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Pharmacologic Inhibition of Porcupine, Disheveled, and β-Catenin in Wnt Signaling Pathway Ameliorates Diabetic Peripheral Neuropathy in Rats

  • Kahkashan Resham
    Affiliations
    Department of Pharmacology & Toxicology, National Institute of Pharmaceutical Education and Research, S.A.S. Nagar, Punjab, India
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  • Shyam S. Sharma
    Correspondence
    Address reprint requests to Prof. Shyam S. Sharma, Department of Pharmacology and Toxicology, National Institute of Pharmaceutical Education and Research (NIPER), Sector 67, SAS Nagar, Mohali, Punjab 160062, India.
    Affiliations
    Department of Pharmacology & Toxicology, National Institute of Pharmaceutical Education and Research, S.A.S. Nagar, Punjab, India
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      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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