Translocator protein (18 kDa) (TSPO) as a therapeutic target for neurological and psychiatric disorders

Rupprecht, Rainer; Papadopoulos, Vassilios; Rammes, Gerhard; Baghai, Thomas C.; Fan, Jinjiang; Akula, Nagaraju; Groyer, Ghislaine; Adams, David H.; Schumacher, Michaël

doi:10.1038/nrd3295

Cited by 803 publications

(840 citation statements)

References 192 publications

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“…Furthermore, in the CA1 and NAc, TSPO is also located in cells that are not labeled with 3a,5a-THP. These cells may be astrocytes, as TSPO is expressed in astrocytes (for review see, Rupprecht et al, 2010). Taken together, the adrenal-dependent effects of ethanol on 3a,5a-THP levels in the mPFC cannot be explained by a lack of local cholesterol transporter.…”

Section: Discussionmentioning

confidence: 91%

Ethanol Alters Local Cellular Levels of (3α,5α)-3-Hydroxypregnan-20-one (3α,5α-THP) Independent of the Adrenals in Subcortical Brain Regions

Cook

Nelli

Neighbors

et al. 2014

Neuropsychopharmacol

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The neuroactive steroid (3a,5a)-3-hydroxypregnan-20-one (3a,5a-THP or allopregnanolone) is a positive modulator of GABA A receptors synthesized in the brain, adrenal glands, and gonads. In rats, ethanol activates the hypothalamic-pituitary-adrenal axis and elevates 3a,5a-THP in plasma, cerebral cortex, and hippocampus. In vivo, these effects are dependent on both the pituitary and adrenal glands. In vitro, however, ethanol locally increases 3a,5a-THP in hippocampal slices, in the absence of adrenal influence. Therefore, it is not known whether ethanol can change local brain levels of 3a,5a-THP in vivo, independent of the adrenals. To directly address this controversy, we administered ethanol (2 g/kg) or saline to rats that underwent adrenalectomy (ADX) or received sham surgery and performed immunohistochemistry for 3a,5a-THP. In the medial prefrontal cortex (mPFC), ethanol increased 3a,5a-THP after sham surgery, compared with saline controls, with no ethanol-induced change in 3a,5a-THP following ADX. In subcortical regions, 3a,5a-THP was increased independent of adrenals in the CA1 pyramidal cell layer, dentate gyrus polymorphic layer, bed nucleus of the stria terminalis, and paraventricular nucleus of the hypothalamus. Furthermore, ethanol decreased 3a,5a-THP labeling in the nucleus accumbens shore and central nucleus of the amygdala, independent of the adrenal glands. These data indicate that ethanol dynamically regulates local 3a,5a-THP levels in several subcortical regions; however, the adrenal glands contribute to 3a,5a-THP elevations in the mPFC. Using double immunofluorescent labeling we determined that adrenal dependence of 3a,5a-THP induction by ethanol is not due to a lack of colocalization of 3a,5a-THP with the cholesterol transporters steroidogenic acute regulatory protein (StAR) or translocator protein (TSPO).

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Section: Discussionmentioning

confidence: 91%

Ethanol Alters Local Cellular Levels of (3α,5α)-3-Hydroxypregnan-20-one (3α,5α-THP) Independent of the Adrenals in Subcortical Brain Regions

Cook

Nelli

Neighbors

et al. 2014

Neuropsychopharmacol

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“…Similarly, anxiolytics such as the benzodiazepine alprazolam ameliorate CCK-4-induced panic attacks in healthy volunteers (Zwanzger et al, 2003). Such effects have also been observed in larger samples using XBD173, a ligand of the translocator (TPSO) protein (Rupprecht et al, 2009), which recently has been identified as a possible new treatment target for anxiety (Rupprecht et al, 2010;Nothdurfter et al, 2012). As shown by neuroimaging studies, experimentally induced panic attacks are accompanied by a significant activation of neuroanatomical key areas responsible for the processing of fear and anxiety, such as the amygdala, hippocampus, insula, and the anterior cingulate cortex (ACC) (Schunck et al, 2006;Eser et al, 2009).…”

