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Research ArticleDrug Discovery and Translational Medicine

Topical Delivery of Muscarinic Receptor Antagonists Prevents and Reverses Peripheral Neuropathy in Female Diabetic Mice

Corinne G. Jolivalt, Katie E. Frizzi, May Madi Han, Andre J. Mota, Lucie S. Guernsey, Lakshmi P. Kotra, Paul Fernyhough and Nigel A. Calcutt
Journal of Pharmacology and Experimental Therapeutics July 2020, 374 (1) 44-51; DOI: https://doi.org/10.1124/jpet.120.265447
Corinne G. Jolivalt
Department of Pathology, University of California San Diego, San Diego, California (C.G.J., K.E.F., M.M.H., A.J.M., L.S.G., N.A.C.); Winsantor Inc. (K.E.F). Center for Molecular Design and Preformulations and Krembil Research Institute, University Health Network and Leslie Dan Faculty of Pharmacy, University of Toronto, Toronto, Ontario, Canada (L.P.K.); and Department of Pharmacology and Therapeutics and Division of Neurodegenerative Disorders, St. Boniface Hospital Albrechtsen Research Center, University of Manitoba, Winnipeg, Manitoba, Canada (P.F.)
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Katie E. Frizzi
Department of Pathology, University of California San Diego, San Diego, California (C.G.J., K.E.F., M.M.H., A.J.M., L.S.G., N.A.C.); Winsantor Inc. (K.E.F). Center for Molecular Design and Preformulations and Krembil Research Institute, University Health Network and Leslie Dan Faculty of Pharmacy, University of Toronto, Toronto, Ontario, Canada (L.P.K.); and Department of Pharmacology and Therapeutics and Division of Neurodegenerative Disorders, St. Boniface Hospital Albrechtsen Research Center, University of Manitoba, Winnipeg, Manitoba, Canada (P.F.)
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May Madi Han
Department of Pathology, University of California San Diego, San Diego, California (C.G.J., K.E.F., M.M.H., A.J.M., L.S.G., N.A.C.); Winsantor Inc. (K.E.F). Center for Molecular Design and Preformulations and Krembil Research Institute, University Health Network and Leslie Dan Faculty of Pharmacy, University of Toronto, Toronto, Ontario, Canada (L.P.K.); and Department of Pharmacology and Therapeutics and Division of Neurodegenerative Disorders, St. Boniface Hospital Albrechtsen Research Center, University of Manitoba, Winnipeg, Manitoba, Canada (P.F.)
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Andre J. Mota
Department of Pathology, University of California San Diego, San Diego, California (C.G.J., K.E.F., M.M.H., A.J.M., L.S.G., N.A.C.); Winsantor Inc. (K.E.F). Center for Molecular Design and Preformulations and Krembil Research Institute, University Health Network and Leslie Dan Faculty of Pharmacy, University of Toronto, Toronto, Ontario, Canada (L.P.K.); and Department of Pharmacology and Therapeutics and Division of Neurodegenerative Disorders, St. Boniface Hospital Albrechtsen Research Center, University of Manitoba, Winnipeg, Manitoba, Canada (P.F.)
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Lucie S. Guernsey
Department of Pathology, University of California San Diego, San Diego, California (C.G.J., K.E.F., M.M.H., A.J.M., L.S.G., N.A.C.); Winsantor Inc. (K.E.F). Center for Molecular Design and Preformulations and Krembil Research Institute, University Health Network and Leslie Dan Faculty of Pharmacy, University of Toronto, Toronto, Ontario, Canada (L.P.K.); and Department of Pharmacology and Therapeutics and Division of Neurodegenerative Disorders, St. Boniface Hospital Albrechtsen Research Center, University of Manitoba, Winnipeg, Manitoba, Canada (P.F.)
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Lakshmi P. Kotra
Department of Pathology, University of California San Diego, San Diego, California (C.G.J., K.E.F., M.M.H., A.J.M., L.S.G., N.A.C.); Winsantor Inc. (K.E.F). Center for Molecular Design and Preformulations and Krembil Research Institute, University Health Network and Leslie Dan Faculty of Pharmacy, University of Toronto, Toronto, Ontario, Canada (L.P.K.); and Department of Pharmacology and Therapeutics and Division of Neurodegenerative Disorders, St. Boniface Hospital Albrechtsen Research Center, University of Manitoba, Winnipeg, Manitoba, Canada (P.F.)
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Paul Fernyhough
Department of Pathology, University of California San Diego, San Diego, California (C.G.J., K.E.F., M.M.H., A.J.M., L.S.G., N.A.C.); Winsantor Inc. (K.E.F). Center for Molecular Design and Preformulations and Krembil Research Institute, University Health Network and Leslie Dan Faculty of Pharmacy, University of Toronto, Toronto, Ontario, Canada (L.P.K.); and Department of Pharmacology and Therapeutics and Division of Neurodegenerative Disorders, St. Boniface Hospital Albrechtsen Research Center, University of Manitoba, Winnipeg, Manitoba, Canada (P.F.)
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Nigel A. Calcutt
Department of Pathology, University of California San Diego, San Diego, California (C.G.J., K.E.F., M.M.H., A.J.M., L.S.G., N.A.C.); Winsantor Inc. (K.E.F). Center for Molecular Design and Preformulations and Krembil Research Institute, University Health Network and Leslie Dan Faculty of Pharmacy, University of Toronto, Toronto, Ontario, Canada (L.P.K.); and Department of Pharmacology and Therapeutics and Division of Neurodegenerative Disorders, St. Boniface Hospital Albrechtsen Research Center, University of Manitoba, Winnipeg, Manitoba, Canada (P.F.)
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Abstract

