Highlights
- •Wnt signaling activation underlies the pathophysiology of diabetic peripheral neuropathy.
- •Wnt (porcupine, disheveled, and β-catenin) inhibitors were investigated in diabetic peripheral neuropathy.
- •Wnt signaling inhibitors attenuated neuropathic pain in diabetic rats.
- •Wnt signaling inhibitors reduced inflammation, ER stress and improved IENFD in diabetic peripheral neuropathy.
Abstract
Wnt signaling pathway has been investigated extensively for its diverse metabolic
and pain-modulating mechanisms; recently its involvement has been postulated in the
development of neuropathic pain. However, there are no reports as yet on the involvement
of Wnt signaling pathway in one of the most debilitating neurovascular complication
of diabetes, namely, diabetic peripheral neuropathy (DPN). Thus, in the present study,
involvement of Wnt signaling was investigated in DPN using Wnt signaling inhibitors
namely LGK974 (porcupine inhibitor), NSC668036 (disheveled inhibitor), and PNU74654
(β-catenin inhibitor). Diabetes was induced by a single intraperitoneal injection
of streptozotocin (50 mg/kg) to male Sprague–Dawley rats. Diabetic rats after 6 weeks
of diabetes induction showed increased expression of Wnt signaling proteins in the
spinal cord (L4–L6 lumbar segment), dorsal root ganglions and sciatic nerves. Subsequent
increase in inflammation, endoplasmic reticulum stress and loss of intraepidermal
nerve fiber density was also observed, leading to neurobehavioral and nerve functional
deficits in diabetic rats. Intrathecal administration of Wnt signaling inhibitors
(each at doses of 10 and 30 µmol/L) in diabetic rats showed improvement in pain-associated
behaviors (heat, cold, and mechanical hyperalgesia) and nerve functions (motor, sensory
nerve conduction velocities, and nerve blood flow) by decreasing the expression of
Wnt pathway proteins, inflammatory marker, matrix metalloproteinase 2, endoplasmic
reticulum stress marker, glucose-regulated protein 78, and improving intraepidermal
nerve fiber density. All these results signify the neuroprotective potential of Wnt
signaling inhibitors in DPN.
Perspective
This study emphasizes the involvement of Wnt signaling pathway in DPN. Blockade of
this pathway using Wnt inhibitors provided neuroprotection in experimental DPN in
rats. This study may provide a basis for exploring the therapeutic potential of Wnt
inhibitors in DPN patients.
Key words
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References
- Role of beta-catenin in synaptic vesicle localization and presynaptic assembly.Neuron. 2003; 40: 719-731
- Argatroban attenuates diabetic cardiomyopathy in rats by reducing fibrosis, inflammation, apoptosis, and protease-activated receptor expression.Cardiovasc Drugs Ther. 2017; 31: 255-267
- Canonical Wnt signaling in diabetic retinopathy.Vision Res. 2017; 139: 47-58
- Simulations of a specific inhibitor of the disheveled PDZ domain.J Mol Model. 2009; 15: 91-96
- Differential role of beta-catenin in VEGF and histamine-induced MMP-2 production in microvascular endothelial cells.J Cell Biochem. 2009; 107: 272-283
- The Wnt signaling pathway in cancer.Crit Rev Oncol Hematol. 2016; 99: 141-149
- New horizons in diabetic neuropathy: Mechanisms, bioenergetics, and pain.Neuron. 2017; 93: 1296-1313
- Painful diabetic polyneuropathy: Epidemiology, pain description, and quality of life.Diabetes Res Clin Pract. 2000; 47: 123-128
- Disheveled: The hub of Wnt signaling.Cell Signal. 2010; 22: 717-727
- Electroacupuncture attenuates mechanical and warm allodynia through suppression of spinal glial activation in a rat model of neuropathic pain.Brain Res Bull. 2011; 86: 403-411
- Discovery and characterization of a small molecule inhibitor of the PDZ domain of disheveled.J Biol Chem. 2009; 284: 16256-16263
- Intrathecal administration of rapamycin inhibits the phosphorylation of DRG Nav1. 8 and attenuates STZ-induced painful diabetic neuropathy in rats.Neurosci Lett. 2018; 619: 21-28