Section: Introductionmentioning

confidence: 78%

“…According to Salt and Eaton (1996), GABAergic and glutamatergic neurotransmission seems to be modulated by presynaptic metabotropic glutamate (mGlu) autoreceptors. Moreover, it has also been suggested that neurosteroids, synthesized in cortical glutamatergic neurons, may exert GABAergic activity through autocrine (targeting postsynaptic receptors at the same neuron) and/or paracrine (targeting receptors at distal neurons) mechanisms (Rupprecht et al, 2010). Finally, GABA released from GABAergic interneurons targets pre-, post-, and extrasynaptic receptors at glutamatergic principal output neurons (for a review, see Rupprecht et al, 2010).…”

Section: Discussionmentioning

confidence: 99%

Acute Shift in Glutamate Concentrations Following Experimentally Induced Panic with Cholecystokinin Tetrapeptide—A 3T-MRS Study in Healthy Subjects

Zwanzger

Zavorotnyy

Gencheva

et al. 2013

Neuropsychopharmacol

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According to preclinical studies, glutamate has been implicated in the pathogenesis of anxiety. In order to elucidate the role of glutamate in anxiety and panic in humans, brain glutamate þ glutamine (Glx) levels were measured during cholecystokinin-tetrapeptide (CCK-4)-induced panic using magnetic resonance spectroscopy (MRS). Eighteen healthy subjects underwent a CCK-4 challenge. MR spectra were obtained from the anterior cingulate cortex (ACC) using a single voxel point-resolved spectroscopy method and analyzed using LCModel. A combined fitting of Glx was performed. Panic was assessed using the Acute Panic Inventory (API) and Panic Symptom Scale (PSS) scores. Moreover, hypothalamic-pituitary-adrenal axis stimulation was monitored throughout the challenge. There was a significant panic response following CCK-4 as revealed by a marked increase in both the panic scores (API: F(1,17) ¼ 149.41; po0.0001; PSS: F(1,17) ¼ 88.03; po0.0001) and heart rate (HR: F(1,17) ¼ 72.79; po0.0001). MRS measures showed a significant increase of brain Glx/creatine (Glx/Cr) levels peaking at 2-10 min after challenge (F(1,17) ¼ 15.94; p ¼ 0.001). There was also a significant increase in CCK-4-related cortisol release (F(6,11) ¼ 8.68; p ¼ 0.002). Finally, significant positive correlations were found between baseline Glx/Cr and both API max (r ¼ 0.598; p ¼ 0.009) and maximum heart rate (HR max ) during challenge (r ¼ 0.519; p ¼ 0.027). Our results suggest that CCK-4-induced panic is accompanied by a significant glutamate increase in the bilateral ACC. The results add to the hypothesis of a disturbance of the inhibitory-excitatory equilibrium and suggest that apart from static alterations rapid and dynamic neurochemical changes might also be relevant for the neural control of panic attacks.

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“…Such a strategy is commonly reported as bifunctional chelate (BFC) approach. 20 Hence, starting from the already known potent and selective TSPO ligand CB86 (Chart 1), 15 we designed a new namely,[2][3][4][5][6][7][8] 1), where, the di(2-picolyl)amine moiety could be used for the synthesis of coordination complexes containing a metallo drug to be used in diagnosis and therapy.Preliminarily, we performed in vitro studies on the newly synthesized TSPO-selective BFC ligand CB256 in order to assess its affinity toward TSPO. In addition, since it is wellknown that TSPO ligands are able to induce apoptosis, we also investigated the cytotoxic activity and the ability to cause morphological changes of the mitochondrion and of the nucleus, the collapse of the mitochondrial membrane potential (ΔΨ m ), and alterations of the cell cycle progression in C6…”

mentioning

confidence: 99%

mentioning

confidence: 99%

Synthesis, Characterization, and in Vitro Evaluation of a New TSPO-Selective Bifunctional Chelate Ligand

Denora

Margiotta

Laquintana

et al. 2014

ACS Med. Chem. Lett.

