Design, synthesis and biological characterization of novel activators of the TrkB neurotrophin receptor

Antonijevic, Mirjana; Charou, Despoina; Ramos, Isbaal; Valcárcel, María; Gravanis, Achille; Villacé, Patricia; Callizot, Noëlle; Since, Marc; Dallemagne, Patrick; Charalampopoulos, Ioannis; Rochais, Christophe

doi:10.1016/j.ejmech.2023.115111

Cited by 6 publications

(24 citation statements)

References 36 publications

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“…In order to evaluate if the novel compounds were able to activate the TrkB receptor, firstly the compounds were screened for their ability to reduce cell death by using the CellTox™ Green Cytotoxicity Assay [ 18 ]. This assay was used for testing the ability of the compounds to counter cell death caused by serum deprivation in NIH-3T3 TrkB cells that specifically express the TrkB receptor by measuring the levels of a dye that stains damaged DNA.…”

Section: Resultsmentioning

confidence: 99%

“…The compounds exhibiting the most promising action at decreasing cell toxicity were tested for their ability to phosphorylate/activate the TrkB receptor and its downstream target, Akt kinase, in TrkB stably transfected NIH-3T3 cells [ 18 ]. In both cases, the phosphorylated and total protein levels were identified using Western blot analysis, as detailed in the relevant methods section.…”

Section: Resultsmentioning

confidence: 99%

“…All the compounds were tested at three concentrations (10 nM, 100 nM, 1000 nM) on human SH-SY5 cells. We used three controls: control FBS (DMEMF12 with 10% FBS), control (cultured 3 days in DMEMF12 with 1% FBS, followed by 2 days in DMEMF12 FBS-free), and retinoic acid—RA (DMEMF12 with 1% FBS in the presence of RA 10 µM, followed by 2 days in DMEMF12 FBS-free) [ 18 ]. To investigate the role of neurite extension, the geometric patterns that were mainly employed in this study are the total neurite count, neurite total length, neurite average length, neurite critical value, neurite ramification index, and branch total point count.…”

Section: Resultsmentioning

confidence: 99%

“…One such small molecule is LM22A-4 [ 17 ]; however, this molecule does not possess a desirable physicochemical profile, since it is quite hydrophilic (chromatographic hydrophobicity index (CHI) at pH = 7.4 is CHI 7 . 4 = 13.8) [ 18 ]. Another issue concerning this molecule is the controversy about its properties in being a direct activator of the TrkB receptor [ 19 , 20 ].…”

Section: Introductionmentioning

confidence: 99%

“…Indeed, in our previous work, we showed that by modifying the third position of LM22A-4, we can improve the TrkB activity [ 18 ]. Other studies have shown that a large variety of substitutions is allowed on the piperidine ring of RS67333 in order to obtain molecules that will possess an affinity towards the 5-HT 6 receptor [ 27 ], antioxidant [ 28 ], or AChE inhibition [ 29 ] properties, while preserving good affinity and an agonistic profile towards the 5-HT 4 receptor.…”

Section: Introductionmentioning

confidence: 99%

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Development of Pleiotropic TrkB and 5-HT4 Receptor Ligands as Neuroprotective Agents

Antonijevic,

Charou,

Davis

et al. 2024

Molecules

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One common event that is the most detrimental in neurodegenerative disorders, even though they have a complex pathogenesis, is the increased rate of neuronal death. Endogenous neurotrophins consist of the major neuroprotective factors, while brain-derived neurotrophic factor (BDNF) and its high-affinity tyrosine kinase receptor TrkB are described in a number of studies for their important neuronal effects. Normal function of this receptor is crucial for neuronal survival, differentiation, and synaptic function. However, studies have shown that besides direct activation, the TrkB receptor can be transactivated via GPCRs. It has been proven that activation of the 5-HT4 receptor and transactivation of the TrkB receptor have a positive influence on neuronal differentiation (total dendritic length, number of primary dendrites, and branching index). Because of that and based on the main structural characteristics of LM22A-4, a known activator of the TrkB receptor, and RS67333, a partial 5-HT4 receptor agonist, we have designed and synthesized a small data set of novel compounds with potential dual activities in order to not only prevent neuronal death, but also to induce neuronal differentiation in neurodegenerative disorders.

