Antidepressant-like effect of Ro5-4864, a peripheral-type benzodiazepine receptor ligand, in forced swimming test

Gavioli, Elaine C.; Duarte, Filipe S.; Bressan, Elisângela; Ferrara, Pascual; Farges, Roseli; Lima, Thereza Christina Monteiro de

doi:10.1016/s0014-2999(03)01789-8

Cited by 26 publications

(14 citation statements)

References 34 publications

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“…Results from Porsolt's forced swimming, the rota-rod, and the openfield tests [90][91][92], evidenced for Ro 5-4864 (2) specific antidepressant-and anxiolytic-like effects, without modification of the locomotor activity or motor coordination of mice. On the contrary, PK 11195 (3) did not produce per se any effect, but pre-treatment with PK 11195 (3) 1 h before was able to inhibit the antidepressant-like effect of Ro 5-4864 (2) [89,93]. All these data seem to suggest that the effects of Ro 5-4864 (2) were exerted through a mechanism involving TSPO, and, at the same time, highlight the different action of the two tested ligands on receptor functions, in particular on the modulation of steroidogenesis [89].…”

Section: Benzodiazepine Benzothiazepine and Benzoxazepine Derivativesmentioning

confidence: 88%

“…On the contrary, PK 11195 (3) did not produce per se any effect, but pre-treatment with PK 11195 (3) 1 h before was able to inhibit the antidepressant-like effect of Ro 5-4864 (2) [89,93]. All these data seem to suggest that the effects of Ro 5-4864 (2) were exerted through a mechanism involving TSPO, and, at the same time, highlight the different action of the two tested ligands on receptor functions, in particular on the modulation of steroidogenesis [89].…”

Section: Benzodiazepine Benzothiazepine and Benzoxazepine Derivativesmentioning

confidence: 88%

“…However, in a recent report, Gavioli and colleagues used Ro 5-4864 (2) and PK 11195 (3) to study the putative role of this receptor as a target for the treatment of psychiatric disorders such as stress, anxiety, and depression [89]. Results from Porsolt's forced swimming, the rota-rod, and the openfield tests [90][91][92], evidenced for Ro 5-4864 (2) specific antidepressant-and anxiolytic-like effects, without modification of the locomotor activity or motor coordination of mice.…”

Section: Benzodiazepine Benzothiazepine and Benzoxazepine Derivativesmentioning

confidence: 99%

“…CBR and TSPO Binding Affinity of Imidazopyridine Derivatives(76)(77)(78)(79)(80)(81)(82)(83)(84)(85)(86)(87)(88)(89) …”

mentioning

confidence: 99%

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Structural Requirements to Obtain Highly Potent and Selective 18 kDa Translocator Protein (TSPO) Ligands

Taliani

Pugliesi²,

Settimo

2011

CTMC

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The (18 kDa) Translocator Protein (TSPO), was initially identified in 1977 as peripheral binding site for the benzodiazepine diazepam and named "Peripheral-type benzodiazepine receptor (PBR)". It is an evolutionarily well-conserved protein particularly located at the outer/inner mitochondrial membrane contact sites, in closely association with the 32 kDa voltage-dependent anion channel (VDAC) and the 30 kDa adenine nucleotide translocase (ANT), thus forming the mitochondrial permeability transition pore (MPTP). TSPO is ubiquitary expressed in peripheral tissues (steroid producing tissues, liver, heart, kidney, lung, immune system) and in lower levels in the central nervous system, where it is mainly located in glial cells, and in neurons. TSPO is involved in a variety of biological processes such as cholesterol transport, steroidogenesis, calcium homeostasis, lipid metabolism, mitochondrial oxidation, cell growth and differentiation, apoptosis induction, and regulation of immune functions. In the last decade, many studies have reported that TSPO basal expression is altered in a number of human pathologies, such as cancer and neurodegenerative disorders (Huntington's and Alzheimer's diseases), as well as in various forms of brain injury and inflammation and anxiety. Consequently, TSPO has not only been suggested as a promising drug target for a number of therapeutic applications (anticonvulsant, anxiolytic, immunomodulating, etc.), but also as valid diagnostic marker for related-disease state and progression, prompting the development of specific labelled ligands as powerful tools for imaging techniques. A number of structurally different classes of ligands have been reported, showing high affinity and selectivity towards TSPO. Indeed, most of these ligands have been designed starting from selective CBR ligands which were structurally modified in order to shift their affinity towards TSPO. Extensive structure-activity relationship studies were performed allowing to hypothesize various TSPO pharmacophore models. The purpose of this paper is to highlight the structural requirements needed to obtain TSPO ligands with high affinity and selectivity.

