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Research ArticleNeuropharmacology

Selective Cathepsin S Inhibition with MIV-247 Attenuates Mechanical Allodynia and Enhances the Antiallodynic Effects of Gabapentin and Pregabalin in a Mouse Model of Neuropathic Pain

Ellen Hewitt, Thomas Pitcher, Biljana Rizoska, Karin Tunblad, Ian Henderson, Britt-Louise Sahlberg, Urszula Grabowska, Björn Classon, Charlotte Edenius, Marzia Malcangio and Erik Lindström
Journal of Pharmacology and Experimental Therapeutics September 2016, 358 (3) 387-396; DOI: https://doi.org/10.1124/jpet.116.232926
Ellen Hewitt
Medivir AB, Huddinge, Sweden (E.H., B.R., K.T., I.H., B.-L.S., U.G., B.C., C.E., E.L.); King´s College London, London, United Kingdom (T.P., M.M.)
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Thomas Pitcher
Medivir AB, Huddinge, Sweden (E.H., B.R., K.T., I.H., B.-L.S., U.G., B.C., C.E., E.L.); King´s College London, London, United Kingdom (T.P., M.M.)
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Biljana Rizoska
Medivir AB, Huddinge, Sweden (E.H., B.R., K.T., I.H., B.-L.S., U.G., B.C., C.E., E.L.); King´s College London, London, United Kingdom (T.P., M.M.)
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Karin Tunblad
Medivir AB, Huddinge, Sweden (E.H., B.R., K.T., I.H., B.-L.S., U.G., B.C., C.E., E.L.); King´s College London, London, United Kingdom (T.P., M.M.)
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Ian Henderson
Medivir AB, Huddinge, Sweden (E.H., B.R., K.T., I.H., B.-L.S., U.G., B.C., C.E., E.L.); King´s College London, London, United Kingdom (T.P., M.M.)
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Britt-Louise Sahlberg
Medivir AB, Huddinge, Sweden (E.H., B.R., K.T., I.H., B.-L.S., U.G., B.C., C.E., E.L.); King´s College London, London, United Kingdom (T.P., M.M.)
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Urszula Grabowska
Medivir AB, Huddinge, Sweden (E.H., B.R., K.T., I.H., B.-L.S., U.G., B.C., C.E., E.L.); King´s College London, London, United Kingdom (T.P., M.M.)
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Björn Classon
Medivir AB, Huddinge, Sweden (E.H., B.R., K.T., I.H., B.-L.S., U.G., B.C., C.E., E.L.); King´s College London, London, United Kingdom (T.P., M.M.)
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Charlotte Edenius
Medivir AB, Huddinge, Sweden (E.H., B.R., K.T., I.H., B.-L.S., U.G., B.C., C.E., E.L.); King´s College London, London, United Kingdom (T.P., M.M.)
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Marzia Malcangio
Medivir AB, Huddinge, Sweden (E.H., B.R., K.T., I.H., B.-L.S., U.G., B.C., C.E., E.L.); King´s College London, London, United Kingdom (T.P., M.M.)
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Erik Lindström
Medivir AB, Huddinge, Sweden (E.H., B.R., K.T., I.H., B.-L.S., U.G., B.C., C.E., E.L.); King´s College London, London, United Kingdom (T.P., M.M.)
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Abstract

Cathepsin S inhibitors attenuate mechanical allodynia in preclinical neuropathic pain models. The current study evaluated the effects when combining the selective cathepsin S inhibitor MIV-247 with gabapentin or pregabalin in a mouse model of neuropathic pain. Mice were rendered neuropathic by partial sciatic nerve ligation. MIV-247, gabapentin, or pregabalin were administered alone or in combination via oral gavage. Mechanical allodynia was assessed using von Frey hairs. Neurobehavioral side effects were evaluated by assessing beam walking. MIV-247, gabapentin, and pregabalin concentrations in various tissues were measured. Oral administration of MIV-247 (100-200 µmol/kg) dose-dependently attenuated mechanical allodynia by up to approximately 50% reversal when given as a single dose or when given twice daily for 5 days. No behavioral deficits were observed at any dose of MIV-247 tested. Gabapentin (58-350 µmol/kg) and pregabalin (63-377 µmol/kg) also inhibited mechanical allodynia with virtually complete reversal at the highest doses tested. The minimum effective dose of MIV-247 (100 µmol/kg) in combination with the minimum effective dose of pregabalin (75 µmol/kg) or gabapentin (146 µmol/kg) resulted in enhanced antiallodynic efficacy without augmenting side effects. A subeffective dose of MIV-247 (50 µmol/kg) in combination with a subeffective dose of pregabalin (38 µmol/kg) or gabapentin (73 µmol/kg) also resulted in substantial efficacy. Plasma levels of MIV-247, gabapentin, and pregabalin were similar when given in combination as to when given alone. Cathepsin S inhibition with MIV-247 exerts significant antiallodynic efficacy alone, and also enhances the effect of gabapentin and pregabalin without increasing side effects or inducing pharmacokinetic interactions.

Footnotes

    • Received February 19, 2016.
    • Accepted June 20, 2016.
  • E.H. and T.P. contributed equally to this work.

  • E.H., B.R., K.T., I.H., B.-L.S., U.G., B.C., C.E., and E.L. were employees at Medivir at the time of the studies. T.P. was sponsored by Medivir. M.M. was a consultant for Medivir.

  • dx.doi.org/10.1124/jpet.116.232926.

  • ↵Embedded ImageThis article has supplemental material available at jpet.aspetjournals.org.

  • Copyright © 2016 by The American Society for Pharmacology and Experimental Therapeutics
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Journal of Pharmacology and Experimental Therapeutics: 358 (3)
Journal of Pharmacology and Experimental Therapeutics
Vol. 358, Issue 3
1 Sep 2016
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Research ArticleNeuropharmacology

Antiallodynic Effects in Response to Cathepsin S Inhibition

Ellen Hewitt, Thomas Pitcher, Biljana Rizoska, Karin Tunblad, Ian Henderson, Britt-Louise Sahlberg, Urszula Grabowska, Björn Classon, Charlotte Edenius, Marzia Malcangio and Erik Lindström
Journal of Pharmacology and Experimental Therapeutics September 1, 2016, 358 (3) 387-396; DOI: https://doi.org/10.1124/jpet.116.232926

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Research ArticleNeuropharmacology

Antiallodynic Effects in Response to Cathepsin S Inhibition

Ellen Hewitt, Thomas Pitcher, Biljana Rizoska, Karin Tunblad, Ian Henderson, Britt-Louise Sahlberg, Urszula Grabowska, Björn Classon, Charlotte Edenius, Marzia Malcangio and Erik Lindström
Journal of Pharmacology and Experimental Therapeutics September 1, 2016, 358 (3) 387-396; DOI: https://doi.org/10.1124/jpet.116.232926
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