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The 18-kDa translocator protein (TSPO) is overexpressed in many types of cancers and is also abundant in activated microglial cells occurring in inflammatory neurodegenerative diseases. Thus, TSPO has become an extremely attractive subcellular target not only for imaging disease states overexpressing this protein, but also for a selective mitochondrial drug delivery. In this work we report the synthesis, the characterization, and the in vitro evaluation of a new TSPO-, which fulfils the requirements for a bifunctional chelate approach. The goal was to provide a new TSPO ligand that could be used further to prepare coordination complexes of a metallo drug to be used in diagnosis and therapy. However, the ligand itself proved to be a potent tumor cell growth inhibitor and DNA double-strand breaker. KEYWORDS: TSPO, PBR, bifunctional chelate approach, apoptosis, DNA cleavage T he 18-kDa mitochondrial translocator protein (TSPO), 1 also known as peripheral-type benzodiazepine receptor or PBR, has become an attractive target for therapeutic and imaging purposes. 2−5 TSPO is poorly expressed in healthy human brain and liver, while it is much more abundant in steroid-synthesizing and rapidly proliferating tissues. In contrast, aberrant TSPO expression has been observed in multiple diseases, including brain, breast, colon, prostate, and ovarian cancers, as well as astrocytomas and hepatocellular and endometrial carcinomas. 6,7 Moreover, TSPO expression is also increased in activated microglial cells occurring in inflammatory neurodegenerative diseases such as Alzheimer, Parkinson, Huntington, and multiple sclerosis. 8 Thus, TSPO has become an extremely attractive subcellular target not only for an early detection of disease states overexpressing this protein, but also for a selective mitochondrial drug delivery. 9−14 Although a wide number of TSPO ligands have been synthesized, only few of them have the ability to deliver metal-based drugs. 15 In particular, very recently were reported potent and selective imidazopyridine-based TSPO ligands, which could carry both a cytostatic platinum species and a rhenium complex as a model of 99m Tc imaging agent. 13,16−19 In the compounds so far investigated, atoms already present in the TSPO ligand were used as donors for anchoring the metal core. A further development could be represented by the use of conjugates in which the TSPO-targeting moiety is covalently linked with an appropriate chelating system, such as di(2-picolyl)amine, forming a strong coordination compound with metal ions in the pertinent oxidation state. The use of an appropriate linker could rule out possible interactions between the metal-core and the targeting moiety so to leave unaltered the pharmacokinetic profile of the tracer. Such a strategy is commonly reported as bifunctional chelate (BFC) approach. 20 Hence, starting from the already known potent and selective TSPO ligand CB86 (Chart 1), 15 we designed a new namely,[2][3][4][5][6][7][8] 1), where, the di(2-picolyl)amine moiety could be used f...

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Translocator protein (18 kDa) (TSPO) as a therapeutic target for neurological and psychiatric disorders

Cited by 803 publications

References 192 publications

Ethanol Alters Local Cellular Levels of (3α,5α)-3-Hydroxypregnan-20-one (3α,5α-THP) Independent of the Adrenals in Subcortical Brain Regions

Ethanol Alters Local Cellular Levels of (3α,5α)-3-Hydroxypregnan-20-one (3α,5α-THP) Independent of the Adrenals in Subcortical Brain Regions

Acute Shift in Glutamate Concentrations Following Experimentally Induced Panic with Cholecystokinin Tetrapeptide—A 3T-MRS Study in Healthy Subjects

Synthesis, Characterization, and in Vitro Evaluation of a New TSPO-Selective Bifunctional Chelate Ligand

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