Translocator protein (TSPO) ligands for the diagnosis or treatment of neurodegenerative diseases: a patent review (2010–2015; part 1)

2016 ◽  
Vol 26 (11) ◽  
pp. 1325-1351 ◽  
Author(s):  
TaeHun Kim ◽  
Ae Nim Pae
Keyword(s):  
Neurodegenerative Diseases ◽  
Translocator Protein ◽  
Patent Review

Synthesis, characterization, and in vitro evaluation of new coordination complexes of platinum(ii) and rhenium(i) with a ligand targeting the translocator protein (TSPO)

2014 ◽  
Vol 43 (43) ◽  
pp. 16252-16264 ◽  
Author(s):  
Nicola Margiotta ◽  
Nunzio Denora ◽  
Sara Piccinonna ◽  
Valentino Laquintana ◽  
Francesco Massimo Lasorsa ◽  
...  
Keyword(s):  
Neurodegenerative Diseases ◽  
Coordination Complexes ◽  
Translocator Protein ◽  
Microglial Cells ◽  
In Vitro Evaluation

The 18 kDa translocator protein (TSPO) is overexpressed in many cancers and is also abundant in activated microglial cells occurring in neurodegenerative diseases.

The mitochondria permeability transition pore complex in the brain with interacting proteins – promising targets for protection in neurodegenerative diseases

2010 ◽  
Vol 391 (6) ◽  
Author(s):  
Tamara Azarashvili ◽  
Rolf Stricker ◽  
Georg Reiser
Keyword(s):  
Cell Death ◽  
Neurodegenerative Diseases ◽  
Permeability Transition Pore ◽  
Permeability Transition ◽  
Benzodiazepine Receptor ◽  
Large Degree ◽  
Mitochondrial Pathway ◽  
Brain Cell ◽  
Translocator Protein ◽  
Tissue Cell

Abstract Mitochondria increasingly attract attention as control points within the mechanisms of neuronal death. Mitochondria play a central role in swinging the balance in favor of either survival or death of brain tissue. Cell death in vertebrates proceeds mostly via the mitochondrial pathway of apoptosis. Permeability transition pore (PTP) development in mitochondria is a decisive stage of apoptosis. Therefore, regulation of the permeability of both outer and inner mitochondrial membranes helps to induce neuroprotection. Through PTP control, mitochondria can to a large degree manage the intracellular calcium homeostasis, and thus control the potent death cascade initiated by excess calcium. Here we summarize the evidence for the role of mitochondria in brain cell death. We describe the involvement of the 18-kDa translocator protein (TSPO; previously called peripheral benzodiazepine receptor), and of two new mitochondrial proteins, that is, 2′,3′-cyclic nucleotide 3′-phosphodiesterase (CNP) and p42IP4 (also designated centaurin α1; ADAP 1), in the control of the PTP. Furthermore, ligands of TSPO, as well as substrates of CNP, are possible modulators of PTP function. This scenario of control and regulation of PTP function might provide multiple important targets, which are suitable for developing protective strategies for neurons and non-neuronal brain cells in therapies of neurodegenerative diseases.

scholarly journals Current paradigm of the 18-kDa translocator protein (TSPO) as a molecular target for PET imaging in neuroinflammation and neurodegenerative diseases

2011 ◽  
Vol 3 (1) ◽  
pp. 111-119 ◽  
Author(s):  
Alex Sik Chung Ching ◽  
Bertrand Kuhnast ◽  
Annelaure Damont ◽  
Dirk Roeda ◽  
Bertrand Tavitian ◽  
...  
Keyword(s):  
Neurodegenerative Diseases ◽  
Pet Imaging ◽  
Molecular Target ◽  
Translocator Protein ◽  
Current Paradigm

scholarly journals Emerging PET Radiotracers and Targets for Imaging of Neuroinflammation in Neurodegenerative Diseases: Outlook Beyond TSPO

2018 ◽  
Vol 17 ◽  
pp. 153601211879231 ◽  
Author(s):  
Vidya Narayanaswami ◽  
Kenneth Dahl ◽  
Vadim Bernard-Gauthier ◽  
Lee Josephson ◽  
Paul Cumming ◽  
...  
Keyword(s):  
Nervous System ◽  
Neurodegenerative Diseases ◽  
Intracellular Signaling ◽  
Glycogen Synthase ◽  
Early Stage ◽  
Translocator Protein ◽  
Imaging Biomarker ◽  
Cellular Expression ◽  
Pet Radiotracers

