Targeting the 18-kDa translocator protein: recent perspectives for neuroprotection

Pozzo, Eleonora Da; Giacomelli, Chiara; Barresi, Elisabetta; Costa, Barbara; Taliani, Sabrina; Passetti, Federico Da Settimo; Martini, Claudia

doi:10.1042/bst20150028

Cited by 35 publications

(36 citation statements)

References 49 publications

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“…These antagonistic expectancies regarding properties of TSPO and its ligands potentially may lead to widely divergent discrepancies in research approaches and interpretations of results. Another confounding aspect does relate to the now well appreciated concept that TSPO has homeostatic functions [20,23,26,38,62,63,70,71]. Assuming this to be true, many of the seemingly contradictory results can be explained as upregulatory and downregulatory characteristics of this potential homeostatic apparatus.…”

Section: Discussionmentioning

confidence: 99%

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Classical and Novel TSPO Ligands for the Mitochondrial TSPO Can Modulate Nuclear Gene Expression: Implications for Mitochondrial Retrograde Signaling

Yasin

Veenman

Singh

et al. 2017

IJMS

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It is known that knockdown of the mitochondrial 18 kDa translocator protein (TSPO) as well as TSPO ligands modulate various functions, including functions related to cancer. To study the ability of TSPO to regulate gene expression regarding such functions, we applied microarray analysis of gene expression to U118MG glioblastoma cells. Within 15 min, the classical TSPO ligand PK 11195 induced changes in expression of immediate early genes and transcription factors. These changes also included gene products that are part of the canonical pathway serving to modulate general gene expression. These changes are in accord with real-time, reverse transcriptase (RT) PCR. At the time points of 15, 30, 45, and 60 min, as well as 3 and 24 h of PK 11195 exposure, the functions associated with the changes in gene expression in these glioblastoma cells covered well known TSPO functions. These functions included cell viability, proliferation, differentiation, adhesion, migration, tumorigenesis, and angiogenesis. This was corroborated microscopically for cell migration, cell accumulation, adhesion, and neuronal differentiation. Changes in gene expression at 24 h of PK 11195 exposure were related to downregulation of tumorigenesis and upregulation of programmed cell death. In the vehicle treated as well as PK 11195 exposed cell cultures, our triple labeling showed intense TSPO labeling in the mitochondria but no TSPO signal in the cell nuclei. Thus, mitochondrial TSPO appears to be part of the mitochondria-to-nucleus signaling pathway for modulation of nuclear gene expression. The novel TSPO ligand 2-Cl-MGV-1 appeared to be very specific regarding modulation of gene expression of immediate early genes and transcription factors.

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Section: Discussionmentioning

confidence: 99%

“…It has been well recognized that TSPO presents a target that can be utilized for treatment of various diseases. In particular its characteristic as a receptor make it per definition a target for the development of ligands designed cure such diseases [22,45,71,73]. …”

Section: Discussionmentioning

confidence: 99%

Classical and Novel TSPO Ligands for the Mitochondrial TSPO Can Modulate Nuclear Gene Expression: Implications for Mitochondrial Retrograde Signaling

Yasin

Veenman

Singh

et al. 2017

IJMS

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“…To this aim, kinetic experiments were performed to measure k on and k off rate constants for each compound at [ 3 H]2 binding site, and their RT was calculated. [29] As should be notedf rom the data reported in Ta ble1,t he majority of the tested compounds were found to be rapid dissociating competitorsoft he binding site of 2 (i.e., 3,4,5,7,9,12 and the reference 1). (14).…”

Section: Nct00502515)mentioning

confidence: 99%

“…Numerous TSPO ligands are able to potently and dose‐dependently stimulate steroid biosynthesis in steroidogenic cells, and they have been proposed as innovative therapeutic tools in several pathological conditions, due to their neuroprotective, anxiolytic, anti‐inflammatory, and regenerating properties in different in vitro and in vivo models . To date, phase II clinical trials have been concluded for the treatment of diabetic peripheral neuropathy (ClinicalTrials.gov identifier: NCT00502515), and generalized anxiety disorder (NCT00108836) …”

Section: Figurementioning

confidence: 99%

“…[6] Numerous TSPO ligandsa re able to potently and dose-dependently stimulate steroid biosynthesis in steroidogenic cells, and they have been proposed as innovative therapeutic tools in several pathological conditions, due to their neuroprotective, anxiolytic, anti-inflammatory,a nd regenerating properties in different in vitro andi nvivo models. [7][8][9][10] To date, phase II clinicalt rials have been concluded for the treatment of diabetic peripheral neuropathy (ClinicalTrials.gov identifier:Ta rgeting the biosyntheticp athway of neuroactive steroids with specific 18 kDa translocator protein (TSPO) ligandsm ay be av iable therapeutic approachf or av ariety of neurodegenerativea nd neuropsychiatric diseases. However,t he lack of correlation betweenb inding affinity and in vitro steroidogenic efficacy has limited the identification of lead compounds by traditional affinity-based drug discoverys trategies.…”