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Section: Benzodiazepine Benzothiazepine and Benzoxazepine Derivativesmentioning

confidence: 88%

Section: Benzodiazepine Benzothiazepine and Benzoxazepine Derivativesmentioning

confidence: 88%

Section: Benzodiazepine Benzothiazepine and Benzoxazepine Derivativesmentioning

confidence: 99%

“…CBR and TSPO Binding Affinity of Imidazopyridine Derivatives(76)(77)(78)(79)(80)(81)(82)(83)(84)(85)(86)(87)(88)(89) …”

mentioning

confidence: 99%

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Structural Requirements to Obtain Highly Potent and Selective 18 kDa Translocator Protein (TSPO) Ligands

Taliani

Pugliesi²,

Settimo

2011

CTMC

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“…Increased neurosteroid synthesis is perhaps the best characterized effect of TSPO ligands and most likely contributes at least in part to the plethora of established neuroprotective actions and anxiolytic and antidepressant behavioral effects (Rupprecht et al, 2010). Consequently, TSPO ligands are under investigation for use in the treatment of a range of neurological disorders including traumatic brain injury (Papadopoulos and Lecanu, 2009), peripheral neuropathies (Giatti et al, 2009), inflammatory conditions (Veiga et al, 2005), chronic pain (Torres et al, 2000), depression (Gavioli et al, 2003) and anxiety (Rupprecht et al, 2009). Although potential therapeutic applications of TSPO ligands to AD has been suggested (Veenman and Gavish, 2000; Papadopoulos et al, 2006a), to date AD-related investigations of TSPO ligands have assessed only their utility in detecting gliosis via in vivo PET imaging in AD patients and mouse models of AD (Edison et al, 2008; Ji et al, 2008; Yasuno et al, 2008).…”

Section: Introductionmentioning

confidence: 99%

Ligand for Translocator Protein Reverses Pathology in a Mouse Model of Alzheimer's Disease

et al. 2013

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Ligands of the translocator protein (TSPO) elicit pleiotropic neuroprotective effects that represent emerging treatment strategies for several neurodegenerative conditions. To investigate the potential of TSPO as a therapeutic target for Alzheimer's disease (AD), the current study assessed the effects of the TSPO ligand Ro5-4864 on the development of neuropathology in 3xTgAD mice. The effects of the TSPO ligand on neurosteroidogenesis and AD-related neuropathology including β-amyloid accumulation, gliosis and behavioral impairment were examined under both early intervention (7 month-old young-adult male mice with low pathology) and treatment (24 month-old, aged male mice with advanced neuropathology) conditions. Ro5-4864 treatment not only effectively attenuated development of neuropathology and behavioral impairment in young adult mice, but also reversed these indices in aged 3xTgAD mice. Reduced levels of soluble β-amyloid were also observed by the combination of TSPO ligands Ro5-4864 and PK11195 in non-transgenic mice. These findings suggest TSPO is a promising target for the development of pleiotropic treatment strategies for the management of AD.

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Ro5-4864, a peripheral benzodiazepine receptor ligand, reduces reactive gliosis and protects hippocampal hilar neurons from kainic acid excitotoxicity

2005

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The peripheral‐type benzodiazepine receptor (PBR) is a critical component of the mitochondrial permeability transition pore, which is involved in the regulation of cell survival. Different forms of brain injury result in induction of the expression of the PBR in the areas of neurodegeneration, mainly in reactive glial cells. The consequences of induction of PBR expression after brain injury are unknown. To test whether PBR may be involved in the regulation of neuronal survival after injury, we have assessed the effect of two PBR ligands, Ro5‐4864 and PK11195, on neuronal loss induced by kainic acid in the hippocampus. Systemic administration of kainic acid to male rats resulted in the induction of a reactive phenotype in astrocytes and microglia and in a significant loss of hilar neurons in the dentate gyrus. Administration of Ro5‐4864, before the injection of kainic acid, decreased reactive gliosis in the hilus and prevented hilar neuronal loss. In contrast, PK11195 was unable to reduce reactive gliosis and did not protect hilar neurons from kainic acid. These findings suggest that the PBR is involved in control of neuronal survival and gliosis after brain injury and identify this molecule as a potential target for neuroprotective interventions. © 2005 Wiley‐Liss, Inc.

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Antidepressant-like effect of Ro5-4864, a peripheral-type benzodiazepine receptor ligand, in forced swimming test

Cited by 26 publications

References 34 publications

Structural Requirements to Obtain Highly Potent and Selective 18 kDa Translocator Protein (TSPO) Ligands

Structural Requirements to Obtain Highly Potent and Selective 18 kDa Translocator Protein (TSPO) Ligands

Ligand for Translocator Protein Reverses Pathology in a Mouse Model of Alzheimer's Disease

Ro5-4864, a peripheral benzodiazepine receptor ligand, reduces reactive gliosis and protects hippocampal hilar neurons from kainic acid excitotoxicity

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