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Papers of the Week

Papers: 11 May 2019 - 17 May 2019

Animal Studies, Pharmacology/Drug Development

2019 Nov

J Pain



Pharmacological Inhibition of Porcupine, Disheveled and β-catenin in Wnt Signaling Pathway Ameliorates Diabetic Peripheral Neuropathy in Rats.


Wnt signaling pathway has been investigated extensively for its diverse metabolic and pain modulating mechanisms and recently its involvement has been postulated in the development of neuropathic pain. However, there are no reports as yet on involvement of Wnt signaling pathway in one of the most debilitating neurovascular complication of diabetes, i.e, 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 (STZ) (50 mg/kg) to male Sprague Dawley rats. Diabetic rats after six weeks of diabetes induction showed increased expression of Wnt signaling proteins in the spinal cord (L4-L6 lumbar segment), dorsal root ganglions (DRGs) and sciatic nerves. Subsequent increase in inflammation, endoplasmic reticulum (ER) stress and loss of intraepidermal nerve fiber density (IENFD) 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 µM) in diabetic rats showed improvement in pain-associated behaviors (heat, cold & 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 (MMP2), ER stress marker, glucose-regulated protein 78 (GRP78) and improving IENFD. All these results signify the neuroprotective potential of Wnt signaling inhibitors in DPN. Perspective: This study emphasizes the involvement of Wnt signaling pathway in diabetic peripheral neuropathy (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.