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Section: Resultsmentioning

confidence: 99%

Section: Resultsmentioning

confidence: 99%

Section: Resultsmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

See 3 more Smart Citations

Development of Pleiotropic TrkB and 5-HT4 Receptor Ligands as Neuroprotective Agents

Antonijevic,

Charou,

Davis

et al. 2024

Molecules

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A TrkB and TrkC partial agonist restores deficits in synaptic function and promotes activity‐dependent synaptic and microglial transcriptomic changes in a late‐stage Alzheimer's mouse model

Latif‐Hernandez,

Yang,

Butler

et al. 2024

Alzheimer's & Dementia

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INTRODUCTIONTropomyosin related kinase B (TrkB) and C (TrkC) receptor signaling promotes synaptic plasticity and interacts with pathways affected by amyloid beta (Aβ) toxicity. Upregulating TrkB/C signaling could reduce Alzheimer's disease (AD)‐related degenerative signaling, memory loss, and synaptic dysfunction.METHODSPTX‐BD10‐2 (BD10‐2), a small molecule TrkB/C receptor partial agonist, was orally administered to aged London/Swedish‐APP mutant mice (APPL/S) and wild‐type controls. Effects on memory and hippocampal long‐term potentiation (LTP) were assessed using electrophysiology, behavioral studies, immunoblotting, immunofluorescence staining, and RNA sequencing.RESULTSIn APPL/S mice, BD10‐2 treatment improved memory and LTP deficits. This was accompanied by normalized phosphorylation of protein kinase B (Akt), calcium‐calmodulin–dependent kinase II (CaMKII), and AMPA‐type glutamate receptors containing the subunit GluA1; enhanced activity‐dependent recruitment of synaptic proteins; and increased excitatory synapse number. BD10‐2 also had potentially favorable effects on LTP‐dependent complement pathway and synaptic gene transcription.DISCUSSIONBD10‐2 prevented APPL/S/Aβ‐associated memory and LTP deficits, reduced abnormalities in synapse‐related signaling and activity‐dependent transcription of synaptic genes, and bolstered transcriptional changes associated with microglial immune response.Highlights Small molecule modulation of tropomyosin related kinase B (TrkB) and C (TrkC) restores long‐term potentiation (LTP) and behavior in an Alzheimer's disease (AD) model. Modulation of TrkB and TrkC regulates synaptic activity‐dependent transcription. TrkB and TrkC receptors are candidate targets for translational therapeutics. Electrophysiology combined with transcriptomics elucidates synaptic restoration. LTP identifies neuron and microglia AD‐relevant human‐mouse co‐expression modules.

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Vitamin D3 Exerts a Neuroprotective Effect in Metabolic Syndrome Rats: Role of BDNF/TRKB/Akt/GS3Kβ Pathway

Aladdin,

Ghareib

2024

J Biochem & Molecular Tox

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Metabolic syndrome (MetS) is usually associated with cognitive impairment, neuropathic pain, and reduced brain‐derived neurotrophic factor (BDNF) levels. BDNF via tropomyosin receptor kinase B (TrkB) exerts neuroprotection by activating protein kinase B (Akt) to inhibit glycogen synthase kinase‐3β (GSK3β). Although Vitamin D3 (VitD3) has demonstrated favorable metabolic and neuronal outcomes in MetS, the precise molecular mechanisms underlying its neuroprotective effects remain poorly elucidated. We aimed to test the hypothesis that VitD3 mitigates MetS‐induced cognition deficits and neuropathic pain via modulating the BDNF/TRKB/Akt/GS3Kβ signaling pathway. MetS was induced in male rats by 10% fructose‐supplemented water and 3% salt‐enriched diet. After 6 weeks, normal and MetS rats received either vehicle or VitD3 (10 µg/kg/day) for an additional 6 weeks. Glycemic status, lipid profile, and behavioral changes were assessed. The advanced glycation end products (AGEs), and markers of inflammation (TNF‐α and NF‐κB), oxidative stress (malondialdehyde), and apoptosis (caspase3), as well as BDNF, TrkB, PI3K, Akt, GSK3β, phosphorylated tau, and amyloid beta (Aβ) were assessed in the cerebral cortex. MetS rats had deteriorated glycemic and lipid profiles, higher AGEs, reduced levels of BDNF, TrkB, PI3K, and active Akt, along with increased GSK3β levels, inflammation, oxidative stress, and apoptosis. These changes were associated with higher levels of cognitive impairment markers phosphorylated tau and Aβ, as well as behavioral changes indicative of cognitive impairment and neuropathic pain. VitD3 improved the cognitive and behavioral alterations, while mitigating the associated molecular derangements. Our results indicate that VitD3 may exert neuroprotective effects by modulating the BDNF/TrkB/PI3K/Akt/GSK3β signaling pathway.

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Design, synthesis and biological characterization of novel activators of the TrkB neurotrophin receptor

Cited by 6 publications

References 36 publications

Development of Pleiotropic TrkB and 5-HT4 Receptor Ligands as Neuroprotective Agents

Development of Pleiotropic TrkB and 5-HT4 Receptor Ligands as Neuroprotective Agents

A TrkB and TrkC partial agonist restores deficits in synaptic function and promotes activity‐dependent synaptic and microglial transcriptomic changes in a late‐stage Alzheimer's mouse model

Vitamin D3 Exerts a Neuroprotective Effect in Metabolic Syndrome Rats: Role of BDNF/TRKB/Akt/GS3Kβ Pathway

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