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

Abstract

Neuroinflammation and cell death are among the common symptoms of many central nervous system diseases and injuries. Neuroinflammation and programmed cell death of the various cell types in the brain appear to be part of these disorders, and characteristic for each cell type, including neurons and glia cells. Concerning the effects of 18-kDa translocator protein (TSPO) on glial activation, as well as being associated with neuronal cell death, as a response mechanism to oxidative stress, the changes of its expression assayed with the aid of TSPO-specific positron emission tomography (PET) tracers’ uptake could also offer evidence for following the pathogenesis of these disorders. This could potentially increase the number of diagnostic tests to accurately establish the stadium and development of the disease in question. Nonetheless, the differences in results regarding TSPO PET signals of first and second generations of tracers measured in patients with neurological disorders versus healthy controls indicate that we still have to understand more regarding TSPO characteristics. Expanding on investigations regarding the neuroprotective and healing effects of TSPO ligands could also contribute to a better understanding of the therapeutic potential of TSPO activity for brain damage due to brain injury and disease. Studies so far have directed attention to the effects on neurons and glia, and processes, such as death, inflammation, and regeneration. It is definitely worthwhile to drive such studies forward. From recent research it also appears that TSPO ligands, such as PK11195, Etifoxine, Emapunil, and 2-Cl-MGV-1, demonstrate the potential of targeting TSPO for treatments of brain diseases and disorders.

Raloxifene as Treatment for Various Types of Brain Injuries and Neurodegenerative Diseases: A Good Start

“…Moreover, compounds acting on the cannabinoid type-2 (CB-2) receptor (including SMM-189, as well as raloxifene) can be very effective for treatment of TBI [ 1 , 23 , 24 , 25 , 26 ]. Finally, two other promising representatives of these five efficacious agent are ligands for the mitochondrial 18-kDa translocator protein (TSPO) and a brown seaweed product fucoidan, reviewed elsewhere [ 27 , 28 , 29 ]. By compiling data from raloxifene studies, this review also hopes to provide aid and direction for attempts to establish standards for evaluation of drugs that present themselves as candidates for treatment of brain damage due to injury and disease.…”

“…It is also well known that these various cell types interact in intricate ways, in relation to brain disease and brain injury, either reducing the damage or contributing to the damage ( Figure 2 ). Briefly, progressing brain damage due to injury and disease typically includes damage and death of neurons and astrocytes, which, in turn causes microglia activation [ 27 , 28 , 29 , 30 , 31 , 32 ]. Briefly, by its mechanical force alone, an impact on the head or other injury can induce neuronal and astrocytic damage and death.…”

“…Neurological disorders typically present activation of glial cells, including their release of pro-inflammatory cytokines and chemokines. This is the normal CNS response to protect neural tissue and is mainly regulated by microglia and astroglia [ 27 , 28 , 29 , 30 , 31 , 32 , 60 , 61 ] ( Figure 2 ). However, while acute glial activation is protective by design, failure of this protective acute activity may consequently lead to chronic glial activation, i.e., to enduring inflammation of neural tissue, and even cell death.…”

“…Thus, from these studies it is clear that close interactions between cell nuclear and mitochondrial activities regarding of estradiol take place [ 73 ]. It was postulated previously that simultaneous modulation of cell nuclear and mitochondrial activity may present a characteristic of efficacious curative agents for neurodegeneration [ 28 , 29 ]. This review indicates that this appears to be also true for the SERMs, raloxifene, and 4-hydroxy-tamoxifen.…”

“…This may be a general property of agents efficacious in treatment of brain disease and brain injury: namely, simultaneous effects on genomic and nongenomic functions, including cell nuclear gene expression and mitochondrial function. Effects on cell nuclear gene expression and mitochondrial function were also observed for other agents efficacious in treatments for neurodegeneration in animal models and cell culture, as reviewed, for example, for TSPO ligands and fucoidan [ 28 , 29 ]. These two sections presented here show that it is very informative to study simultaneous activities of mitochondria and cell nuclei.…”