TSPO ligand PK11195 alleviates neuroinflammation and beta-amyloid generation induced by systemic LPS administration

Ma, Li; Zhang, Hui; Liu, Na; Wang, Pei‐Qi; Guo, Wenzhi; Fu, Qiang; Jiao, Liping; Ma, Yue; Mi, Weidong

doi:10.1016/j.brainresbull.2016.02.001

Cited by 53 publications

(31 citation statements)

References 75 publications

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“…Therefore, it is safe to assume that ligand-mediated TSPO tracking may be a valuable diagnostic tool for the severity and for localization of TBI, apart from its use as a therapeutic target, considering the effects of some radiotracers developed over the years. In line with these assumptions, it was reported that high-affinity ligands of TSPO, such as PK-11195, by themselves can reduce proinflammatory gene expression of cyclooxygenase-2 (COX-2), TNF-α, and IL-6 after lipopolysaccharide (LPS) stimulation [166], with a concomitant reduction in the number of activated microglia, associated with mitigated degeneration [167]. A recent study confirmed the therapeutic effects of two more novel TSPO ligands: 2-Cl-MGV-1 and MGV-1, which can alleviate the inflammatory response in microglial cells in culture via a reduction of COX2 and iNOS expression, as well as nitric oxide (NO) generation [66].…”

Section: Tspo and Traumatic Brain Injuries (Tbis)mentioning

confidence: 90%

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

Dimitrova-Shumkovska

Krstanoski

Veenman

2020

Cells

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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.

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Section: Tspo and Traumatic Brain Injuries (Tbis)mentioning

confidence: 90%

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

Dimitrova-Shumkovska

Krstanoski

Veenman

2020

Cells

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“…TSPO and the binding of its ligands are associated with a broad range of physiological outcomes (Chung et al, ; Soustiel et al, ; Le Fur et al, ; Lee et al, ). Ro5‐4864, an inverse agonist and PK 11195, an antagonist, can exhibit both opposite and similar physiologic changes in a dose dependent manner, ranging from anxiogenesis to neuroprotection and sedation (Le Fur et al, ; Ma et al, ; Lee et al, ; Soustiel et al, ). The TSPO agonist FGIN‐1‐27 is correlated with increased apoptosis in tumor cells and neuroprotection (Santidrián et al, 2007).…”

Section: Translocator Proteinmentioning

confidence: 99%

“…TSPO antagonists have been shown to increase ROS production and convert microglia to an activated state consistent with what is seen during normal AD progression (Choi et al, 2011). Additionally, the TSPO antagonist, PK 11195, has been shown to increase neurosteroid biosynthesis and decrease Aβ accumulation in a mouse model of AD (Ma et al, ). Suggested mechanisms by which neuroprotection occur are conflicting.…”

Section: Alzheimer's Diseasementioning

confidence: 99%

TSPO regulation in reactive gliotic diseases

McNeela

Bernick

Hines

et al. 2018

J of Neuroscience Research

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The brain is the most metabolically active organ in the body. This high metabolic demand is apparent in that 60% of the brain is comprised of mitochondria-enriched cells. A disruption of the brain's ability to meet this immense metabolic demand is central to the pathogenesis of a multitude of neurological disorders, which range from depression to Alzheimer's disease. Central to these pathologies are glial signaling and energy metabolism cascades regulating apoptosis and inflammation. Thus, diseases causing inflammation and disruption of metabolism can be correlated with glial reactivity. Acutely, reactive gliosis provides a mechanism for limiting the progression of a disease. Following chronic activation, the ability of reactive gliosis to limit disease progression decreases and, in some cases, transitions into a harmful state. The necessity for a noninvasive biomarker of disease in the brain has linked reactive gliosis with an upregulation of translocator protein (TSPO). TSPO is an 18kDa protein that is both a therapeutic target for multiple acute and chronic neuroinflammatory diseases and the leading biomarker for Alzheimer's disease. Although a central function of TSPO is not well known, the protein was named for its ability to translocate cholesterol. Increased TSPO expression is an indicator of disrupted metabolic activity and increased reactive oxygen production. The changes in TSPO expression levels both temporally and spatially relate to the pathogenesis of stroke, Alzheimer's disease, traumatic brain injury, and depression. Therefore, research into the basic function and potential therapeutics targeting TSPO will have broad implications for many diseases of the brain.

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“…Specific ligands and the use of in vivo neuroimaging techniques such as Positron Emission Tomography (PET) have implicated TSPO in multifarious disease states of the nervous system, including neurodegenerative disorders [159], [160], [161], [162], dementia [163], amyotrophic lateral sclerosis [164], [165], multiple sclerosis [158], [166], [167] and brain tumours [168], [169]. In experimental models, ligands of TSPO such as PK11195 have been found to reduce pro-inflammatory gene expression of COX-2, TNF-α and IL-6 after stimulation with lipopolysaccharide (LPS) [170], [171], with a concomitant reduction in the number of activated microglia, sparing further degeneration [172]. Thus, TSPO is now the target of research into high affinity therapeutic ligands against various pathologies of the CNS [173].…”

Section: Mitochondrial Translocator Protein 18 Kda (Tspo) In Neuroinfmentioning

confidence: 99%

The impact of high and low dose ionising radiation on the central nervous system

et al. 2016

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Responses of the central nervous system (CNS) to stressors and injuries, such as ionising radiation, are modulated by the concomitant responses of the brains innate immune effector cells, microglia. Exposure to high doses of ionising radiation in brain tissue leads to the expression and release of biochemical mediators of ‘neuroinflammation’, such as pro-inflammatory cytokines and reactive oxygen species (ROS), leading to tissue destruction. Contrastingly, low dose ionising radiation may reduce vulnerability to subsequent exposure of ionising radiation, largely through the stimulation of adaptive responses, such as antioxidant defences. These disparate responses may be reflective of non-linear differential microglial activation at low and high doses, manifesting as an anti-inflammatory or pro-inflammatory functional state. Biomarkers of pathology in the brain, such as the mitochondrial Translocator Protein 18 kDa (TSPO), have facilitated in vivo characterisation of microglial activation and ‘neuroinflammation’ in many pathological states of the CNS, though the exact function of TSPO in these responses remains elusive. Based on the known responsiveness of TSPO expression to a wide range of noxious stimuli, we discuss TSPO as a potential biomarker of radiation-induced effects.

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TSPO ligand PK11195 alleviates neuroinflammation and beta-amyloid generation induced by systemic LPS administration

Cited by 53 publications

References 75 publications

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

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

TSPO regulation in reactive gliotic diseases

The impact of high and low dose ionising radiation on the central nervous system

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