- Antagonising Wnt/beta-catenin signalling ameliorates lens-capsulotomy-induced retinal degeneration in a mouse model of diabetes.Diabetologia. 2018; 61: 1-14
- Involvement of Wnt/beta-catenin signaling in the development of neuropathic pain.Neurosci Res. 2014; 79: 34-40
- Allodynia and hyperalgesia in neuropathic pain: Clinical manifestations and mechanisms.Lancet Neurol. 2014; 13: 924-935
- Matrix metalloprotease regulation of neuropathic pain.Trends Pharmacol Sci. 2009; 30: 336-340
- Domains of axin and disheveled required for interaction and function in wnt signaling.Biochem Biophys Res Commun. 2000; 276: 1162-1169
- Can we safely target the WNT pathway?.Nat Rev Drug Discov. 2014; 13: 513
- Distinct roles of matrix metalloproteases in the early-and late-phase development of neuropathic pain.Nat Med. 2008; 14: 331
- Rufinamide improves functional and behavioral deficits via blockade of tetrodotoxin-resistant sodium channels in diabetic neuropathy.Curr Neurovasc Res. 2015; 12: 262-268
- Involvement of oncogenic protein beta-catenin in LPS-induced cytotoxicity in mouse mononuclear leukemia RAW 264.7 cells.Oncol Res. 2013; 21: 59-65
- Characterization and diagnostic evaluation of chronic polyneuropathies induced by oxaliplatin and docetaxel comparing skin biopsy to quantitative sensory testing and nerve conduction studies.Eur J Neurol. 2014; 21: 623-629
- NF-kB inhibitory action of resveratrol: A probable mechanism of neuroprotection in experimental diabetic neuropathy.Biochem Biophys Res Commun. 2010; 394: 360-365
- Early diabetic neuropathy: Thermal thresholds and intraepidermal nerve fibre density in patients with normal nerve conduction studies.J Neurol. 2008; 255: 1197-1202
- Inhibition of the Tcf/beta-catenin complex increases apoptosis and impairs adrenocortical tumor cell proliferation and adrenal steroidogenesis.Oncotarget. 2015; 6: 43016
- The ER chaperone and signaling regulator GRP78/BiP as a monitor of endoplasmic reticulum stress.Methods. 2005; 35: 373-381
- Activation of nuclear beta-catenin/c-Myc axis promotes oxidative stress injury in streptozotocin-induced diabetic cardiomyopathy.Biochem Biophys Res Commun. 2017; 493: 1573-1580
- Wnt/Ryk signaling contributes to neuropathic pain by regulating sensory neuron excitability and spinal synaptic plasticity in rats.Pain. 2015; 156: 2572-2584
- The Wnt signaling pathway in development and disease.Annu Rev Cell Dev Biol. 2004; 20: 781-810
- Endoplasmic reticulum stress plays a key role in the pathogenesis of diabetic peripheral neuropathy.Diabetes. 2013; 62: 944-952
- Metformin attenuates hyperalgesia and allodynia in rats with painful diabetic neuropathy induced by streptozotocin.Eur J Pharmacol. 2015; 764: 599-606
- The dynamic role of beta-catenin in synaptic plasticity.Neuropharmacology. 2012; 62: 78-88
- Wnts as ligands: Processing, secretion and reception.Oncogene. 2006; 25: 7461
- Role of matrix metalloproteinases 2 in spinal cord injury-induced neuropathic pain.Ann Neurosci. 2016; 23: 25-32
- Minocycline completely reverses mechanical hyperalgesia in diabetic rats through microglia-induced changes in the expression of the potassium chloride cotransporter 2 (KCC2) at the spinal cord.Diabetes Obes Metab. 2011; 13: 150-159
- Wnt inhibition induces persistent increases in intrinsic stiffness of human trabecular meshwork cells.Exp Eye Res. 2015; 132: 174-178
- Nrf2 and NF-kB modulation by sulforaphane counteracts multiple manifestations of diabetic neuropathy in rats and high glucose-induced changes.Curr Neurovasc Res. 2011; 8: 294-304
- Inhibition of IkB kinase (IKK) protects against peripheral nerve dysfunction of experimental diabetes.Mol Neurobiol. 2015; 51: 591-598
- Oxidative-nitrosative stress and poly (ADP-ribose) polymerase (PARP) activation in experimental diabetic neuropathy: The relation is revisited.Diabetes. 2005; 54: 3435-3441
- Intraepidermal nerve fibers are indicators of small-fiber neuropathy in both diabetic and nondiabetic patients.Diabetes Care. 2004; 27: 1974-1979
- Targeting PKC: A novel role for beta-catenin in ER stress and apoptotic signaling.Blood. 2009; 113: 1513-1521
