Table 2.
Interventions directly targeting WβC‐signalling activation (WβC‐AC)‐targeted in the central nervous system
| Intervention | Outcome | References |
|---|---|---|
| Modulation of Fzd/β‐catenin/Nurr1 | ||
| Wnt1, Wnt3a, Wnt5a | Wnt1, ‐3a, and ‐5a expression is differentially regulated during development. Wnt3a promoted the proliferation of precursor Nurr1+ cells. Wnt‐1 and ‐5a increased the number of rat midbrain DAergic neurons in E14.5 precursor cultures. Wnt‐1 increased the proliferation of Nurr1+ precursors, up‐regulated cyclins D1 and D3, and down‐regulated p27 and p57 mRNAs | Castelo‐Branco et al. (2004) |
| Wnt5a increases differentiation of midbrain DAergic cells and phosphorylation of dishevelled | Schulte et al. (2005) | |
| VM glia express region‐specific transcription factors and regulate DAergic neurogenesis through Wnt5a secretion | Castelo‐Branco et al. (2006) | |
| Wnt5a‐treated midbrain NSCs improve DA cell replacement therapy in parkinsonian mice | Parish et al. (2017) | |
| Wnt1 and astrocyte‐derived Wnt1 promote proliferation and neuron differentiation of adult SVZ‐NSCs | L'Episcopo et al. (2011a) | |
| Astrocyte‐derived Wnt1 and chemokine‐primed aged astrocytes promote proliferation and DAergic differentiation of Aq‐PVR‐NSCs via WβC‐AC | L'Episcopo et al. (2014a) | |
| Modulation of Axin‐LRP5/6 | ||
| Phenanthridine derivatives (HLY78 and novel molecules) | HLY78 targets the DIX domain of Axin and potentiates the Axin‐LRP6 association, thus promoting LRP6 phosphorylation and transduction of WβC‐signalling | Wang et al. (2012) |
| Identification of structure‐activity relationship‐optimized phenanthridine derivatives as new WβC‐AC pathway agonists | Chen et al., 2019 | |
| N‐(3‐(1H‐imidazol‐1‐yl)propyl)‐5‐(furan‐2‐yl)isoxazole‐3‐carboxamide (SKL 2001) | Protective role in in vivo cytotoxicity models | Huang, Tang, et al., 2019a |
| Wnt surrogates | Water‐soluble Fzd‐Lrp5/6 heterodimerizers consisting of Fzd5/8‐specific and Fzd‐reactive binding domains, endowed with a WβC‐AC potential through ligand‐induced receptor heterodimerization. Promote growth in a broad range of primary human organoid cultures in a fashion comparable to Wnt3a. Exhibit Wnt activity in vivo | Janda et al. (2017) |
| Modulation of protein phosphatase 2A (PP2a) | ||
| Sodium selenite IQ1 | Interacts with Axin, APC, and β‐catenin; identified as target of Wnt agonist/IQ and sodium selenite; activates WβC‐AC via increased activation of β‐catenin and decreased GSK‐3β levels in a triple transgenic mouse model of Alzheimer's disease | Jin et al. (2017) |
| Inhibition of sFRPs | ||
| N‐substituted piperidinyl diphenylsulfonyl sulphonamides (e.g. WAY‐316606) | Modulators of Wnt signalling through inhibition of secreted frizzled‐related protein I (sFRP‐1) | Moore et al. (2009), Bodine et al. (2009), Warrier et al. (2007) |
| Gene KO | sFRP‐mediated Wnt sequestration represents a potential therapeutic target for Alzheimer's disease. sFRP3 inhibition improves age‐related cellular changes in BubR1 progeroid mice | Cho et al. (2019) |
| Inhibition of ADP ribosylation factor GTPase activating protein 1 (ARFGAP1) | ||
| QS11 | QS11 analogues act as small Wnt molecule synergist; direct inhibition of enzymatic activity of purified ARFAP1 protein and cellular activation of the WβC‐pathway confirm the direct inhibition of ARFGAP1 by QS11 and also suggest the presence of other potential cellular targets of QS11 | Jin et at al., 2017 |
| GSK‐3 antagonists | ||
| Indirubin‐3‐monoxime, kenpaullone | GSK−3β inhibition/β‐catenin stabilization in ventral midbrain precursors increases differentiation into DAergic neurons via WβC‐AC | Castelo‐Branco et al. (2006), Reviewed by Arenas (2014), Toledo et al. (2019) |