Muscarinic antagonists promote sensory neurite outgrowth in vitro and prevent and/or reverse multiple indices of peripheral neuropathy in rodent models of diabetes, chemotherapy-induced peripheral neuropathy, and HIV protein-induced neuropathy when delivered systemically. We measured plasma concentrations of the M1 receptor–selective muscarinic antagonist pirenzepine when delivered by subcutaneous injection, oral gavage, or topical application to the skin and investigated efficacy of topically delivered pirenzepine against indices of peripheral neuropathy in diabetic mice. Topical application of 2% pirenzepine to the paw resulted in plasma concentrations 6 hours postdelivery that approximated those previously shown to promote neurite outgrowth in vitro. Topical delivery of pirenzepine to the paw of mice with streptozotocin-induced diabetes dose-dependently (0.1%–10.0%) prevented tactile allodynia, thermal hypoalgesia, and loss of epidermal nerve fibers in the treated paw and attenuated large fiber motor nerve conduction slowing in the ipsilateral limb. Efficacy against some indices of neuropathy was also noted in the contralateral limb, indicating systemic effects following local treatment. Topical pirenzepine also reversed established paw heat hypoalgesia, whereas withdrawal of treatment resulted in a gradual decline in efficacy over 2–4 weeks. Efficacy of topical pirenzepine was muted when treatment was reduced from 5 to 3 or 1 day/wk. Similar local effects were noted with the nonselective muscarinic receptor antagonist atropine when applied either to the paw or to the eye. Topical delivery of muscarinic antagonists may serve as a practical therapeutic approach to treating diabetic and other peripheral neuropathies.

SIGNIFICANCE STATEMENT Muscarinic antagonist pirenzepine alleviates diabetic peripheral neuropathy when applied topically in mice.

Footnotes

    • Received January 29, 2020.
    • Accepted April 20, 2020.
  • This work was supported by National Institutes of Health, National Institute of Neurologic Disorders and Stroke [Grant RO1-NS081082 to N.A.C.].

  • P.F. and L.P.K. are cofounders, shareholders, and serve on the Board of Directors of Winsantor Inc. N.A.C. is a cofounder and shareholder in Winsantor Inc. K.E.F. is an employee of Winsantor Inc. and UCSD.

  • https://doi.org/10.1124/jpet.120.265447.

  • Copyright © 2020 by The American Society for Pharmacology and Experimental Therapeutics
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Journal of Pharmacology and Experimental Therapeutics: 374 (1)
Journal of Pharmacology and Experimental Therapeutics
Vol. 374, Issue 1
1 Jul 2020
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Research ArticleDrug Discovery and Translational Medicine

Topical Antimuscarinics in Diabetic Neuropathy

Corinne G. Jolivalt, Katie E. Frizzi, May Madi Han, Andre J. Mota, Lucie S. Guernsey, Lakshmi P. Kotra, Paul Fernyhough and Nigel A. Calcutt
Journal of Pharmacology and Experimental Therapeutics July 1, 2020, 374 (1) 44-51; DOI: https://doi.org/10.1124/jpet.120.265447

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Research ArticleDrug Discovery and Translational Medicine

Topical Antimuscarinics in Diabetic Neuropathy

Corinne G. Jolivalt, Katie E. Frizzi, May Madi Han, Andre J. Mota, Lucie S. Guernsey, Lakshmi P. Kotra, Paul Fernyhough and Nigel A. Calcutt
Journal of Pharmacology and Experimental Therapeutics July 1, 2020, 374 (1) 44-51; DOI: https://doi.org/10.1124/jpet.120.265447
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