- Wnt signalling in stem cells and cancer.Nature. 2005; 434: 843
- Porcupine is not required for the production of the majority of Wnts from primary human astrocytes and CD8+ T cells.PloS One. 2014; 9: e92159
- CTGF/CCN2 activates canonical Wnt signalling in mesangial cells through LRP6: Implications for the pathogenesis of diabetic nephropathy.FEBS Lett. 2011; 585: 531-538
- Diabetic neuropathic pain: Physiopathology and treatment.World J Diabetes. 2015; 6: 432
- Identification of a specific inhibitor of the disheveled PDZ domain.Biochemistry. 2005; 44: 15495-15503
- Effects of 4-phenyl butyric acid on high glucose-induced alterations in dorsal root ganglion neurons.Neurosci Lett. 2016; 635: 83-89
- Wnt-Fzd signaling sensitizes peripheral sensory neurons via distinct noncanonical pathways.Neuron. 2014; 83: 104-121
- Distinct Roles of Wnt Co-receptors in the Regulation of Wnt Signaling in Diabetic Retinopathy.Invest Ophthalmol Vis Sci. 2018; 59: 5371
- Targeting cancer stem cells by inhibiting Wnt, Notch, and Hedgehog pathways.Nat Rev Clin Oncol. 2011; 8: 97
- Secreted frizzled-related protein 1 regulates the progression of neuropathic pain in mice following spinal nerve ligation.J Cell Physiol. 2018; 233: 5815-5822
- Alveolar epithelial cells undergo epithelial to mesenchymal transition in response to endoplasmic reticulum stress.J Biol Chem. 2011; 286: 30972-30980
- Diabetic peripheral neuropathy may not be as its name suggests: Evidence from magnetic resonance imaging.Pain. 2016; 157: S72-S80
- Wnt signaling pathway in mammary gland development and carcinogenesis.Pathobiology. 2006; 73: 213-223
- Intraepidermal nerve fiber density as a marker of early diabetic neuropathy.Muscle Nerve. 2007; 35: 591-598
- Wnt/beta-catenin signaling and small molecule inhibitors.Curr Pharm Des. 2013; 19: 634-664
- Targeted inhibition of disheveled PDZ domain via NSC668036 depresses fibrotic process.Exp Cell Res. 2015; 331: 115-122
- Wnt proteins are lipid-modified and can act as stem cell growth factors.Nature. 2003; 423: 448
- Direct binding of the PDZ domain of Disheveled to a conserved internal sequence in the C-terminal region of Frizzled.Mol Cell. 2003; 12: 1251-1260
- CHOP/ORP150 ratio in endoplasmic reticulum stress: A new mechanism for diabetic peripheral neuropathy.Cell Physiol Biochem. 2013; 32: 367-379
- Activation of Wnt/beta-catenin/GSK3beta signaling during the development of diabetic cardiomyopathy.Cardiovasc Pathol. 2015; 24: 179-186
- Adenosine monophosphate-activated protein kinase modulation by berberine attenuates mitochondrial deficits and redox imbalance in experimental diabetic neuropathy.Neuropharmacology. 2018; 131: 256-270
- Novel pathogenic pathways in diabetic neuropathy.Trends Neurosci. 2013; 36: 439-449
- Drosophila wnt-1 undergoes a hydrophobic modification and is targeted to lipid rafts, a process that requires porcupine.J Biol Chem. 2004; 279: 33220-33227
- Endoplasmic reticulum stress impairment in the spinal dorsal horn of a neuropathic pain model.Sci Rep. 2015; 5: 11555
- Canonical wnt signaling is required for pancreatic carcinogenesis.Cancer Res. 2013; 73: 4909-4922
- WNT signaling underlies the pathogenesis of neuropathic pain in rodents.J Clin Invest. 2013; 123: 2268-2286
- Effect of Wnt signaling pathway on pathogenesis and intervention of neuropathic pain.Exp Ther Med. 2018; 16: 3082-3088
- Implication of dysregulation of the canonical wingless-type MMTV integration site (WNT) pathway in diabetic nephropathy.Diabetologia. 2012; 55: 255-266
Article info
Publication history
Published online: May 07, 2019
Accepted:
March 15,
2019
Received in revised form:
February 22,
2019
Received:
November 28,
2018
Footnotes
This study was funded by the Department of Pharmaceuticals, Ministry of Chemicals & Fertilizers, Government of India to carry out this research work in National Institute of Pharmaceutical Education and Research, S.A.S. Nagar. There is no conflict of interest.
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© 2019 by the American Pain Society