| GSK‐3β siRNA | GSK−3β siRNA treatment of NSCs from MPTP‐injured mice resulted in a significant increase in the percentage of cells expressing BrdU associated with an increased percentage of MAP2a+ cells via WβC‐AC | L'Episcopo et al. (2011b), L'Episcopo et al. (2012) |
| CHIR99201, SB‐216763, SB‐415286 | CHIR99201 is a substituted aminopyrimidine derivative that potently and selectively inhibits GSK−3 in vitro and in vivo | Ring et al. (2003) |
| SB−216763 and SB−415286 are cell‐permeable, structurally distinct maleimides that potently and selectively inhibit GSK−3 | Coghlan et al. (2000) | |
| Midbrain floor plate precursors are derived from hPSCs in 11 days following exposure to small molecule activators of sonic hedgehog and WβC‐AC. Enrichment for canonical Wnt signalling upon CHIR99021 treatment. Induction and neurogenic conversion of hESC‐derived midbrain floor plate precursors is dependent on CHIR99021 addition | Kriks et al. (2011) | |
| Establishes a means of obtaining a scalable source of FOXA2+/TH+ neurons for neural transplantation, a major step on the road towards considering a cell‐based therapy for PD | ||
| CHIR99201 counteracts the altered differentiation potential of Gaucher's disease iPSC neuronal progenitors due to Wnt/β‐catenin downregulation by WβC‐AC | Awad et al. (2017) | |
| GSK−3 inhibition via CHIR99021 known to promote proliferation of neuroprogenitors by activating β‐catenin and Notch‐related cell cycle genes in the presence of bFGF and EGF, increased neural differentiation. | Esfandiari et al. (2012) | |
| CHIR99201‐mediated WβC‐AC exploited in a step‐by‐step protocol for generation of regionally specified neural progenitors and functional neurons from human embryonic stem cells under defined conditions. | Kirkeby et al. (2012) | |
| Generation of VM DA progenitors and mature VM DA neurons from hPSCs under defined, xeno‐free conditions onvolving the use of CHIR99201. DA cells are primed for clinical translation, capable of correcting motor asymmetry in 6‐OHDA lesioned rats: significant increases in the yield of appropriately specified OTX2/FOXA2‐expressing progenitors and FOXA2/TH DA neurons; elevated DA metabolism and functional electrophysiological properties reflective of mature VM DA neurons | Niclis et al. (2016) | |
| Combined treatment of trans‐retinoic acid with CHIR 99,201 significantly enhanced neurogenesis via WβC‐AC | Nierode et al. (2012) | |
| Ro3303544 | Selective and potent maleimide inhibitor of GSK−3β that increases the number of newborn neurons in the olfactory bulb via WβC‐AC when administered systemically or via stereotaxic icv | Adachi et al. (2007) |
| N‐(4‐Methoxybenzyl)‐N′‐(5‐nitro‐1,3‐thiazol−2‐yl)urea (AR‐A014418) | Specific and potent inhibitor of GSK−3β with neuroprotective effects | Bhat et al. (2003) |
| Counteracts SNpc cell death in murine PD models after systemic treatment via WβC‐AC | Wang et al. (2013) | |
| Counteracts MPTP‐induced neurotoxicity upon systemic or icv administration via WβC‐AC | L'Episcopo et al. (2011a;b) | |
| Counteracts MPTP‐induced inhibition of SVZ‐NSC proliferation and neuron differentiation in young and aged mice via WβC‐AC | L'Episcopo et al. (2012) | |
| Counteracts aging and MPTP‐induced nigrostriatal degeneration of aged mice via WβC‐AC | L'Episcopo et al. (2013) | |
| Counteracts age and MPTP‐induced decrease Aq‐PVR‐NSC proliferation and activates pre‐DAergic Aq‐PVR Nurr1+/TH‐ precursors after intracerebral injection around the Aq‐PVRs and increased Nurr1+/TH+ neurons in the SNpc, via WβC‐AC | L'Episcopo et al. (2014a) | |
| Results in decreased tau phosphorylation and hippocampal neuron death and decreased proinflammatory cytokines in transgenic mouse models of Huntington disease | L'Episcopo et al. (2016) | |