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confidence: 99%

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Residence Time, a New parameter to Predict Neurosteroidogenic Efficacy of Translocator Protein (TSPO) Ligands: the Case Study of N,N‐Dialkyl‐2‐arylindol‐3‐ylglyoxylamides

et al. 2017

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Neuroactive steroids are endogenousn euromodulators that, by binding to membrane receptors and tuning gene expression via intracellular receptors, regulate many physiological functions. They can be synthesized in the brain de novo, so that they are termedn eurosteroids, or reach the central nervous system (CNS) from peripheral steroidogenico rgans,s uch as adrenals and gonads, and are locally metabolized. Neurosteroid levels are alteredi ns everal psychiatric and neurodegenerative diseases as ac onsequence of an impairment of neurosteroidogenesis;b oth preclinical and clinical studies emphasize atherapeutic potentialofn euroactive steroids for these diseases, whereby symptomatology ameliorates upon restoration of neuroactive steroid concentrations. [1][2][3] Neuroactive steroids exert potent anxiolytic, antidepressant, anticonvulsant, sedative, analgesic and amnesic effects, mainly acting as positive allosteric modulators at specific sites on the a-subunit of the g-aminobutyric acid type Ar eceptor (GABA A R).[4] In addition, neuroactive steroids exert neuroprotective, neurotrophic, anti-inflammatory and anti-apoptotic activitiesi ns everala nimal modelso ft raumatic brain and spinal cord injury,c erebral ischemia, peripheraln europathy,a nd neurodegeneratived iseases (e.g.,A lzheimer's and Parkinson's diseases,m ultiple sclerosis, etc.). [2] However,d irect administration of neuroactive steroids has several challenges, including short half-life,l ow bioavailability, poor aqueouss olubility,d evelopmento ft olerance, and undesired side effects such as sedationa nd memory impairment that limit their therapeutic use. Consequently,m odulation of neurosteroidogenesis to restoret he alterede ndogenous neuroactive steroidt one may be ab etter therapeutic approach. [1][2][3] The neuroactive steroidb iosynthetic pathway may be targeted at variousl evels in order to promote neurosteroidogenesis, [3] including the 18 kDat ranslocator protein (TSPO), an outer mitochondrial membrane protein expressed at high levels in peripheral and CNS steroid-producing cells.[5] TSPO plays ak ey role in the rate-limiting step of neuroactive steroid synthesis, consistingo fc holesterol translocation into mitochondria in order to supply it to the cytochrome P450 enzyme CYP11A1 for conversion into pregnenolone, the precursor of all neurosteroids. [6] Numerous TSPO ligandsa re able to potently and dose-dependently stimulate steroid biosynthesis in steroidogenic cells, and they have been proposed as innovative therapeutic tools in several pathological conditions, due to their neuroprotective, anxiolytic, anti-inflammatory,a nd regenerating properties in different in vitro andi nvivo models. [7][8][9][10] To date, phase II clinicalt rials have been concluded for the treatment of diabetic peripheral neuropathy (ClinicalTrials.gov identifier:Ta rgeting the biosyntheticp athway of neuroactive steroids with specific 18 kDa translocator protein (TSPO) ligandsm ay be av iable therapeutic approachf or av ariety of neurodegenerativea nd neuropsychiatri...

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Midazolam Prevents the Adverse Outcome of Neonatal Asphyxia

Welzel

Schmidt

Johne

et al. 2022

Annals of Neurology

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Objective Birth asphyxia (BA) is the most frequent cause of neonatal death as well as central nervous system (CNS) injury. BA is often associated with neonatal seizures, which only poorly respond to anti‐seizure medications and may contribute to the adverse neurodevelopmental outcome. Using a non‐invasive rat model of BA, we have recently reported that the potent benzodiazepine, midazolam, prevents neonatal seizures in ~50% of rat pups. In addition to its anti‐seizure effect, midazolam exerts anti‐inflammatory actions, which is highly relevant for therapeutic intervention following BA. The 2 major aims of the present study were to examine (1) whether midazolam reduces the adverse outcome of BA, and (2) whether this effect is different in rats that did or did not exhibit neonatal seizures after drug treatment. Methods Behavioral and cognitive tests were performed over 14 months after asphyxia, followed by immunohistochemical analyses. Results All vehicle‐treated rats had seizures after asphyxia and developed behavioral and cognitive abnormalities, neuroinflammation in gray and white matter, neurodegeneration in the hippocampus and thalamus, and hippocampal mossy fiber sprouting in subsequent months. Administration of midazolam (1 mg/kg i.p.) directly after asphyxia prevented post‐asphyctic seizures in ~50% of the rats and resulted in the prevention or decrease of neuroinflammation and the behavioral, cognitive, and neurodegenerative consequences of asphyxia. Except for neurodegeneration in the thalamus, seizures did not seem to contribute to the adverse outcome of asphyxia. Interpretation The disease‐modifying effect of midazolam identified here strongly suggests that this drug provides a valuable option for improving the treatment and outcome of BA. ANN NEUROL 2023;93:226–243

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Targeting the 18-kDa translocator protein: recent perspectives for neuroprotection

Cited by 35 publications

References 49 publications

Classical and Novel TSPO Ligands for the Mitochondrial TSPO Can Modulate Nuclear Gene Expression: Implications for Mitochondrial Retrograde Signaling

Classical and Novel TSPO Ligands for the Mitochondrial TSPO Can Modulate Nuclear Gene Expression: Implications for Mitochondrial Retrograde Signaling

Residence Time, a New parameter to Predict Neurosteroidogenic Efficacy of Translocator Protein (TSPO) Ligands: the Case Study of N,N‐Dialkyl‐2‐arylindol‐3‐ylglyoxylamides

Midazolam Prevents the Adverse Outcome of Neonatal Asphyxia

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