The dynamic and multicellular processes of neuroinflammation are mediated by the nonneuronal cells of the central nervous system, which include astrocytes and the brain’s resident macrophages, microglia. Although initiation of an inflammatory response may be beneficial in response to injury of the nervous system, chronic or maladaptive neuroinflammation can have harmful outcomes in many neurological diseases. An acute neuroinflammatory response is protective when activated neuroglia facilitate tissue repair by releasing anti-inflammatory cytokines and neurotrophic factors. On the other hand, chronic neuroglial activation is a major pathological mechanism in neurodegenerative diseases, likely contributing to neuronal dysfunction, injury, and disease progression. Therefore, the development of specific and sensitive probes for positron emission tomography (PET) studies of neuroinflammation is attracting immense scientific and clinical interest. An early phase of this research emphasized PET studies of the prototypical imaging biomarker of glial activation, translocator protein-18 kDa (TSPO), which presents difficulties for quantitation and lacks absolute cellular specificity. Many alternate molecular targets present themselves for PET imaging of neuroinflammation in vivo, including enzymes, intracellular signaling molecules as well as ionotropic, G-protein coupled, and immunoglobulin receptors. We now review the lead structures in radiotracer development for PET studies of neuroinflammation targets for neurodegenerative diseases extending beyond TSPO, including glycogen synthase kinase 3, monoamine oxidase-B, reactive oxygen species, imidazoline-2 binding sites, cyclooxygenase, the phospholipase A2/arachidonic acid pathway, sphingosine-1-phosphate receptor-1, cannabinoid-2 receptor, the chemokine receptor CX3CR1, purinergic receptors: P2X7 and P2Y12, the receptor for advanced glycation end products, Mer tyrosine kinase, and triggering receptor expressed on myeloid cells-1. We provide a brief overview of the cellular expression and function of these targets, noting their selectivity for astrocytes and/or microglia, and highlight the classes of PET radiotracers that have been investigated in early-stage preclinical or clinical research studies of neuroinflammation.

scholarly journals TSPO Ligands PK11195 and Midazolam Reduce NLRP3 Inflammasome Activation and Proinflammatory Cytokine Release in BV-2 Cells

2020 ◽  
Vol 14 ◽  
Author(s):  
Hao Feng ◽  
Yongxin Liu ◽  
Rui Zhang ◽  
Yingxia Liang ◽  
Lina Sun ◽  
...  
Keyword(s):  
Neurodegenerative Diseases ◽  
Nlrp3 Inflammasome ◽  
Microglial Activation ◽  
Translocator Protein ◽  
Receptor Protein ◽  
Inflammasome Activation ◽  
Nlrp3 Inflammasome Activation ◽  
Bv2 Cells ◽  
Translocator Protein 18 Kda ◽  
Inflammatory Effect

Neuroinflammation related to microglial activation plays an important role in neurodegenerative diseases. Translocator protein 18 kDa (TSPO), a biomarker of reactive gliosis, its ligands can reduce neuroinflammation and can be used to treat neurodegenerative diseases. Therefore, we explored whether TSPO ligands exert an anti-inflammatory effect by affecting the nucleotide-binding domain-like receptor protein 3 (NLRP3) inflammasome, thereby inhibiting the release of inflammatory cytokines in microglial cells. In the present study, BV-2 cells were exposed to lipopolysaccharide (LPS) for 6 h to induce an inflammatory response. We found that the levels of reactive oxygen species (ROS), NLRP3 inflammasome, interleukin-1β (IL-1β), and interleukin-18 (IL-18) were significantly increased. However, pretreatment with TSPO ligands inhibited BV-2 microglial and NLRP3 inflammasome activation and significantly reduced the levels of ROS, IL-1β, and IL-18. Furthermore, a combination of LPS and ATP was used to activate the NLRP3 inflammasome. Both pretreatment and post-treatment with TSPO ligand can downregulate the activation of NLRP3 inflammasome and IL-1β expression. Finally, we found that TSPO was involved in the regulation of NLRP3 inflammasome with TSPO ligands treatment in TSPO knockdown BV2 cells. Collectively, these results indicate that TSPO ligands are promising targets to control microglial reactivity and neuroinflammatory diseases.

Autophagy and ageing: implications for age-related neurodegenerative diseases

2013 ◽  
Vol 55 ◽  
pp. 119-131 ◽  
Author(s):  
Bernadette Carroll ◽  
Graeme Hewitt ◽  
Viktor I. Korolchuk
Keyword(s):  
Neurodegenerative Diseases ◽  
Energy Availability ◽  
Future Studies ◽  
Intracellular Degradation ◽  
Age Related ◽  
Autophagy Induction ◽  
Social Importance ◽  
Cellular Dysfunction ◽  
Autophagy Activity ◽  
Intense Research

Autophagy is a process of lysosome-dependent intracellular degradation that participates in the liberation of resources including amino acids and energy to maintain homoeostasis. Autophagy is particularly important in stress conditions such as nutrient starvation and any perturbation in the ability of the cell to activate or regulate autophagy can lead to cellular dysfunction and disease. An area of intense research interest is the role and indeed the fate of autophagy during cellular and organismal ageing. Age-related disorders are associated with increased cellular stress and assault including DNA damage, reduced energy availability, protein aggregation and accumulation of damaged organelles. A reduction in autophagy activity has been observed in a number of ageing models and its up-regulation via pharmacological and genetic methods can alleviate age-related pathologies. In particular, autophagy induction can enhance clearance of toxic intracellular waste associated with neurodegenerative diseases and has been comprehensively demonstrated to improve lifespan in yeast, worms, flies, rodents and primates. The situation, however, has been complicated by the identification that autophagy up-regulation can also occur during ageing. Indeed, in certain situations, reduced autophagosome induction may actually provide benefits to ageing cells. Future studies will undoubtedly improve our understanding of exactly how the multiple signals that are integrated to control appropriate autophagy activity change during ageing, what affect this has on autophagy and to what extent autophagy contributes to age-associated pathologies. Identification of mechanisms that influence a healthy lifespan is of economic, medical and social importance in our ‘ageing’ world.

Sign in / Sign up

Export Citation Format

Share Document