| 6‐bromoindirubin‐3′‐oxime (BIO) | Selective inhibitor of Tyr216/276 phosphorylation of GSK−3; maintains pluripotency in human and mouse embryonic stem cells via WβC‐AC | Sato et al. (2016) |
| Stimulates post‐stroke neurogenesis, neuroblast migration to the ischemic cortex, neuronal differentiation and functional recovery after ischemic stroke via WβC‐AC | Wang et al. (2014) | |
| Valproic acid | Has been recently shown to increase β‐catenin levels and to induce the expression of NeuroD1, a Wnt target gene involved in neurogenesis in the hippocampus of 3xTg‐Alzeimer's disease model mice via WβC‐AC | Zeng et al. (2019) |
| Lithium chloride (LiCl) | Non‐specific antagonism of GSK−3 modulates a panel of signalling pathways | Clément‐Lacroix et al. (2005) |
| Synergy between NSC transplantation and systemic LiCl‐mediated GSK−3β antagonism promoted recovery upon spinal cord injury via WβC‐AC | Zhang, Zhang, Deng, et al. (2018a) | |
| L807mts |
Peptide GSK−3β inhibitor reduces inflammation and promotes neuroprotection and behavioural recovery in Alzheimer's disease model mice; WβC‐AC involvement to be elucidated. |
Licht‐Murava et al. (2016) |
| TWS119 | A 4,6‐disubstituted pyrrolopyrimidine GSK−3β inhibitor that induces neurogenesis, based on counting of TuJ1 positive cells with correct neuronal morphology |
Ding et al. (2003) Huang, Tang, et al. (2019a) |
| Herbal derivatives | ||
| Andrographolide | As a competitor of GSK−3β, stimulates neurogenesis in the adult hippocampus via increased WβC‐AC | Varela‐Nallar et al. (2015) |
| Ilexonin A | Chinese medicine component; neuroprotective during ischemic injury via WβC‐AC | Zhang, Zheng, Yang et al. (2016a) |
| Resveratrol |
Protects SAMP8 brain under metabolic stress, ameliorating mitochondrial function and activating WβC‐signalling Counteracts neurodegeneration and abnormal neurogeneis in a rodent model of status epilepticus via suppression of inflammation; WβC‐AC involvement to be elucidated |
Palomera‐Avalos et al. (2017), Mishra et al. (2015) |
| Tricin | Modulates WβC‐AC by upregulating Wnt3a expression and downregulating GSK−3β expression |
Zhang and Li (2018) |
| Gedunin (from seeds of Azadirachta indica) | Inhibits neuroinflammation arising from Aβ−1−42 oligomer exposure in a microglial cell line via the activation of the Nrf2 anti‐inflamatory and anti‐oxidant axis, WβC‐AC involvement to be elucidated | Tom et al. (2019) |
| Flavonoids (e.g. quercetin, taxifolin), curcumin | Modulate proliferation, differentiation, growth and apoptosis via direct/indirect WβC‐AC. See also Table 1 | Sivrastava and Sivrastava (2019), Mohana et al. (2018), Razak et al. (2018) |
| Ginsenoside Rb1 | A derivative of traditional Chinese medicine ginseng; metabolite shown to promote WβC‐AC | Zhou et al. (2018), Reviewed by Liu et al. (2019) |
3xTg, APP/PS1/Nestin‐GFP triple transgenic mice; 6‐OHDA, 6‐hydroxydopamine; APC, adenomatous polyposis coli; Aq‐PVR, mesencephalic aqueduct‐periventricular region; bFGF, basic fibroblast growth factor; DA, dopamine; EGF, epidermal growth factor; FOXA2, forkhead box A2; Fzd, frizzled; GSK‐3β, glycogen synthase kinase 3β; hESC, human embryonic stem cell; hPSC, human pluripotent stem cell; icv, intracerebroventricularly; iPSC, induced pluripotent stem cell; KO, knockout; Lrp, low‐density lipoprotein receptor‐related protein; MAP2A, microtubule‐associated protein 2a; MPTP, 1‐methyl‐4‐phenyl‐1,2,3,6‐tetrahydropyridine; NSC, neural stem/progenitor cell; Nurr1, nuclear receptor related 1 protein; OTX2, orthodenticle homeobox 2; PD, Parkinson's disease; SAMP8, senescence accelerated mouse‐prone 8; sFRP, secreted Frizzled‐related proteins; SNpc, substantia nigra pars compacta; SVZ, sub‐ventricular zone; TH, thyrosine‐ hydroxylase; VM, ventral midbrain; WβC‐AC, Wnt/β‐catenin signalling activation.