], the distribution of constitutively expressed TSPO has not been fully validated. To this end, we have previously generated a viable global TSPO knockout mouse model to validate the selectivity and specificity of TSPO ligands and antibodies [ 3 ].…”

“…Much of the interest in TSPO in the central nervous system has been based on the observation that injury or progressive disease induces a marked upregulation of TSPO in mitochondria of microglia upon their transition from a resting to an activated state [ 2 , 6 ]. The subsequent development of radioligands for TSPO has given rise to a field of molecular imaging aimed at detecting activated microglia, often generically referred to as “neuroinflammation” in neurological disorders [ 7 , 8 , 9 , 10 , 11 , 12 , 13 , 14 ] and also psychiatric illnesses [ 15 , 16 , 17 , 18 , 19 , 20 ]. The term “neuroinflammation” has become a generic term that does not distinguish between a local immune response and microglial activation in the wake of neural or other injury [ 21 ].…”

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

“…Thus, TSPO based treatments of brain disease and brain injury, including stroke, may become increasingly more successful [9,169,172,182,195,196]. Further, as mentioned, non-TSPO targeting agents may also reduce the inflammatory response after stroke [182,185].…”

Translocator protein mediates olfactory repulsion

“…[10][11][12][13][14] The expression level of TSPO is strongly upregulated in areas of brain injury, [15][16][17] including Alzheimer's and Parkinson's diseases. [10][11][12][13][14] The expression level of TSPO is strongly upregulated in areas of brain injury, [15][16][17] including Alzheimer's and Parkinson's diseases.…”